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Naveiras, Olaia, Valentina Nardi, and George Q. Daley. "Bone Marrow Adipocytes Prevent Hematopoietic Expansion in Homeostasis and in Bone Marrow Transplantation." Blood 112, no. 11 (November 16, 2008): 551. http://dx.doi.org/10.1182/blood.v112.11.551.551.
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Abstract In mammalian bone marrow (BM), osteoblasts and endothelium constitute functional niches that support hematopoietic stem cells (HSC). Adult BM also contains numerous adipocytes, whose numbers correlate inversely with the hematopoietic activity of the marrow. As described by Neumann’s law in 1882, distal skeletal regions are adipocytic and thus non-hematopoietic in the adult. Fatty infiltration of the hematopoietic red marrow also occurs following irradiation or chemotherapy and is a diagnostic feature in biopsies from patients with marrow aplasia. However, whether adipocytes participate in hematopoietic regulation or simply expand to fill marrow space is unclear. We have found that murine hematopoiesis is reduced in adipocyte-rich marrow during homeostasis, and that adipocytes antagonize marrow recovery post-irradiation. By flow cytometry, colony forming assay, and competitive repopulation, we found a reduced frequency of HSCs and short-term hematopoietic progenitors in the adipocyte-rich vertebrae of the tail compared to the adipocyte-free vertebrae of the thorax. In A-ZIP/F1 “fatless” mice, which are genetically incapable of forming adipocytes, post-irradiation marrow engraftment is accelerated relative to wild type mice. Likewise, pharmacologic inhibition of adipocyte formation with the PPARg inhibitor Bisphenol-A-DiGlycidyl-Ether (BADGE) enhances hematopoietic recovery after BM transplant. Moreover, we have found that mice deficient in the adipocyte-specific protein adiponectin, which has been described to inhibit hematopoietic progenitor expansion in vitro, have increased progenitors in fatty marrow both during homeostasis and after BM transplant. Our data implicate adipocytes as negative regulators of the bone marrow microenvironment, and demonstrate that antagonizing adipogenesis is advantageous for enhancing hematopoietic recovery in the setting of bone marrow transplantation.
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Yang, S., W. Lu, C. Zhao, Y. Zhai, Y. Wei, J. Liu, Y. Yu, Z. Li, and J. Shi. "PF457 MECHANISM OF MORPHOLOGICAL REMODELING OF BONE MARROW ADIPOCYTES IN ACUTE MYELOID LEUKEMIA." HemaSphere 3, S1 (June 2019): 180. http://dx.doi.org/10.1002/j.2572-9241.2019.tb00056.x.
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Background:We have previously found that morphological remodeling of bone marrow adipocytes in acute myeloid leukemia (AML) patients is closely related to poor prognosis, and growth differentiation factor 15 (GDF15) may be a key factor in this pathological phenomenon.Aims:In this study, we further explored the mechanism of GDF15 regulating the bone marrow adipocyte remodeling from the perspective of calcium channel TRPV4.Methods:GDF15‐induced adipocytes were analyzed using gene expression profiling, and gene knockdown cells were generated by lentiviral‐mediated shRNA. Chip‐qPCR was used to evaluate the interaction between transcription factors and TRPV4. Signaling pathway downstream of GDF15 involved in adipocytes was analyzed by inhibitor experiments. An experimental AML mouse model was generated to investigate the role of TRPV4 in leukemia cell‐induced bone marrow adipocyte remodeling.Results:Western blot and RT‐qPCR showed that GDF15 could regulate TRPV4 expression in bone marrow adipocytes. In vitro, Transwell assay and neutralizing antibody assay further found that GDF15 secreted by leukemia cells regulated bone marrow adipocyte remodeling through TRPV4. The phenomenon was verified in obese C57/BL6 mice. Specific inhibition experiments showed that GDF15 secreted by leukemia cells combined with TGFβRII in bone marrow adipocytes, and then activated PI3K / AKT pathway. Using RNA‐Seq technique, we found that transcription factor FOXC1 mediated the inhibition of GDF15 on TRPV4 expression in bone marrow adipocytes, which causes the morphological remodeling of bone marrow adipocytes.Summary/Conclusion:GDF15 secreted by leukemia cells inhibits the expression of TRPV4 by regulating the transcription factor FOXC1 in bone marrow adipocytes, which promote the lipolysis of adipocytes. The free fatty acids released by this process provide energy support for the growth of leukemia cells. This paper provides a new perspective for the study of leukemia cell remodeling of bone marrow adipocyte microenvironment.
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Kwak, Jun-Goo, and Jungwoo Lee. "Bone Marrow Adipocytes Contribute to Tumor Microenvironment-Driven Chemoresistance via Sequestration of Doxorubicin." Cancers 15, no. 10 (May 12, 2023): 2737. http://dx.doi.org/10.3390/cancers15102737.
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Chemoresistance is a significant problem in the effective treatment of bone metastasis. Adipocytes are a major stromal cell type in the bone marrow and may play a crucial role in developing microenvironment-driven chemoresistance. However, detailed investigation remains challenging due to the anatomical inaccessibility and intrinsic tissue complexity of the bone marrow microenvironment. In this study, we developed 2D and 3D in vitro models of bone marrow adipocytes to examine the mechanisms underlying adipocyte-induced chemoresistance. We first established a protocol for the rapid and robust differentiation of human bone marrow stromal cells (hBMSCs) into mature adipocytes in 2D tissue culture plastic using rosiglitazone (10 μM), a PPARγ agonist. Next, we created a 3D adipocyte culture model by inducing aggregation of hBMSCs and adipogenesis to create adipocyte spheroids in porous hydrogel scaffolds that mimic bone marrow sinusoids. Simulated chemotherapy treatment with doxorubicin (2.5 μM) demonstrated that mature adipocytes sequester doxorubicin in lipid droplets, resulting in reduced cytotoxicity. Lastly, we performed direct coculture of human multiple myeloma cells (MM1.S) with the established 3D adipocyte model in the presence of doxorubicin. This resulted in significantly accelerated multiple myeloma proliferation following doxorubicin treatment. Our findings suggest that the sequestration of hydrophobic chemotherapeutics by mature adipocytes represents a potent mechanism of bone marrow microenvironment-driven chemoresistance.
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Lecka-Czernik, Beata, and Larry J. Suva. "Resolving the Two “Bony” Faces of PPAR-γ." PPAR Research 2006 (2006): 1–9. http://dx.doi.org/10.1155/ppar/2006/27489.
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Bone loss with aging results from attenuated and unbalanced bone turnover that has been associated with a decreased number of bone forming osteoblasts, an increased number of bone resorbing osteoclasts, and an increased number of adipocytes (fat cells) in the bone marrow. Osteoblasts and adipocytes are derived from marrow mesenchymal stroma/stem cells (MSC). The milieu of intracellular and extracellular signals that controls MSC lineage allocation is diverse. The adipocyte-specific transcription factor peroxisome proliferator-activated receptor-gamma (PPAR-γ) acts as a critical positive regulator of marrow adipocyte formation and as a negative regulator of osteoblast development.In vivo, increased PPAR-γactivity leads to bone loss, similar to the bone loss observed with aging, whereas decreased PPAR-γactivity results in increased bone mass. Emerging evidence suggests that the pro-adipocytic and the anti-osteoblastic properties of PPAR-γare ligand-selective, suggesting the existence of multiple mechanisms by which PPAR-γcontrols bone mass and fat mass in bone.
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Liu, Huan, Jin He, Su Pin Koh, Yuping Zhong, Zhiqiang Liu, Zhiqiang Wang, Yujin Zhang, et al. "Reprogrammed marrow adipocytes contribute to myeloma-induced bone disease." Science Translational Medicine 11, no. 494 (May 29, 2019): eaau9087. http://dx.doi.org/10.1126/scitranslmed.aau9087.
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Osteolytic lesions in multiple myeloma are caused by osteoclast-mediated bone resorption and reduced bone formation. A unique feature of myeloma is a failure of bone healing after successful treatment. We observed adipocytes on trabecular bone near the resorbed area in successfully treated patients. Normal marrow adipocytes, when cocultured with myeloma cells, were reprogrammed and produced adipokines that activate osteoclastogenesis and suppress osteoblastogenesis. These adipocytes have reduced expression of peroxisome proliferator–activated receptor γ (PPARγ) mediated by recruitment of polycomb repressive complex 2 (PRC2), which modifies PPARγ promoter methylation at trimethyl lysine-27 histone H3. We confirmed the importance of methylation in the PPARγ promoter by demonstrating that adipocyte-specific knockout of EZH2, a member of the PRC2, prevents adipocyte reprogramming and reverses bone changes in a mouse model. We validated the strong correlation between the frequency of bone lesions and the expression of EZH2 in marrow adipocytes from patients in remission. These results define a role for adipocytes in genesis of myeloma-associated bone disease and that reversal of adipocyte reprogramming has therapeutic implications.
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Jin, Linhua, Marina Konopleva, Yixin Zhou, Akimichi Osaka, Michael Andreeff, Takashi Miida, and Yoko Tabe. "Pro-Apoptotic and Proliferative Effects of Bone Marrow Adipocytes on Myeloid Leukemia Cells." Blood 114, no. 22 (November 20, 2009): 4572. http://dx.doi.org/10.1182/blood.v114.22.4572.4572.
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Abstract Abstract 4572 Bone marrow stromal cells (MSCs) from elderly subjects have a reduced capacity to differentiate into osteoblasts and an increased capacity to differentiate into adipocytes, which leads to progressive accumulation of fat in the bone marrow space with increasing age. Adipocytes are the prevalent stromal cell type in adult BM that play an important role in the leukemic bone marrow microenvironment (Tabe et al., Blood 2004 103:1815-22). In this study, we examined the role of BM-derived adipocytes at different stages of differentiation on proliferation and apoptosis of AML cells. U937 cells were co-cultured with BM-derived MSC, MSC-differentiated pre-adipocytes (containing few small lipid vesicles), and mature adipocytes (with multiple hypertrophic lipid vesicules). Under serum-starved conditions, MSC and premature/mature adipocytes induced cell cycle progression of U937 cells with increase in the proportion of cells in S- and G2/M-phase fractions, and inhibited spontaneous cell death with decrease in subG1 fractions. However, only pre-adipocytes inhibited Ara-C-induced cell killing (Table 1). We next focused on lepin and plasminogen activator inhibitor 1(PAI-1) as potential mediators of these effects by adipocytes. Leptin mRNA and protein levels were upregulated during adipocytic differentiation (mRNA relative expression to GAPDH (PCR): MSC 0, premature adipocyte 2.0±0.5, mature adipocyte 123.3± 35.0; leptin secretion: MSC 23.1±2.9, premature adipocyte 49.3±11.3, mature adipocyte 110.0±4.6 pg/mL (ELISA). PAI-1 mRNA levels were increased in mature adipocyte (relative expression to GAPDH: MSC 314.9±46.5, premature adipocyte 215.1, mature adipocyte 3766.1±656.2). Since PPARÿ activation is known to promote maturation and re-generation of fat-derived adipocytes, we next examined the potential of the synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) on the BM adipocytes, leptin and PAI-1 production and the survival of the leukemic cells. CDDO induced adipocyte re-generation with significant increase of the number of Oil-Red(+) small sized lipid vesicles without apoptosis induction. This resulted in a markedly enhanced leptin release from adipocytes (10-fold and 23-fold increase at 0.5 μM and 1.0 μM CDDO, respectively, at 72 hrs) without change in leptin mRNA transcription. On the contrary, PAI-1 mRNA levels were significantly decreased by CDDO (6 fold decrease in MSC, 4 fold decrease in premature adipocyte, 6 fold decrease in mature adipocyte). Co-culture of U937 cells with CDDO-primed premature adipocytes and mature adipocytes resulted in increased spontaneous apoptosis of U937 cells compared to adipocytes not exposed to CDDO (% specific apoptosis, U937 co-cultured with CDDO-primed premature adipocytes 26.9 %, mature adipocytes 20.9 %). At the same time, CDDO-primed premature adipocytes induced significant cell cycle progression with decreased proportion of G0/G1-phase and increase in S-phase fractions in U937 cells (Table 2). Co-culture with CDDO-primed premature adipocytes or with premature adipocytes co-treated with recombinant leptin increased subG1- and S-phase fractions in Ara-C-treated U937 cells compared to U937 cells co-cultured with premature adipocytes (Table 3). In mature adipocytes, which already produce high levels of leptin, CDDO or leptin treatment failed to modulate anti-apoptotic or proliferative effects of AraC on U937 cells. In contrast, human recombinant PAI-1 effectively inhibited spontaneous and Ara-C induced apoptosis of U937 cells (decreased % of Annexin V: spontaneous apoptosis 11.2±1.1%, Ara-C induced apoptosis 15.1± 1.7%). In summary, these results suggest that BM pre-adipocytes support proliferation and survival of myeloid leukemia cells in part through complementary effects of leptin and PAI-1. Our findings indicate that secretion of leptin during MSC differentiation or through PPARg ligation promotes cell cycle progression, while PAI-1 primarily inhibits apoptosis of AML cells. It is conceivable that increased adipocyte content of BM in elderly AML patients may negatively affect the responsiveness of AML cells to chemotherapy. Disclosures: No relevant conflicts of interest to declare.
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Naveiras, Olaia, Valentina Nardi, Parul Sharma, Peter Hauschka, and George Q. Daley. "Bone Marrow Adipocytes: A Novel Negative Regulator of the Hematopoietic Microenvironment." Blood 110, no. 11 (November 16, 2007): 1405. http://dx.doi.org/10.1182/blood.v110.11.1405.1405.
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Abstract In the bone marrow (BM), osteoblasts and endothelium constitute functional niches providing positive or negative signals for hematopoietic stem cell (HSC) self-renewal. In addition to hematopoietic cells, endothelial cells, and osteoblasts, adult BM contains numerous adipocytes. Interestingly, the number of adipocytes correlates inversely with the gross hematopoietic activity of the marrow. Whether adipocytes have a direct effect on hematopoietic progenitors or whether they act as mere space-fillers in this context remains unclear. To determine the potential role of bone marrow adipocytes in hematopoiesis, we induced bone marrow-derived OP9 mesenchymal cells to differentiate into either osteoblastic or adipocytic stroma, and then tested their capacity to serve as surrogate HSC niches during in vitro hematopoietic culture in the absence of exogenous growth factors. We found that the presence of BM-derived adipocytes suppresses the expansion of short-term hematopoietic progenitors by at least two fold, as measured by the number of CD45+ cells expanded, the number of colony forming unit cells (CFU-Cs) and the competitive repopulation units (CRUs) during the first two months post-transplant. As an in vivo correlate, we compared the hematopoietic activity within the BM of the adipocyte-poor thoracic vertebrae and the adipocyte-rich proximal tail vertebrae. Indeed, we found that the percentage of HSCs (ckit+Lin-Sca1+), CMPs, GMPs and MEPs was decreased by two fold in the adipocyte-rich BM as determined phenotypically by FACS and functionally by short-term and long-term competitive repopulation assays. Mechanistically, oligonucleotide expression microarrays and conditioned media experiments on the OP9 co-cultures suggest that the inhibition of the progenitor compartment in adipocyte-rich environments is due to the loss of supportive factors (Notch ligands, N-cadherin, Angiopoietin-1, SCF, BMPs and Wnt5a) in addition to the presence of an active inhibitor. Finally, we found bone marrow adipocytes to accumulate in great numbers upon bone marrow ablation, a process that is hindered in genetically adipocyte-deficient mice. Since early BM transplant survival depends on the rapid accumulation of short term hematopoietic progenitors, whose replication we found hindered in adipocyte-rich BM, we were interested to explore whether the absence of adipocytes in the context of BM transplantation would foster faster recovery of lethally irradiated mice. As predicted, circulating leukocyte counts on the third week post-transplant were 3–5 times higher on the recovering fatless mice. Accordingly, the percentage of CFU-Cs, HSCs, CMPs, GMPs and MEPs on day 17 post-transplant was doubled on the adipocyte-depleted mice as compared to their wildtype littermates. We therefore conclude that, as seen in vitro, the presence of adipocytes in the recovering HSC niche is detrimental to the rapid hematopoietic expansion required to reconstitute blood production. We are currently examining the pharmacologic modulation of adipocyte formation for its effects in BM transplantation.
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Horowitz, Mark C., Ryan Berry, Brandon Holtrup, Zachary Sebo, Tracy Nelson, Jackie A. Fretz, Dieter Lindskog, et al. "Bone marrow adipocytes." Adipocyte 6, no. 3 (July 3, 2017): 193–204. http://dx.doi.org/10.1080/21623945.2017.1367881.
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Kastrenopoulou, Afroditi, Kyriakos E. Kypreos, Nicholaos I. Papachristou, Stavros Georgopoulos, Ioulia Mastora, Ioanna Papadimitriou-Olivgeri, Argyro Spentzopoulou, et al. "ApoA1 Deficiency Reshapes the Phenotypic and Molecular Characteristics of Bone Marrow Adipocytes in Mice." International Journal of Molecular Sciences 23, no. 9 (April 27, 2022): 4834. http://dx.doi.org/10.3390/ijms23094834.
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In the present study, we studied the effect of apolipoprotein A-1 (APOA1) on the spatial and molecular characteristics of bone marrow adipocytes, using well-characterized ApoA1 knockout mice. APOA1 is a central regulator of high-density lipoprotein cholesterol (HDL-C) metabolism, and thus HDL; our recent work showed that deficiency of APOA1 increases bone marrow adiposity in mice. We found that ApoA1 deficient mice have greatly elevated adipocytes within their bone marrow compared to wild type counterparts. Morphologically, the increased adipocytes were similar to white adipocytes, and displayed proximal tibial-end localization. Marrow adipocytes from wild type mice were significantly fewer and did not display a bone-end distribution pattern. The mRNA levels of the brown/beige adipocyte-specific markers Ucp1, Dio2, Pat2, and Pgc1a; and the expression of leptin were greatly reduced in the ApoA1 knock-out in comparison to the wild-type mice. In the knock-out mice, adiponectin was remarkably elevated. In keeping with the close ties of hematopoietic stem cells and marrow adipocytes, using flow cytometry we found that the elevated adiposity in the ApoA1 knockout mice is associated with a significant reduction in the compartments of hematopoietic stem cells and common myeloid, but not of the common lymphoid, progenitors. Moreover, the ‘beiging’-related marker osteopontin and the angiogenic factor VEGF were also reduced in the ApoA1 knock-out mice, further supporting the notion that APOA1—and most probably HDL-C—regulate bone marrow microenvironment, favoring beige/brown adipocyte characteristics.
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Philchenkov, A. A. "Bone marrow adipocytes and multiple myeloma." Oncohematology 14, no. 1 (April 10, 2019): 60–75. http://dx.doi.org/10.17650/1818-8346-2019-14-1-60-75.
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Multiple myeloma originating from clonal proliferation of plasma cells in the bone marrow is one of the most prevalent hematological malignancies worldwide. The pathogenetic mechanisms of multiple myeloma are far from being elucidated. Nevertheless, it is known that the adipocytes as the prevalent cellular component of bone marrow microenvironment contribute significantly to multiple myeloma growth and progression. The review discloses the recent data on the interactions between bone marrow adipocytes and myeloma cells, hematopoietic stemcells, hematopoietic progenitor cells, mesenchimal stem cells, osteoblasts, osteoclasts, endothelial cells, and cells of immune system. Also, the review places special emphasis on bone marrow adipocyte-produced adipokines, growth factors, cytokines, chemokines, and fatty acids providing the conditions for the preferential growth and migration of malignant plasma cells and contributing to hematopoiesis supression, bone tissue resorption, angiogenesis activation and immunosuppression.
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Trotter, Timothy N., Tshering D. Lama-Sherpa, Deniz Peker, Amjad Javed, Larry J. Suva, and Yang Yang. "The Role of Adipocyte Lineage Cells in Myeloma Growth and Dissemination in Bone." Blood 126, no. 23 (December 3, 2015): 1797. http://dx.doi.org/10.1182/blood.v126.23.1797.1797.
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Abstract Background: Multiple myeloma (MM) is hematologic malignancy of plasma cells that thrives in and progresses throughout the bone marrow microenvironment. The bone marrow is host to a variety of cell types, including bone marrow stromal cells and hematopoietic cells, as well as osteoblasts, osteoclasts and adipocytes. We and others have shown that MM cells not only alter the local bone microenvironment to support MM progression, but also modify distant bone sites through secretion of soluble factors before arrival of tumor cells. One critical alteration in bone is the shift of osteoblast progenitor cells from osteoblastogenesis towards adipogenesis. Whether and how these increased adipocyte lineage cells contribute to MM cells homing to and growth in bone are currently unknown. Both mature and pre-adipocytes have multiple endocrine functions such as cytokine and growth factor secretion. Thus, an increase in adipocyte lineage cells likely alters the bone microenvironment in favor of supporting MM. Here, we hypothesized that adipocytes and their precursors play an active role in MM progression that contributes to MM growth and dissemination throughout bone. Methods: Our hypothesis was tested using a co-culture system in which 3T3-L1 mouse pre-adipocytes or mature adipocytes were separated by a porous membrane from 5TGM1-luc mouse MM cells. This system allowed cross-talk by secreted molecules but not through direct cell-cell contact. After three days of co-culture, MM cells were collected for (i) intravenous (I.V.) tail-vein injections into syngeneic C57Bl/KaLwRiJ mice or (ii) protein collection for Western blot analyses. For in vivo experiments, tumor progression was tracked by bioluminescent luciferase imaging and total tumor burden was evaluated by IgG2bκ (a soluble marker of 5TGM1-luc MM cells) levels in mouse serum. In addition, conditioned medium (CM) was collected from either pre-adipocytes or mature adipocytes for MM cell migration assays or for analyses of soluble factors in the CM by cytokine/chemokine array. Results: I.V. injection of 5TGM1-luc MM cells into mice revealed that those previously co-cultured with pre-adipocytes more rapidly homed to bone and grew larger tumors compared to 5TGM1-luc MM cells cultured alone, whereas the MM cells cultured with mature adipocytes showed no significant increase in either bone homing or growth. Analysis of pre-adipocyte and mature adipocyte CM by cytokine/chemokine arrays demonstrated that pre-adipocytes secrete significantly more HGF, MCP-1, OPN and SDF-1α compared to mature adipocytes. Migration assays in which pre-adipocyte or mature adipocyte CM was used as a chemoattractant indicated that MM cells migrate significantly more towards both pre-adipocyte and mature adipocyte CM than fresh media. However, the pre-adipocyte CM exhibited significantly more chemoattraction than mature adipocyte CM. Furthermore, addition of an MCP-1 or SDF-1α neutralizing antibody to both pre-adipocyte CM and mature adipocyte CM resulted in significantly reduced migration of MM cells. However, pre-adipocyte CM required higher concentrations of antibodies than mature adipocyte CM, indicating a higher concentration of MCP-1 and SDF-1α in pre-adipocyte CM. MM cells also exhibited a significant dose-dependent migration towards recombinant pre-adipocyte factor-1 (Pref-1), a marker of pre-adipocytes that is down-regulated during adipogenesis. Finally, Western blots revealed that co-culture of MM cells with pre-adipocytes resulted in activation of β-catenin signaling, which is important for cell proliferation, survival and motility, in MM cells. Conclusions: These data indicate that adipocyte lineage cells play active but differentiation-dependent roles in MM progression, likely via the secretion of soluble factors. Both pre-adipocytes and mature adipocytes directly attract MM cells by secreting chemoattractants such as MCP-1 and SDF-1α. Interestingly, our data identify pre-adipocytes, and not mature adipocytes, as the main driver of the aggressive bone phenotype of MM cells. In sum, these data suggest that an increase in adipocyte lineage cells in the bone marrow at distant bone sites could feed back to MM cells and support MM dissemination to these distant bone sites. Studies to determine the intricacies of this novel role of pre-adipocytes in MM are currently ongoing. Disclosures Suva: University of Arkansas for Medical Sciences: Employment.
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Tencerova, Michaela, Meshail Okla, and Moustapha Kassem. "Insulin Signaling in Bone Marrow Adipocytes." Current Osteoporosis Reports 17, no. 6 (November 20, 2019): 446–54. http://dx.doi.org/10.1007/s11914-019-00552-8.
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Abstract Purpose of Review The goal of this review is to discuss the role of insulin signaling in bone marrow adipocyte formation, metabolic function, and its contribution to cellular senescence in relation to metabolic bone diseases. Recent Findings Insulin signaling is an evolutionally conserved signaling pathway that plays a critical role in the regulation of metabolism and longevity. Bone is an insulin-responsive organ that plays a role in whole body energy metabolism. Metabolic disturbances associated with obesity and type 2 diabetes increase a risk of fragility fractures along with increased bone marrow adiposity. In obesity, there is impaired insulin signaling in peripheral tissues leading to insulin resistance. However, insulin signaling is maintained in bone marrow microenvironment leading to hypermetabolic state of bone marrow stromal (skeletal) stem cells associated with accelerated senescence and accumulation of bone marrow adipocytes in obesity. Summary This review summarizes current findings on insulin signaling in bone marrow adipocytes and bone marrow stromal (skeletal) stem cells and its importance for bone and fat metabolism. Moreover, it points out to the existence of differences between bone marrow and peripheral fat metabolism which may be relevant for developing therapeutic strategies for treatment of metabolic bone diseases.
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Zhang, Lili, Mengmeng Liu, Xiaokang Zhou, Yi Liu, Bo Jing, Xiaogang Wang, Qi Zhang, and Yao Sun. "Role of Osteoprotegerin (OPG) in Bone Marrow Adipogenesis." Cellular Physiology and Biochemistry 40, no. 3-4 (2016): 681–92. http://dx.doi.org/10.1159/000452580.
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Background/Aims: Bone marrow adipogenesis is one of the major characteristics of aged bone. Bone marrow mesenchymal stem cells (BMMSCs) prefer to differentiate into adipocytes instead of osteoblasts in the bone marrow cavity in aged hosts. The mechanism of formation and function of adipocytes in aged bone marrow needs further investigation. Osteoprotegerin (OPG) is a member of the tumor necrosis factor receptor (TNFR) super family, and it can inhibit the activities of osteoclasts. We found that adipocyte numbers increased in the bone marrow of Opg knockout mice. In this study, we investigated the role of OPG in the differentiation of BMMSCs and bone marrow adipogenesis. Methods: Histological analyses were performed on the bone tissues of Opg knockout (Opg-KO) and wild-type (WT) mice of different ages. BMMSCs obtained from mice were cultured in vitro to evaluate their differentiation abilities. Results: With aging, the expression of Opg in the bone marrow of WT mice markedly decreased, but that of the adipogenic specific transcription factor peroxisome proliferator-activated receptor γ (Ppar-γ) increased. Adipocytes formed in the bone marrow of Opg-KO mice at a relative young age, and the number of adipocytes increased dramatically with age. Compared with the WT control, the osteogenic differentiation of Opg-KO BMMSCs decreased, but the adipogenic differentiation increased. Moreover, exogenous OPG could inhibit the adipogenic differentiation and promote the osteogenic differentiation of Opg-KO BMMSCs in vitro. Conclusions: OPG plays an important role in regulating BMMSC differentiation and bone marrow adipogenesis.
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Starling, Shimona. "Characterizing bone marrow adipocytes." Nature Reviews Endocrinology 16, no. 4 (February 17, 2020): 196. http://dx.doi.org/10.1038/s41574-020-0333-0.
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Lu, Wei, and Jun Shi. "Bone Marrow Small Adipocytes in Acute Myeloid Leukemia Correlate with Prognosis." Blood 128, no. 22 (December 2, 2016): 2874. http://dx.doi.org/10.1182/blood.v128.22.2874.2874.
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Abstract Introduction: Adipocytes have a substantial effect on the outcome and progression of certain solid tumors. However, little attention has been paid to the role of bone marrow (BM) adipocytes in acute myeloid leukemia (AML) because it is difficult to observe adipocytes through clinical BM aspiration. Although it was reported that adipocytes affected the behavior of leukemia cells in vitro, there is still no direct in vivo evidence. In the present study, we investigated the influence of adipocytes by focusing on their changing size in BM from primary AML patients. Methods: We retrospectively analyzed the biopsy specimens of BM from 70 patients with newly diagnosed AML and 70 controls with lymphoma or solid tumors without infiltration of BM. The size and type of adipocytes were analyzed for average diameter (Ad.Dm) and area (Ad.Ar) by tracing each individual adipocyte with Image-Pro Plus 5.1. Then, AML patients were further divided into 32 patients with continuous complete remission and 38 patients who were refractory based on the treatment effects. Adipocyte number (Ad.N; per square millimeter) and the percentage of adipocyte volume per tissue volume (Ad.V/TV) were compared between these two groups. Furthermore, the prognostic impact of adipocytes on the overall survival (OS) and relapse-free survival (RFS) in AML patients was analyzed by Cox regression analysis and Kaplan-Meier curves. Finally, the phenotype of adipocytes was determined by immunohistochemistry of UCP-1 and Perilipin1 to further explore the possible mechanism of the effect of adipocytes on the prognosis. Results: The Ad.Dm and Ad.Ar in BM from AML patients were 38.3±14.7 µm and 559.4±271.9 µm2, respectively, and both values were significantly smaller than those for the controls (P<0.001). The Ad.Dm exhibited no relation to the number of blasts in BM, indicating that the decreased size of adipocytes in AML cannot be attributed to extensive marrow blasts. Adipocytes were classified as small, medium and large adipocytes according to the frequency distribution of Ad.Dm in BM from controls. A significant difference was detected only in the proportion of small adipocytes (Ad.Dm<42.6 µm) between AML patients and controls (43.9% vs 25%, P=0.005). Furthermore, the Ad.V/TV and Ad.N of the adipocytes in the refractory group were 6.70±3.18% and 31.56±11.72/mm2, respectively, which were significantly higher than those of the remission subjects (P<0.001). This outcome prompted us to further analyze the role of small adipocytes in AML. Patients with Ad.V/TV of small adipocytes≤ 2.3% exhibited a longer OS than patients with Ad.V/TV of small adipocytes >2.3% (P<.001). Similarly, the subjects with Ad.N of small adipocytes <10.6/mm2 (P<.001) had a longer OS. Meanwhile, for the remission AML patients, those with Ad.V/TV of small adipocytes ≤2.5% had a shorter RFS than patients with Ad.V/TV of small adipocytes >2.5% (P<.001), and similar significant differences were also found between patients with Ad.N of small adipocytes ≥9.2/mm2 and Ad.N of small adipocytes <9.2/mm2(P<.001). In the biopsy specimens of BM, the subgroup of small adipocytes exhibited expression of Perilipin1 but not mitochondrial membrane protein UCP-1. Combination with the unilocular lipid droplets in adipocytes indicated that small adipocytes did not play a role in the conversion to brown adipose tissue. Conclusions: We first defined a subpopulation of small adipocytes in BM and demonstrated that only these cells but not all adipocytes were related to a poor prognosis in AML patients. The morphological changes of marrow adipocytes could be helpful to judge the prognosis of leukemia and could lead to other therapeutic perspectives. Disclosures No relevant conflicts of interest to declare.
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Appiagyei-Dankah, Yaw, Carmen D. Tapiador, Jodi F. Evans, Mariano Castro-Magana, John F. Aloia, and James K. Yeh. "Influence of growth hormone on bone marrow adipogenesis in hypophysectomized rats." American Journal of Physiology-Endocrinology and Metabolism 284, no. 3 (March 1, 2003): E566—E573. http://dx.doi.org/10.1152/ajpendo.00213.2002.
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The hypophysectomized rat has been used as a model to study the effects of growth hormone deficiency on bone. Here, we have investigated the influence of growth hormone administration to hypophysectomized rats (HX) for 6 wk on accumulation of triglycerides in bone marrow and on the differentiation of primary marrow stromal cells into adipocytes under in vitro conditions. We found that hypophysectomy significantly increased triglyceride concentration in bone marrow, which was attenuated by growth hormone administration. Primary bone marrow stromal cells derived from HX rats also had more adipocytes at confluence compared with growth hormone-treated hypophysectomized (GH) rats. When stimulated with 3-isobutyl-1-methylxanthine plus dexamethasone (IBMX-Dex), preadipocyte colony counts increased more significantly in GH rats. Markers of adipocyte differentiation were higher in HX than in control or GH rats at confluence. However, after stimulation with IBMX-Dex, increased expression of markers was seen in GH compared with HX rats. In conclusion, growth hormone administration to hypophysectomized rats attenuated triglyceride accumulation in bone marrow and inhibited the differentiation of stromal cells into adipocytes in vitro.
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de Paula, Francisco J. A., and Clifford J. Rosen. "Marrow Adipocytes: Origin, Structure, and Function." Annual Review of Physiology 82, no. 1 (February 10, 2020): 461–84. http://dx.doi.org/10.1146/annurev-physiol-021119-034513.
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The skeleton harbors an array of lineage cells that have an essential role in whole body homeostasis. Adipocytes start the colonization of marrow space early in postnatal life, expanding progressively and influencing other components of the bone marrow through paracrine signaling. In this unique, closed, and hypoxic environment close to the endosteal surface and adjacent to the microvascular space the marrow adipocyte can store or provide energy, secrete adipokines, and target neighboring bone cells. Adipocyte progenitors can also migrate from the bone marrow to populate white adipose tissue, a process that accelerates during weight gain. The marrow adipocyte also has an endocrine role in whole body homeostasis through its varied secretome that targets distant adipose depots, skeletal muscle, and the nervous system. Further insights into the biology of this unique and versatile cell will undoubtedly lead to novel therapeutic approaches to metabolic and age-related disorders such as osteoporosis and diabetes mellitus.
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Beekman, Kerensa M., Marleen Zwaagstra, Annegreet G. Veldhuis-Vlug, Huib W. van Essen, Martin den Heijer, Mario Maas, Greet Kerckhofs, Tatjana N. Parac-Vogt, Peter H. Bisschop, and Nathalie Bravenboer. "Ovariectomy increases RANKL protein expression in bone marrow adipocytes of C3H/HeJ mice." American Journal of Physiology-Endocrinology and Metabolism 317, no. 6 (December 1, 2019): E1050—E1054. http://dx.doi.org/10.1152/ajpendo.00142.2019.
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Estrogen deficiency induces bone loss by increasing bone resorption, in part through upregulation of receptor activator of nuclear factor-κB ligand (RANKL). RANKL is secreted by osteoblasts and osteocytes, but more recently bone marrow (pre)adipocytes have also been shown to express RANKL. Estrogen deficiency increases bone marrow adipose tissue (BMAT). The aim of this study was to determine the effect of ovariectomy (OVX) on RANKL protein expression by bone marrow adipocytes in C3H/HeJ mice. Fourteen-week-old female C3H/HeJ mice ( n = 20) were randomized to sham surgery (Sham) or OVX. After 4 wk animals were euthanized. BMAT volume fraction (BMAT volume/marrow volume) was quantified by polyoxometalate-based contrast-enhanced nano-computed tomography. The percentage of RANKL-positive bone marrow adipocytes (RANKL-positive bone marrow adipocytes/total adipocytes) and the percentage of RANKL-positive osteoblasts covering the bone surface (bone surface covered in RANKL-positive osteoblasts/total bone surface) were quantified in the distal metaphysis of immunohistochemically stained sections of the left femur. The effects of OVX were analyzed by Student’s t test or Mann–Whitney U test. RANKL was detected in osteoblasts, osteocytes, and bone marrow adipocytes. OVX significantly increased mean percentage of RANKL-positive bone marrow adipocytes [mean (SD): Sham 42 (18)%; OVX 64 (12)%; P = 0.029] as well as BMAT volume/marrow volume [median (interquartile range): Sham 1.4 (4.9)%; OVX 7.2 (7.3)%; P = 0.008] compared with Sham. We show that OVX increased both the percentage of RANKL-positive bone marrow adipocytes and the total BMAT volume fraction in C3H/HeJ mice. Therefore, RANKL produced by bone marrow adipocytes could be an important contributor to OVX-induced bone loss in C3H/HeJ mice.
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Jin, Linhua, Marina Konopleva, Masato Shikami, Takako Ikegami, Kensuke Kojima, Michael Andreeff, Takashi Miida, and Yoko Tabe. "Molecular Mechanisms of Pro-Survival and Differentiating Function of Bone Marrow-Derived Adipocytes On Acute Monoblastic Leukemia Cells." Blood 120, no. 21 (November 16, 2012): 2582. http://dx.doi.org/10.1182/blood.v120.21.2582.2582.
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Abstract Abstract 2582 Survival of adult patients with acute monocytic leukemia remains dismal. We proposed the hypothesis that bone marrow (BM) adipocytes abundant in aging marrow microenvironment play a role in chemoresistance of AML cells. We have reported that BM adipocytes promote monocytic differentiation, activation, and survival of monoblastic leukemia cells (ASH, 2012).In this study, we examined the molecular mechanism of BM adipocytes causing survival and differentiation of monoblastic leukemia cells. Monoblastic leukemia cell line U937 and primary samples from acute monoblastic leukemia patients (n=6) were co-cultured with BM-derived marrow stromal cells (MSC) and MSC-differentiated adipocytes. Under limiting serum conditions, MSCs and adipocytes inhibited spontaneous cell death of U937 cells with decrease in subG1 fractions, more prominently in co-cultures with adipocytes than with MSCs (% subG1 fraction; cultured alone 23.9+9.0, co-cultured with MSC 15.7+1.9%, co-cultured with adipocytes 11.9+1.2%, p=0.04). Adipocytes but not MSC moderately reduced spontaneous apoptosis in primary leukemic blasts (n=6, p=0.02). We next focused on adipocytokines, lepin and plasminogen activator inhibitor 1(PAI-1), both implicated in cancer progression, as potential mediators of the protective effects by adipocytes. mRNA levels of leptin, leptin receptor and PAI-1 were up-regulated in MSC-derived adipocytes during adipocytic differentiation (relative expression to GAPDH, leptin: MSC 0, adipocyte 123.3+35.0; leptin receptor: MSC 0.16+0.05, adipocyte 4.47+0.37; PAI-1: MSC 314.9+46.5, adipocyte 3766.1+656.2). High level of secreted leptin was confirmed by ELISA in adipocyte conditioning medium (MSC 23.1+2.9, adipocyte 110.0+4.6 pg/mL). In serum-starved conditions, human recombinant leptin (5ng/mL) stimulated cell growth of monoblastic U937 cells known to express leptin receptor (35.8+7.9% increase of viable cell number at 48 hours, p=0.02) and inhibited apoptosis (%subG1 fraction; control 26.2+3.9, leptin16.4+4.1%, p=0.04).Human recombinant PAI-1 inhibited spontaneous and ara-C-induced apoptosis in U937 cells (11.2+1.1% and 15.1+1.7% decrease of Annexin V posivitity p=0.01). These results suggest that BM adipocytes produced leptin and PAI-1contribute to support myeloid leukemia cells survival within BM microenvironment. We next focused on molecular changes in U937 cells co-cultured with adipocytes. We found up-regulation of monocyte/macrophage differentiation gene PPARg and of PPARg target genes, CD36 and FABP4, by quantitative RT-PCR (relative expression to GAPDH, control vs co-culture with adipocytes: PPARg: 8.8+0.9 v.s.18.8+2.6, CD36; 105.0+11.8v.s.425.7+35.6; FABP4: 0.27+0.03v.s.153.7+12.8). The purity of U937 cells separated from adipocytes was confirmed by lack of CD90 mRNA expression by PCR. PPARγ is known to promote monocytic differentiation and uptake of oxidized cholesterol through the induction of scavenger receptor CD36, a protein marker of mature monocytes/macrophages. The up-regulation of cell surface CD36 expression by co-culture with adipocytes was indeed found in U937 cells and in 4 of the 6 primary AML samples by flow cytometory (increase in CD36 MFI: U937; 230.28, Pt samples; 46.4+20.2). These data suggest that BM adipocytes promote monocytic differentiation of monoblastic leukemia cells. In summary, our findings indicate that secretion of leptin and PAI-1 by BM adipocytes supports leukemic cell survival, while PAI-1 primarily and directly inhibits apoptosis of AML cells. It is conceivable that increased adipocyte content of BM in elderly AML patients may negatively affect the responsiveness of monocytic leukemia cells to chemotherapy. Disclosures: No relevant conflicts of interest to declare.
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Zhou, Haodong, Guy Trudel, Konstantin Alexeev, Justin Thomas, and Odette Laneuville. "Hyperplasia and accelerated hypertrophy of marrow adipocytes with knee immobilization were sustained despite remobilization." Journal of Applied Physiology 129, no. 4 (October 1, 2020): 701–8. http://dx.doi.org/10.1152/japplphysiol.00539.2020.
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This longitudinal study elucidates the response of marrow adipose tissue adipocytes in weight-bearing joints to changes in different mechanical environments, and we provide insight on the malleability of the changes over time. In a rat animal model, knee immobilization induced hyperplasia and accelerated the age-dependent hypertrophy of adipocytes. Changes in adipocyte number and size were sustained despite unassisted remobilization. Multimodal distributions of cell size were characteristic of bone marrow adipocytes.
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Yang, Xiaoyu, Jing Li, Liting Zhao, Yazhuo Chen, Zhijun Cui, Taotao Xu, Xu Li, Shufang Wu, and Yan Zhang. "Targeting adipocytic discoidin domain receptor 2 impedes fat gain while increasing bone mass." Cell Death & Differentiation 29, no. 4 (October 13, 2021): 737–49. http://dx.doi.org/10.1038/s41418-021-00887-9.
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AbstractObesity is closely associated with low-bone-mass disorder. Discoidin domain receptor 2 (DDR2) plays essential roles in skeletal metabolism, and is probably involved in fat metabolism. To test the potential role of DDR2 in fat and fat-bone crosstalk, Ddr2 conditional knockout mice (Ddr2Adipo) were generated in which Ddr2 gene is exclusively deleted in adipocytes by Adipoq Cre. We found that Ddr2Adipo mice are protected from fat gain on high-fat diet, with significantly decreased adipocyte size. Ddr2Adipo mice exhibit significantly increased bone mass and mechanical properties, with enhanced osteoblastogenesis and osteoclastogenesis. Marrow adipocyte is diminished in the bone marrow of Ddr2Adipo mice, due to activation of lipolysis. Fatty acid in the bone marrow was reduced in Ddr2Adipo mice. RNA-Seq analysis identified adenylate cyclase 5 (Adcy5) as downstream molecule of Ddr2. Mechanically, adipocytic Ddr2 modulates Adcy5-cAMP-PKA signaling, and Ddr2 deficiency stimulates lipolysis and supplies fatty acid for oxidation in osteoblasts, leading to the enhanced osteoblast differentiation and bone mass. Treatment of Adcy5 specific inhibitor abolishes the increased bone mass gain in Ddr2Adipo mice. These observations establish, for the first time, that Ddr2 plays an essential role in the crosstalk between fat and bone. Targeting adipocytic Ddr2 may be a potential strategy for treating obesity and pathological bone loss simultaneously.
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Rozman, C., JC Reverter, E. Feliu, L. Berga, M. Rozman, and C. Climent. "Variations of fat tissue fraction in abnormal human bone marrow depend both on size and number of adipocytes: a stereologic study." Blood 76, no. 5 (September 1, 1990): 892–95. http://dx.doi.org/10.1182/blood.v76.5.892.892.
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Abstract Studies dealing with the number or size of individual adipose cells in abnormal human bone marrow are lacking. To ascertain whether variations in fat tissue fraction depend on the size of individual adipocytes or their number or both, a stereologic study of 30 human bone marrow specimens (10 with aplasia, 10 with hyperplasia, and 10 with dysplasia) was performed. A total of 23,435 adipocyte profiles were measured and two stereologic parameters were obtained in each specimen: mean diameter and number of cells per mm3 of bone marrow. The fat tissue fraction correlated positively with the size (r = .79; P less than .001) and the number/volume (r = .77; P less than .001) of adipocytes. The significance of both adipocyte size and adipocyte number/volume was confirmed by stepwise multiple regression, in which the size alone explained 62.5% of fat tissue fraction and both size and number/volume explained 95.8% of fat tissue fraction. These results are discussed from a pathophysiologic point of view.
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Rozman, C., JC Reverter, E. Feliu, L. Berga, M. Rozman, and C. Climent. "Variations of fat tissue fraction in abnormal human bone marrow depend both on size and number of adipocytes: a stereologic study." Blood 76, no. 5 (September 1, 1990): 892–95. http://dx.doi.org/10.1182/blood.v76.5.892.bloodjournal765892.
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Studies dealing with the number or size of individual adipose cells in abnormal human bone marrow are lacking. To ascertain whether variations in fat tissue fraction depend on the size of individual adipocytes or their number or both, a stereologic study of 30 human bone marrow specimens (10 with aplasia, 10 with hyperplasia, and 10 with dysplasia) was performed. A total of 23,435 adipocyte profiles were measured and two stereologic parameters were obtained in each specimen: mean diameter and number of cells per mm3 of bone marrow. The fat tissue fraction correlated positively with the size (r = .79; P less than .001) and the number/volume (r = .77; P less than .001) of adipocytes. The significance of both adipocyte size and adipocyte number/volume was confirmed by stepwise multiple regression, in which the size alone explained 62.5% of fat tissue fraction and both size and number/volume explained 95.8% of fat tissue fraction. These results are discussed from a pathophysiologic point of view.
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Lewis, Kenneth T., and Ormond A. MacDougald. "Bone marrow adipocytes in 3D." Nature Reviews Endocrinology 14, no. 5 (March 16, 2018): 254–55. http://dx.doi.org/10.1038/nrendo.2018.31.
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Shafat, Manar S., Thomas Oellerich, Sebastian Mohr, Stephen D. Robinson, Dylan R. Edwards, Christopher R. Marlein, Rachel E. Piddock, et al. "Leukemic blasts program bone marrow adipocytes to generate a protumoral microenvironment." Blood 129, no. 10 (March 9, 2017): 1320–32. http://dx.doi.org/10.1182/blood-2016-08-734798.
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Diedrich, Jonathan D., Craig E. Cole, Matthew J. Pianko, Justin A. Colacino, and Jamie J. Bernard. "Non-Toxicological Role of Aryl Hydrocarbon Receptor in Obesity-Associated Multiple Myeloma Cell Growth and Survival." Cancers 15, no. 21 (November 1, 2023): 5255. http://dx.doi.org/10.3390/cancers15215255.
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Obesity is not only a risk factor for multiple myeloma (MM) incidence, but it is also associated with an increased risk of progression from myeloma precursors—monoclonal gammopathy of undetermined significance—and smoldering myeloma. Adipocytes in the bone marrow (BMAs) microenvironment have been shown to facilitate MM cell growth via secreted factors, but the nature of these secreted factors and their mechanism of action have not been fully elucidated. The elevated expression of aryl hydrocarbon receptor (AhR) is associated with a variety of different cancers, including MM; however, the role of AhR activity in obesity-associated MM cell growth and survival has not been explored. Indeed, this is of particular interest as it has been recently shown that bone marrow adipocytes are a source of endogenous AhR ligands. Using multiple in vitro models of tumor–adipocyte crosstalk to mimic the bone microenvironment, we identified a novel, non-toxicological role of the adipocyte-secreted factors in the suppression of AhR activity in MM cells. A panel of six MM cell lines were cultured in the presence of bone marrow adipocytes in (1) a direct co-culture, (2) a transwell co-culture, or (3) an adipocyte-conditioned media to interrogate the effects of the secreted factors on MM cell AhR activity. Nuclear localization and the transcriptional activity of the AhR, as measured by CYP1A1 and CYP1B1 gene induction, were suppressed by exposure to BMA-derived factors. Additionally, decreased AhR target gene expression was associated with worse clinical outcomes. The knockdown of AhR resulted in reduced CYP1B1 expression and increased cellular growth. This tumor-suppressing role of CYP1A1 and CYP1B1 was supported by patient data which demonstrated an association between reduced target gene expression and worse overall survival. These data demonstrated a novel mechanism by which bone marrow adipocytes promote MM progression.
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Yang, Jing, Zhiqiang Liu, Huan Liu, Jin He, Pei Lin, Robert Z. Orlowski, Larry W. Kwak, Qiang Tong, and Robert Gagel. "Myeloma Cells Switch Osteoblastogenesis to Adipogenesis and Suppress Bone Formation." Blood 124, no. 21 (December 6, 2014): 3386. http://dx.doi.org/10.1182/blood.v124.21.3386.3386.
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Abstract Bone destruction is a hallmark of myeloma, and has a severe impact on patients’ quality of life and survival. Unfortunately, current treatment only offers moderate palliative effects, and this disease remains incurable. The bone changes in myeloma patients results from increased osteoclast-mediated bone resorption and decreased osteoblast-mediated bone formation. In particular, new bone formation that usually occurs at sites of previously resorbed bones is deeply suppressed; as a result, areas of bone destruction rarely heal. Previous studies have shown that myeloma cells inhibit osteoblast differentiation from mesenchymal stem cells (MSCs), and the Wnt/b-catenin signaling pathway is suppressed via myeloma-produced Wnt antagonists such as dickkopf-1. However, the role of dickkopf-1 in myeloma-induced inhibition of bone formation remains controversial since myeloma cells alone do not produce sufficient dickkopf-1 to suppress osteoblast differentiation. In addition, the administration of an antibody against dickkopf-1 in myeloma patients failed to restore new bone formation, indicating there must be an additional mechanism for inhibition of osteoblast differentiation seen in myeloma. While MSCs can differentiate into mature osteoblasts, they are also capable of differentiating into adipocytes, which is a major cell type in marrow stroma. We observed that myeloma cells (cell lines and primary cells isolated from myeloma patients’ bone marrow) injected into human or mouse bone not only reduced osteoblast number, but also increased adipocyte number and activity in bone marrow. Similar observations were seen in the clinical setting where collections of adipocytes were found in the bone marrow of newly diagnosed, untreated myeloma patients. Patients with greater bone destruction had higher adipocyte numbers than those in patients with less bone destruction, indicating a relationship among myeloma cells, adipogenesis, and osteoblastogenesis. We hypothesized that inhibition of osteoblast differentiation is a consequence of myeloma-dependent alterations in the control of the MSCs’ fate into osteoblasts or into adipocytes. In our studies, we co-cultured MSCs with myeloma cells in a mixed medium (that contained both adipocyte and osteoblast media), and we observed co-culture with myeloma cells induced more adipocyte than osteoblast formation. Moreover, co-culture with myeloma cells enhanced adipocyte differentiation in vitro. Interestingly, separation of the cells by transwell inserts significantly reduced such effect. By analysis of the adhesion molecules in myeloma cells, we identified integrin α4β1 as a novel contributor in regulation of adipogenesis and osteoblastogenesis. Thus, our studies indicate that in the presence of myeloma cells, MSCs may be more prone to differentiate into adipocytes than into osteoblasts via α4β1. Our studies also suggest the development of new strategies to improve the care of myeloma patients with bone destruction by targeting α4β1 and its signaling pathways. Disclosures No relevant conflicts of interest to declare.
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Sebo, Zachary L., Elizabeth Rendina-Ruedy, Gene P. Ables, Dieter M. Lindskog, Matthew S. Rodeheffer, Pouneh K. Fazeli, and Mark C. Horowitz. "Bone Marrow Adiposity: Basic and Clinical Implications." Endocrine Reviews 40, no. 5 (April 25, 2019): 1187–206. http://dx.doi.org/10.1210/er.2018-00138.
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AbstractThe presence of adipocytes in mammalian bone marrow (BM) has been recognized histologically for decades, yet, until recently, these cells have received little attention from the research community. Advancements in mouse transgenics and imaging methods, particularly in the last 10 years, have permitted more detailed examinations of marrow adipocytes than ever before and yielded data that show these cells are critical regulators of the BM microenvironment and whole-body metabolism. Indeed, marrow adipocytes are anatomically and functionally separate from brown, beige, and classic white adipocytes. Thus, areas of BM space populated by adipocytes can be considered distinct fat depots and are collectively referred to as marrow adipose tissue (MAT) in this review. In the proceeding text, we focus on the developmental origin and physiologic functions of MAT. We also discuss the signals that cause the accumulation and loss of marrow adipocytes and the ability of these cells to regulate other cell lineages in the BM. Last, we consider roles for MAT in human physiology and disease.
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Shaoxin Yang, Wei Lu, Chong Zhao, Yuanmei Zhai, Yanyu Wei, Jiali Liu, Yehua Yu, Zhiqiang Li, and Jun Shi. "Leukemia cells remodel marrow adipocytes via TRPV4-dependent lipolysis." Haematologica 105, no. 11 (December 19, 2019): 2572–83. http://dx.doi.org/10.3324/haematol.2019.225763.
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Remodeling of adipocyte morphology and function plays a critical role in prostate cancer development. We previously reported that leukemia cells secrete growth differentiation factor 15 (GDF15)，which remodels the residual bone marrow (BM) adipocytes into small adipocytes and is associated with a poor prognosis in acute myeloid leukemia (AML) patients. However, little is known about how GDF15 drives BM adipocyte remodeling. In this study, we examined the role of the transient receptor potential vanilloid (TRPV) channels in the remodeling of BM adipocytes exposed to GDF15. We found that TRPV4 negatively regulated GDF15-induced remodeling of BM adipocytes. Furthermore, transforming growth factor-β type II receptor (TGFβRII) was identified as the main receptor for GDF15 on BM adipocytes. PI3K inhibitor treatment reduced GDF15-induced pAKT, identifying PI3K/AKT as the downstream stress response pathway. Subsequently, GDF15 reduced the expression of the transcription factor Forkhead box C1 (FOXC1) in BM adipocytes subjected to RNA-seq screening and Western blot analyse. Moreover, it was also confirmed that FOXC1 combined with the TRPV4 promoter by the Chip-qPCR experiments, which suggests that FOXC1 mediates GDF15 regulation of TRPV4. In addition, an AML mouse model exhibited smaller BM adipocytes, whereas the TRPV4 activator 4α-phorbol 12,13-didecanoate (4αPDD) partly rescued this process and increased survival. In conclusion, TRPV4 plays a critical role in BM adipocyte remodeling induced by leukemia cells, suggesting that targeting TRPV4 may constitute a novel strategy for AML therapy.
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Shu, Ling-Ling, Shuzhao Chen, Jinyuan Li, Weida Wang, Yang Liu, Yang Li, Han-Ying Huang, Xiaoping Wu, and Yang Liang. "Bone Marrow Adipocyte Promotes Epithelial-Mesenchymal-Transition-like Activation in Multiple Myeloma Via CXCL-12/CXCR4 Axis." Blood 138, Supplement 1 (November 5, 2021): 1584. http://dx.doi.org/10.1182/blood-2021-152400.
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Abstract Extra-medullary disease (EMD) in multiple myeloma (MM) is associated with poor prognosis and resistance to chemotherapy. The bone marrow microenvironment is a key regulator of myeloma metastatic progression through the secretion of growth factors that activate epithelial-mesenchymal transition (EMT)-like characters. Bone marrow adipocyte (BMA) accumulates in obese patients and displays distinct immune regulatory properties rather than provides energy substrates, forming a bulk portion of the bone marrow microenvironment. Emerging evidence indicates the potential for adipocytes to influence cancer cell progression through the secretion of adipokines that can induce EMT activation. The molecular mechanisms underlying how adipocytes enhance multiple myeloma progression is largely unknown. The present study aims to investigate the precise mechanism of BMA promoting myeloma EMT-like activation and new potential therapeutic strategies targeting bone marrow adipocytes. Newly diagnosed MM patients in our cancer center were recruited and divided into lean or obese group according to their body mass index (BMI). The bioinformatics-based analysis of transcriptome sequencing data for bone marrow stromal cells (BMSCs) derived from lean and obese MM patients identified that obese patients showed more obvious EMT-like transcriptional regulation characteristics and altered the expression of genes regulating EMT (Fig A), which was further confirmed by the immunohistochemistry staining of bone marrow biopsy (Fig B). Co-culture bone marrow adipocytes with myeloma cells significantly enhanced the proliferation and migration (Fig C-D). The transcriptome sequencing data of BMA further demonstrated that CXCL12 was enriched in BMA derived from obese MM patients (Fig E). We further confirmed that CXCL12 secreted by adipocytes induce EMT-like activation in myeloma cells, and the effect of CXCL12 expression on EMT is mediated through activation of CXCR4 (Fig F-G). Blocking of CXCR4 signaling in myeloma cells, decreased proliferation and invasion capabilities of myeloma cells cultured with CXCL12 (Fig H-I). Together, our results suggest that bone marrow adipocytes can enhance the aggressive behavior of myeloma cells and induce an EMT-like activation through paracrine CXCL12/CXCR4 signaling (Fig J). In conclusion, paracrine signaling by BMAs can induce EMT-like activation and results in increased proliferation and invasion characteristics of myeloma cells. These results suggested that targeting CXCL12/CXCR4 may act as a regulator of EMD through EMT-like transcriptional modulation, thus representing a potential therapeutic strategy to prevent MM disease progression. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
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Kennedy, Domenick Edward, and Katherine L. Knight. "Bone marrow fat induces inflammation that inhibits B lymphopoiesis." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 122.11. http://dx.doi.org/10.4049/jimmunol.196.supp.122.11.
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Abstract Adipocytes accumulate in the bone marrow (BM) during aging and obesity, correlating with decreased B lymphopoiesis. We previously found that adipocyte factors induce MDSCs, which in turn inhibit B lymphopoiesis via IL-1 production. In this study, we asked what adipocyte factor(s) promotes MDSC accumulation. By cytokine array, we found that adipocyte conditioned medium (ACM) contains inflammatory cytokines known to induce MDSCs (ex. IL-6, G-CSF, C3a). These and other adipocyte factors can activate the NLRP3 inflammasome, leading us to test if blocking NLRP3 activation would prevent MDSC accumulation. Cultures of mouse BM progenitors with OP9 cells in the presence of ACM yielded many MDSCs and few B lineage cells. However, glybenclamide (NLRP3 inhibitor) treatment reduced MDSC accumulation and increased B lymphopoiesis, suggesting that adipocyte factors induce MDSCs through inflammasome activation. Adipocytes fill the BM of rabbits by 2 months of age, a time when B lymphopoiesis is arrested. To determine if the arrest of B lymphopoiesis could be due to adipocyte-initiated BM microenvironmental changes, we co-cultured BM progenitors and OP9 cells with or without conditioned medium generated from BM fat explants (BM fat-CM) taken from >2 month old rabbits. These cultures resulted in decreased numbers of B lineage cells and increased numbers of myeloid cells, similar to the myeloid skew seen in BM of >2 month rabbits. We conclude that rabbit BM fat can initiate the loss of B cell development. Strategies to modulate BM fat volume and inflammatory state could be useful for boosting B lymphopoiesis in the aging and obese populations.
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Wang, Feng-Sheng, Yu-Shan Chen, Jih-Yang Ko, Chung-Wen Kuo, Huei-Jing Ke, Chin-Kuei Hsieh, Shao-Yu Wang, Pei-Chen Kuo, Holger Jahr, and Wei-Shiung Lian. "Bromodomain Protein BRD4 Accelerates Glucocorticoid Dysregulation of Bone Mass and Marrow Adiposis by Modulating H3K9 and Foxp1." Cells 9, no. 6 (June 19, 2020): 1500. http://dx.doi.org/10.3390/cells9061500.
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Glucocorticoid provokes bone mass loss and fatty marrow, accelerating osteoporosis development. Bromodomain protein BRD4, an acetyl–histone-binding chromatin reader, regulates stem cell and tissue homeostasis. We uncovered that glucocorticoid inhibited acetyl Lys-9 at the histone 3 (H3K9ac)-binding Runx2 promoter and decreased osteogenic differentiation, whereas bromodomain protein 4 (BRD4) and adipocyte formation were upregulated in bone-marrow mesenchymal progenitor cells. BRD4 knockdown improved H3K9ac occupation at the Runx2 promoter and osteogenesis, but attenuated glucocorticoid-mediated adipocyte formation together with the unaffected H3K9ac-binding PPARγ2 promoter. BRD4 regulated epigenome related to fatty acid metabolism and the forkhead box P1 (Foxp1) pathway, which occupied the PPARγ2 promoter to modulate glucocorticoid-induced adipocytic activity. In vivo, BRD4 inhibitor JQ-1 treatment mitigated methylprednisolone-induced suppression of bone mass, trabecular microstructure, mineral acquisition, and osteogenic differentiation. Foxp1 signaling, marrow fat, and adipocyte formation in glucocorticoid-treated skeleton were reversed upon JQ-1 treatment. Taken together, glucocorticoid-induced H3K9 hypoacetylation augmented BRD4 action to Foxp1, which steered mesenchymal progenitor cells toward adipocytes at the cost of osteogenic differentiation in osteoporotic skeletons. BRD4 inhibition slowed bone mass loss and marrow adiposity. Collective investigations convey a new epigenetic insight into acetyl histone reader BRD4 control of osteogenesis and adipogenesis in skeleton, and highlight the remedial effects of the BRD4 inhibitor on glucocorticoid-induced osteoporosis.
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Tabe, Yoko, Linhua Jin, Saiko Kazuno, Tsutomu Fujimura, Hiromichi Matsushita, Takashi Ueno, Michael Andreeff, Jordan U. Gutterman, and Marina Konopleva. "A Plant Triterpenoid Avicin D Stimulates Adipocytic Differentiation of Bone Marrow Stromal Cells and Promotes Their Pro-Survival Effects On Acute Monoblastic Leukemia Cells." Blood 120, no. 21 (November 16, 2012): 4315. http://dx.doi.org/10.1182/blood.v120.21.4315.4315.
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Abstract Abstract 4315 A natural triterpene Avicin D induces apoptosis in various tumor cells and regulates cellular metabolism via Glucocorticoid receptor (GR) signalling, known to be involved in adipocyte differentiation (Tang, Annu Rev Biochem. 2012;81:715). Since adipocytes represent an essential component of the aging bone marrow (BM) microenvironment (Tabe, Blood 2004;103:1815), and promote monocytic differentiation and survival of monoblastic leukemia cells (Tabe, ASH, 2011), we examined the potential of Avicin D to modulate BM adipocytes and its effects on the survival of the leukemic cells. In mature adipocytes derived from BM mesenchymal stem cells (MSCs), Avicin D (1ƒÊM, 48 hrs) significantly increased the number of lipid vesicles without apoptosis induction or significant cell cycle arrest. This was associated with upregulation of adipose-specific genes, PPARG and fatty acid binding protein 4 (FABP4), and inflammation-related haptoglobin (HP) gene (p<0.005, Figure 1). Avicin D further enhanced leptin release from adipocytes and inflammatory cytokines production, IL-6 and IL-8, from both MSCs and adipocytes (Figure 2). Of note, Avicin D increased pro-survival Bcl-2 mRNA expression in adipocytes (fold increase compared to MSCs: MSCs+Avicin D 1.0±0, adipocytes 1.8±0.1, adipocytes+Avicin D 4.4±0.6, p=0.02). We next investigated the effects of MSCs and adipocytes pre-treated with 1mM Avicn D for 24 hours on co-cultured monoblastic leukemia cell line U937. Avicin D (1ƒÊM) moderately (26±5 %) inhibited cell proliferation of U937 cells cultured alone as detected by MTT assay. Serum-starvation induced cell death in U937 cells was inhibited by MCS or adipocyte co-culture, and further blocked by Avicin D-pretreated adipocytes, which was accompanied with cell cycle arrest (sub-G1 fraction; control U937 36.1±7.1%, co-culture with MSC 17.9±4.1%, MSC+Avicin D 20.9±3.9%, adipocyte 16.9±2.9, adipocyte+Avicin D 11.5±0.8%, p=0.03, G0/G1 phase; control 39.1±5.9%, with MSC 44.3±1.0%, MSC+Avicin D 40.3±1.3%, adipocyte 40.6±1.3, adipocyte+Avicin D 50.4±2.3%, p=0.03). Co-culture of U937 cells with Avicin D-pretreated adipocytes induced upregulation of PPARG and CD36, markers of monocytes/macrophages maturation in U937 cells (fold increase compared to control U937: PPARG: co-culture with adipocytes 2.1±0.4, adipocytes+Avicin D 13.8±6.2; CD36: adipocytes 2.2±0.4, adipocytes+Avicin D 4.7±2.9). Co-culture with Avicin D-pretreated adipocytes also caused 3.1 ±0.4 fold increase of BCL2 mRNA in U937 cells compared to the one of co-cultured with control adipocytes (p=0.02). The purity of U937 cells separated from adipocytes was confirmed by lack of CD90 mRNA expression by PCR. Utilization of the proteomic technology of isobaric tags for relative and absolute quantitation (iTRAQ) with two-dimensional-liquid chromatography-tandem mass spectrometry allowed the identification of 1,634 proteins. We found changes in 14 proteins in U937 cells co-cultured with Avicin D-pretreated adipocytes compared to untreated adipocytes. Among 13 down-regulated proteins, three are involved in pyruvate metabolism (Glyoxalase I; p=0.01, Lactate dehydrogenase B; p=0.02, Pyruvate kinase; p=0.03), and four proteins participate in cell cycle progression (DNA replication licensing factor MCM4, MCM5; p=0.02, p=0.03, DNA-dependent protein kinase; p=0.02, Interleukin enhancer-binding factor 3; p=0.005). Voltage-dependent anion-selective channel protein 2, which is involved in the mitochondrial apoptotic pathway via regulation of Bcl-2, and an enzymatic antioxidant Superoxide dismutase were up-regulated (p=0.04, p=0.03). These data indicate that U937 cells co-cultured with Avicin D pretreated adipocytes were induced to undergo cell cycle arrest, escape apoptosis with down-regulation of glucose metabolism. Altogether, these results suggest that Avicin D induces adipocytic differentiation of BM-derived stromal cells, promotes production of leptin and inflammatory cytokines, which in turn supports survival of monocytic leukemia cells. These findings suggest a contributory role of the aging “pro-inflammatory” bone marrow microenvironment in the reduced efficacy of cytotoxic chemotherapy which is prevalent in elderly AML patients. Disclosures: No relevant conflicts of interest to declare.
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Li, Jingyuan, Xiaoyu Lai, and Huang He. "Study on Telomerase Activity of Human Bone Marrow Mesenchymal Stem Cells." Blood 104, no. 11 (November 16, 2004): 4255. http://dx.doi.org/10.1182/blood.v104.11.4255.4255.
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Abstract Human mesenchymal stem cells(hMSCs) have multiple differentiate potential, and it can differentiate into adipocytes, osteogenic cells, chondrocyte and neural cells et al. It has been reported that telomerase activity in hMSCs is negative, but it is still controversial and telomerase activity in hMSCs-derived adipocytes has not been reported. We investigate the telomerase activity in hMSCs before and after their committed differentiation into adipocytes in vitro and cryopreservation. hMSCs were isolated from normal human bone marrow fellowed by cell culture in DMEM with low glucose containing 10% FBS. The FACS was performed to examine the expression of cell surface molecules and analyze cell cycle of primary hMSCs.Then some of hMSCs were induced to differentiate into adipocytes in vitro by being treated with adipocytic medium fellowed by being stained with oil red O, and the others were cryopreserved in liguid nitrogon for three months. TRAP assay(telomerase repeat amplification protocol assay)was employed to detect telomerase activity in those hMSCs. T293 cells and α-Interferon were analyzed with each test as an additional positive control and negative control respectively. Telomerase activity was expressed as a percentage of the relative telomerase activity (RTA) of the hMSCs relative to the RTA of T293 cells. The results indicated the cells were positive for SH2, SH3, CD90 and negative for CD34, CD45, AC133. It was showed that the majority of primary hMSCs(85%) was at cell cycle of G0/G1 phase and the minority of hMSCs was at S, G2 or M phase. 80% hMSCs was orange adipocytes after they were treated with adipocytic medium for 3–4weeks. Telomerase activity was negative in hMSCs both at the beginning of culture and at the later stages during cell expansion,telomerase activity in hMSCs-passage 1–3(n=10) and hMSCs-passage 4–7(n=9) made no significant difference(1.46±0.83% vs 1.46±0.67%, p=0.99). Cryopreservation did not affect the telomerase activity in hMSCs. Telomerase activity in fresh hMSCs(n=13) and frozen hMSCs(n=6) made no significant difference(1.41±0.44% vs 1.51±1.07%, p=0.64). Telomerase activity in hMSCs-derived adipocytes(n=3) was significantly higher than in hMSCs(n=19)( 11.8±2.52% vs 1.46. ±0.67%, p<0.00001). It is concluded that hMSCs are telomerase-negative, and the stage of culture or cryopreservation does not affect their telomerase activity. After being induced to differentiated into adipocytes, hMSCs telomerase activity is upregulated.
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Frączak, Ewa, Mateusz Olbromski, Aleksandra Piotrowska, Natalia Glatzel-Plucińska, Piotr Dzięgiel, Jarosław Dybko, Kazimierz Kuliczkowski, and Tomasz Wróbel. "Bone marrow adipocytes in haematological malignancies." Acta Histochemica 120, no. 1 (January 2018): 22–27. http://dx.doi.org/10.1016/j.acthis.2017.10.010.
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Okla, Meshail, and Moustapha Kassem. "Thermogenic potentials of bone marrow adipocytes." Bone 143 (February 2021): 115658. http://dx.doi.org/10.1016/j.bone.2020.115658.
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Vashum, Yaongamphi, and Zenith Khashim. "Obesity and Cathepsin K: A Complex Pathophysiological Relationship in Breast Cancer Metastases." Endocrine, Metabolic & Immune Disorders - Drug Targets 20, no. 8 (October 15, 2020): 1227–31. http://dx.doi.org/10.2174/1871530320666200505115132.
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Background: Breast cancer appears in a strong inclination to metastasize in bone tissue. Several strategies are discussed in combating bone metastasis in breast cancer. However, therapy is only palliative and does not provide any improvement in survival to the majority of patients with advanced cancer. Obese and overweight women with breast cancer are three times more likely to develop metastatic disease compared to normal-weight women with the same treatment regimen. Overweight greatly intensify adipocytes formation in the bone marrow affecting bone metabolism by decreasing osteoblast differentiation and bone formation. Cathepsin K (CTSK), a cysteine protease, effectively degrades several components of the extracellular matrix and has the ability to differentiate adipocytes from bone marrow lineage. Therefore, the purpose of this review is to emphasize the underlying mechanism of CTSK and obesity role in breast cancer metastasis. Methods: Systematic review was performed using PubMed, EMBASE. The evidence of obesity and CTSK in breast cancer skeletal metastasis were analyzed, summarized and compared. Results: The present investigation argues for a specific association of CTSK with breast cancer skeletal metastasis by promoting adipocyte differentiation. The potential tumor-supporting roles of adipocytes are well documented, and in fact, suppressing adipocyte could be a new therapeutic option in the battle against lethal metastatic breast cancers. Conclusion: This review emphasizes CTSK through its multifaceted role in differentiating adipocytes, inflammation, and extracellular degradation, may be a critical factor in an obesity-cancer connection. Thus, integration of CTSK targeting strategies into established traditional therapies seems to hold substantial promise.
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Gimble, J. M., M. A. Dorheim, Q. Cheng, P. Pekala, S. Enerback, L. Ellingsworth, P. W. Kincade, and C. S. Wang. "Response of bone marrow stromal cells to adipogenic antagonists." Molecular and Cellular Biology 9, no. 11 (November 1989): 4587–95. http://dx.doi.org/10.1128/mcb.9.11.4587-4595.1989.
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Adipocytes constitute a major part of the bone marrow stroma in vivo and may play an active role in lymphohematopoiesis. Earlier studies had shown that the bone marrow stromal cell clone BMS2 was capable of adipocyte differentiation in vitro, in addition to its well-defined ability to support B lymphopoiesis. We now demonstrate that the process of adipogenesis in this functional bone marrow stromal cell clone can be inhibited by the cytokines interleukin-1 alpha, tumor necrosis factor, and transforming growth factor beta. Exposure of preadipocyte BMS2 cells to these agents blocked the induction of adipocyte differentiation as assessed by morphologic criteria and analysis of the neutral lipid content. Both interleukin-1 alpha and tumor necrosis factor elicited a rapid transient elevation in the steady-state mRNA levels of c-fos, c-jun, and JE. When added to differentiated adipocytes, the three cytokines continued to act as adipogenic antagonists. This was indicated by concentration- and time-dependent decreases in the activity of an adipocyte-specific enzyme, lipoprotein lipase. These changes in enzyme activity correlated directly with a decrease in steady-state levels of lipoprotein lipase mRNA. Another RNA marker of adipocyte differentiation (adipsin) was less influenced by the adipogenic antagonists. This may reflect the longer half-life of this mRNA transcript compared with those of lipoprotein lipase. Our results dramatically demonstrate that the differentiation state of bone marrow stromal cells can be modulated by exogenous factors in vitro. It is also the first report that transformation growth factor beta regulates the activity of lipoprotein lipase. These data suggest potential physiologic actions for these cytokines in vivo within the overall context of lymphohematopoiesis.
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Gimble, J. M., M. A. Dorheim, Q. Cheng, P. Pekala, S. Enerback, L. Ellingsworth, P. W. Kincade, and C. S. Wang. "Response of bone marrow stromal cells to adipogenic antagonists." Molecular and Cellular Biology 9, no. 11 (November 1989): 4587–95. http://dx.doi.org/10.1128/mcb.9.11.4587.
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Adipocytes constitute a major part of the bone marrow stroma in vivo and may play an active role in lymphohematopoiesis. Earlier studies had shown that the bone marrow stromal cell clone BMS2 was capable of adipocyte differentiation in vitro, in addition to its well-defined ability to support B lymphopoiesis. We now demonstrate that the process of adipogenesis in this functional bone marrow stromal cell clone can be inhibited by the cytokines interleukin-1 alpha, tumor necrosis factor, and transforming growth factor beta. Exposure of preadipocyte BMS2 cells to these agents blocked the induction of adipocyte differentiation as assessed by morphologic criteria and analysis of the neutral lipid content. Both interleukin-1 alpha and tumor necrosis factor elicited a rapid transient elevation in the steady-state mRNA levels of c-fos, c-jun, and JE. When added to differentiated adipocytes, the three cytokines continued to act as adipogenic antagonists. This was indicated by concentration- and time-dependent decreases in the activity of an adipocyte-specific enzyme, lipoprotein lipase. These changes in enzyme activity correlated directly with a decrease in steady-state levels of lipoprotein lipase mRNA. Another RNA marker of adipocyte differentiation (adipsin) was less influenced by the adipogenic antagonists. This may reflect the longer half-life of this mRNA transcript compared with those of lipoprotein lipase. Our results dramatically demonstrate that the differentiation state of bone marrow stromal cells can be modulated by exogenous factors in vitro. It is also the first report that transformation growth factor beta regulates the activity of lipoprotein lipase. These data suggest potential physiologic actions for these cytokines in vivo within the overall context of lymphohematopoiesis.
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Caers, Jo, Zakia Belaid, Sarah Deleu, Marie Paule Defresne, and Karin Vanderkerken. "Bone Marrow Adipocytes Influence Multiple Myeloma Development by Secretion of Different Growth Factors and Chemokines." Blood 108, no. 11 (November 16, 2006): 5030. http://dx.doi.org/10.1182/blood.v108.11.5030.5030.
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Abstract In multiple myeloma (MM) monoclonal plasma cells accumulate in the bone marrow (BM) where they interact with neighboring cells to receive supportive signals. Since BM adipocytes are known to participate in normal and malignant hematopoiesis, we presumed interactions between BM adipocytes and myeloma cells. Using an adipocytic cell line and primary isolated BM adipocytes, we performed functional assays indicating that adipocytes support MM cell development by affecting proliferation, apoptosis, cell migration and adhesion. We subsequently analyzed the secretion of different cytokines by BM adipocytes and analyzed the contribution of a specific adipokine, leptin, to these processes. We confirmed the expression of leptin by adipocytes and leptin receptor by myeloma cells. Immunostaining showed strong presence of leptin receptor on MM cells in 13 of 28 patients tested. This expression was not correlated to disease stage. On cell proliferation, leptin acted as a moderate growth factor. We conclude that, next to the earlier described interactions within the BM, adipocytes influence MM cell behavior by affecting proliferation, apoptosis and migration and that part of these effects may be contributed to leptin.
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Liu, Haiyan, Yuanmei Zhai, Wenli Zhao, Yun Wan, Wei Lu, Shaoxin Yang, Yehua Yu, Yanyu Wei, Zhiqiang Li, and Jun Shi. "Consolidation Chemotherapy Prevents Relapse by Indirectly Regulating Bone Marrow Adipogenesis in Patients with Acute Myeloid Leukemia." Cellular Physiology and Biochemistry 45, no. 6 (2018): 2389–400. http://dx.doi.org/10.1159/000488225.
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Background/Aims: Chemotherapy is still the main strategy used to prevent the relapse of acute myeloid leukaemia (AML). As the most abundant stromal component in bone marrow (BM), marrow adipocytes have been previously shown to promote leukaemogenesis. The present study was designed to further validate whether marrow adipocytes exert synergistic effects on strengthening chemotherapeutic efficacy and evaluate the underlying mechanism. Methods: A retrospective study of BM biopsies from 80 patients with AML in remission and 71 control subjects was applied to quantitatively analyse the marrow adipocyte volume. Toxicity tests were used to assess the effect of chemotherapy drugs on BM cells. The possible mechanisms by which chemotherapy regulated the reduced marrow adipocyte content were investigated using antibody neutralization experiments, with an emphasis on growth differentiation factor 15 (GDF15). Results: In our study, the marrow adipocyte content was obviously reduced in the AML- complete remission (CR) group compared with the control group (P<0.001). Moreover, patients with a reduced adipocyte content exhibited longer relapse-free survival (RFS) (P<0.001). We also confirmed that GDF15 was overexpressed in mononuclear cells (MNCs) after treatment with chemotherapy drugs and partially blocked mesenchymal stem cells (MSCs) adipogenesis. Intriguingly, this inhibitory effect on adipogenesis was rescued by treatment with a neutralizing anti-GDF15 antibody. Conclusion: Chemotherapy indirectly inhibited adipogenesis by promoting GDF15 secretion from BM MNCs, subsequently strengthening the efficacy of consolidation chemotherapy in patients with AML during CR.
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Shu, Lingling, Jinyuan Li, Weida Wang, Xiaoping Wu, Hanying Huang, Fang Hu, and Yang Liang. "Adipocyte Fatty Acid Binding Protein Promotes Multiple Myeloma through Regulating Bone Marrow Microenvironment." Blood 136, Supplement 1 (November 5, 2020): 31–32. http://dx.doi.org/10.1182/blood-2020-140732.
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Multiple myeloma (MM) is a plasma cell malignancy in bone marrow, which often occurs in middle-aged and elderly people and also obese patients. Aging and obesity can lead to the ectopic accumulation of adipocytes in bone marrow, which can cause the change of bone marrow microenvironment. Bone marrow adipocyte (BMA) displays distinct immune regulatory properties rather than provides energy substrates. Despite BMA accounts for 70% of the entire volume of bone marrow microenvironment, while the mechanisms still remain elusive. The present study aims to investigate the precise mechanism of BMA promoting myeloma pathogenesis and new potential therapeutic strategies targeting bone marrow microenvironment. Newly diagnosed MM patients and their relative healthy control in our cancer center were recruited. We found that the quantity of BMA increased significantly in multiple myeloma patients, accompanied with the elevated level of adipocyte fatty acid binding protein (A-FABP) by flow cytometry and immunohistochemistry staining. A-FABP is a fatty acid chaperone, which abundantly expressed in adipocytes, playing a critical role in lipid metabolism and immune response. To further explore the role of A-FABP in the pathogenesis of MM, A-FABP knockout (KO) mice and their wide type (WT) littermates were employed and fed with stand chow or high fat diet (HFD). Tumor burden and MM-related osteolytic lesions were significantly lower in A-FABP KO mice comparing to their WT littermates fed with HFD. It was observed that A-FABP deficiency did not change the content of BMA in bone marrow, but cytokines levels in bone marrow such as TNFα, IL-6, RANKL, DPP4 were significantly reduced. The infiltration and pro-inflammatory polarization (M1/M2) of macrophages (MΦ) decreased significantly. Moreover, A-FABP promotes the expression of Th1 and Th17 cells, while the percentage of Th2 and Treg cells are significantly declined. Furthermore, pharmacological inhibition of A-FABP by administration BMS309403 also alleviates the invasion and metastasis of MM in mouse. In addition, co-culture of myeloma cells with pharmacological inhibition or genetic depletion of A-FABP in adipocytes significantly decreased the uptake of free fatty acid and oxygen consumption of myeloma cells. In conclusion, A-FABP increased in BMA in response to aging or obesity, remodeled the energy and lipid metabolism of myeloma cells, and manipulated bone marrow microenvironment to a pro-tumor environment, promoting the proliferation and migration of myeloma cells. This study will shed light on the potential of A-FABP specific inhibitor BMS309403 as the therapeutic strategy of multiple myeloma targeting bone marrow microenvironment. Disclosures No relevant conflicts of interest to declare.
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Wilson, Alexis, Mackenzie Herroon, Shane Mecca, Laimar Garmo, and Izabela Podgorski. "Abstract B039: Adipocyte regulation of ER stress and mTOR signaling in bone-metastatic PCa: The role of stearoyl-CoA desaturase." Cancer Research 83, no. 2_Supplement_2 (January 15, 2023): B039. http://dx.doi.org/10.1158/1538-7445.metastasis22-b039.
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Abstract Bone metastatic disease is correlated with increased morbidity and mortality in prostate cancer (PCa) patients. Current treatments for bone-metastatic PCa are palliative, and new targets for therapy are desperately needed for this presently incurable disease. Various studies have determined that the supportive nature of the bone marrow (BM) niche and crosstalk between the bone-resident cells and the tumor lead to increased tumor cell survival and escape from therapy. Specifically, studies from our lab highlighted the critical role of bone marrow adipose tissue and its expansion due to obesity or age in PCa progression and chemoresistance in bone. Bone marrow adipocytes are metabolically active cells that, through secretion of lipids and adipokines, have the potential to affect the neighboring cells, including the tumor cells that have disseminated into the BM niche. We have shown previously that interaction with marrow adipocytes promotes lipid uptake by PCa cells, modulates their metabolic phenotype, and activates pro-survival signaling and ER/oxidative stress pathways; however, the molecular mechanisms behind the tumor-promoting effects of adipocytes are not understood. The main objective of this study was to investigate the molecular mechanisms underlying lipid-induced stress during tumor cell-adipocyte crosstalk and its functional relationship to tumor growth and progression in bone. Our preliminary data showed that adipocyte-tumor cell crosstalk increases lipid peroxidation in PCa cells, which coincides with augmented expression of ER stress markers and activation of mTOR signaling. We also observed that PCa cells under adipocyte exposure had augmented gene expression of stearoyl-CoA desaturase (SCD), an ER-resident enzyme responsible for the conversion of saturated fatty acids (SFA) to monounsaturated fatty acids (MUFA). We, therefore, hypothesized that SCD is a metabolic regulator that protects metastatic PCa cells against lipid-induced toxicity and ER stress and promotes tumor survival via activation of mTOR signaling. Here, we show that the inhibition of mTORC1 by Everolimus (EVO) decreases the gene expression of ER stress markers in PCa cells exposed to adipocytes. We also demonstrate that adipocyte-mediated induction of ER stress coincides with an increase in active mTOR signaling in PCa cells, indicating possible bidirectional crosstalk between ER stress and mTOR pathways. Notably, inhibition of SCD in PCa cells grown in Transwell co-culture with adipocytes by either siRNA or the small molecule inhibitor CAY10566 leads to reduced mTOR signaling and an increase in lipid peroxidation in PCa cells. SCD inhibition also increases the gene and protein expression of ER stress markers, specifically XBP1 (S) and ATF4, suggesting apoptosis induction. Collectively, our results place SCD as a mediator of ER stress-mTOR crosstalk and a promoter of tumor survival and suggest that targeting SCD activity might be a viable approach to rewire tumor metabolism, and inhibit metastatic progression in bone and sensitize PCa tumors to therapy. Citation Format: Alexis Wilson, Mackenzie Herroon, Shane Mecca, Laimar Garmo, Izabela Podgorski. Adipocyte regulation of ER stress and mTOR signaling in bone-metastatic PCa: The role of stearoyl-CoA desaturase [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr B039.
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Cohen, Adi, David W. Dempster, Emily M. Stein, Thomas L. Nickolas, Hua Zhou, Donald J. McMahon, Ralph Müller, et al. "Increased Marrow Adiposity in Premenopausal Women with Idiopathic Osteoporosis." Journal of Clinical Endocrinology & Metabolism 97, no. 8 (August 1, 2012): 2782–91. http://dx.doi.org/10.1210/jc.2012-1477.
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Abstract Context: We have previously reported that premenopausal women with idiopathic osteoporosis based on fractures (IOP) or idiopathic low bone mineral density (ILBMD) exhibit markedly reduced bone mass, profoundly abnormal trabecular microstructure, and significant deficits in trabecular bone stiffness. Bone remodeling was heterogeneous. Those with low bone turnover had evidence of osteoblast dysfunction and the most marked deficits in microstructure and stiffness. Objective: Because osteoblasts and marrow adipocytes derive from a common mesenchymal precursor and excess marrow fat has been implicated in the pathogenesis of bone fragility in anorexia nervosa, glucocorticoid excess, and thiazolidinedione exposure, we hypothesized that marrow adiposity would be higher in affected women and inversely related to bone mass, microarchitecture, bone formation rate, and osteoblast number. Design: We analyzed tetracycline-labeled transiliac biopsy specimens in 64 premenopausal women with IOP or ILBMD and 40 controls by three-dimensional micro-computed tomography and two-dimensional quantitative histomorphometry to assess marrow adipocyte number, perimeter, and area. Results: IOP and ILBMD subjects did not differ with regard to any adipocyte parameter, and thus results were combined. Subjects had substantially higher adipocyte number (by 22%), size (by 24%), and volume (by 26%) than controls (P < 0.0001 for all). Results remained significant after adjusting for age, body mass index, and bone volume. Controls demonstrated expected direct associations between marrow adiposity and age and inverse relationships between marrow adiposity and bone formation, volume, and microstructure measures. No such relationships were observed in the subjects. Conclusions: Higher marrow adiposity and the absence of expected relationships between marrow adiposity and bone microstructure and remodeling in women with IOP or ILBMD suggest that the relationships between fat and bone are abnormal; excess marrow fat may not arise from a switch from the osteoblast to the adipocyte lineage in this disorder. Whether excess marrow fat contributes to the pathogenesis of this disorder remains unclear.
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Kokabu, Shoichiro, Jonathan W. Lowery, and Eijiro Jimi. "Cell Fate and Differentiation of Bone Marrow Mesenchymal Stem Cells." Stem Cells International 2016 (2016): 1–7. http://dx.doi.org/10.1155/2016/3753581.
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Osteoblasts and bone marrow adipocytes originate from bone marrow mesenchymal stem cells (BMMSCs) and there appears to be a reciprocal relationship between adipogenesis and osteoblastogenesis. Alterations in the balance between adipogenesis and osteoblastogenesis in BMMSCs wherein adipogenesis is increased relative to osteoblastogenesis are associated with decreased bone quality and quantity. Several proteins have been reported to regulate this reciprocal relationship but the exact nature of the signals regulating the balance between osteoblast and adipocyte formation within the bone marrow space remains to be determined. In this review, we focus on the role of Transducin-Like Enhancer of Split 3 (TLE3), which was recently reported to regulate the balance between osteoblast and adipocyte formation from BMMSCs. We also discuss evidence implicating canonical Wnt signalling, which plays important roles in both adipogenesis and osteoblastogenesis, in regulating TLE3 expression. Currently, there is demand for new effective therapies that target the stimulation of osteoblast differentiation to enhance bone formation. We speculate that reducing TLE3 expression or activity in BMMSCs could be a useful approach towards increasing osteoblast numbers and reducing adipogenesis in the bone marrow environment.
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James, Sophie C., Samantha Atkinson, Richard Burt, Cristina Lo Celso, and Paolo Gallipoli. "Specific Bone Marrow Niche Components Determine Degree of Protection from Gilteritinib Induced Differentiation Response in FLT3-ITD AML." Blood 144, Supplement 1 (November 5, 2024): 4152. https://doi.org/10.1182/blood-2024-205582.
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Background:the FLT3 tyrosine kinase inhibitor (TKI) gilteritinib relieves the differentiation blockade in around 50% of acute myeloid leukaemia (AML) patients carrying FLT3 internal tandem duplication (ITD) mutations. However, differentiation responses are often incomplete and are poorly understood. This limited understanding is partly due to the strong cytotoxic effects seen with gilteritinib in cellular in vitro models and suggests that the in vivo bone marrow microenvironment (BMM) plays roles in modulating the differentiation response. Recent evidence suggests that the BMM induces changes to the signalling and metabolism of FLT3-ITD AML cells (Joshi et al, 2021). However, links between specific bone marrow cells, gilteritinib induced differentiation in FLT3-ITD AML and the underlying mechanisms have not been explored. Aims:to uncover the degree and mechanisms by which specific BMM cellular components modulate differentiation in response to gilteritinib in FLT3-ITD AML. Methods:we treated a murine model of NPM1c/FLT3-ITD AML and a patient derived xenograft (PDX) with gilteritinib and determined responses in different bone marrow regions. We designed manipulable in vitro co-culture systems of human AML cell lines and primary cells with several cellular components of BMM derived from both stromal cell lines and healthy donor mesenchymal stromal cells. Following mono- and co-culture experiments, we performed viability, immunophenotypic, transcriptional and metabolic analysis. Results:treatment of NPM1c/FLT3-ITD murine leukaemia with gilteritinib reduces the primitive pool (Lineage- cKit+ Sca-1+) and increases the proportion and number of cells expressing lineage markers, indicative of a differentiation response. This results in a moderate but sub-optimal increase in the survival of gilteritinib treated mice reminiscent of responses seen in patients. Analysis of AML immunophenotypes in different BM regions reveals that in the highly haematopoietic adipocyte sparse thoracic vertebrae gilteritinib induces a strong differentiation response. However, in the highly adipocytic tail vertebrae upon gilteritinib treatment the proportion of quiescent primitive cells remains the same, revealing adipocyte protection of the leukaemia stem cell pool. A similar effect is also observed in a gilteritinib treated PDX. Furthermore, in vitro adipocytes protect FLT3-ITD AML cells from death and block induction of myeloid differentiation to a greater extent than other BMM cellular components. As such, we focused on adipocyte driven protection and show that, while this is partly retained in transwell assays, it is most potent upon direct contact. Adipocyte conditioned media is not protective, suggesting that cellular proximity and/or reprogramming of adipocytes by AML cells is needed for protection. Transcriptional profiling of co-cultured adipocytes and AML cells and cytokine analysis of spent media suggest that metabolic reprogramming contributes to protection. Indeed, metabolic profiling of AML cells reveals that adipocyte co-culture rescues the abundance of tricarboxylic acid (TCA) cycle intermediates following gilteritinib treatment. Uniformly labelled 13Carbon6 glucose (U13C6-Gluc) tracing shows that the increase of TCA cycle intermediates in co-culture is caused both by unlabelled and U13C6-Gluc labelled carbon sources. This is likely due to fatty acids contribution to the unlabelled pool, as previously described (Ye et al, 2016) and indeed in vitro adipocyte labelling confirms transfer from adipocytes to AML cells. Moreover, metabolic analysis of co-culture media and AML cells following adipocyte U13C6-Gluc pre-labelling show presence of adipocyte derived labelled glycolytic and TCA cycle intermediates both in media and AML cells. This suggests that adipocytic derived polar metabolites also provide an important carbon source to AML cells in co-culture. Conclusion: the degree of gilteritinib induced differentiation in FLT3-ITD AML is dependent on specific components of the BMM. The adipocytic BM niche protects against gilteritinib induced differentiation and this correlates with metabolic reprogramming of AML cells, driven by both fatty acid and glucose derived carbon sources. These findings offer opportunities for therapeutic interventions aimed at overcoming BM stromal protection and promoting positive responses following FLT3-TKI therapy.
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Bilwani, Fareena, and Katherine Knight. "Alterations in Bone Marrow Stroma with Aging (36.5)." Journal of Immunology 184, no. 1_Supplement (April 1, 2010): 36.5. http://dx.doi.org/10.4049/jimmunol.184.supp.36.5.
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Abstract B lymphopoiesis arrests in rabbits by 16 weeks of age, and data suggest that the bone marrow (BM) environment is responsible for this. We hypothesize that this arrest is due to differences in the BM stroma of young and adult rabbits. Using limiting dilution analysis to quantify the number of CFU in BM of 2 to 6 wk-old rabbits, we found an 8-10 fold decrease in the number of stromal progenitors by 6 wk-of-age. This decrease in stromal progenitors is reflective of the age-related decline in progenitor B cells in BM. Histology of BM sections reveals trabecular bone formation in young rabbits but not in adults; in contrast, BM from adults shows large amounts of adipose tissue. We tested the capability of stromal progenitors to differentiate into adipocytes or osteoblasts in vitro , and found that stromal progenitors from BM of young rabbits displayed a higher propensity to form oseoblastic colonies than do stromal progenitors from BM of adults, which more readily formed adipocytic colonies. We conclude that with aging, the number of BM stromal progenitors decreases dramatically, and further, that these progenitors from adults more readily differentiate into adipocytes than into osteoblasts. We suggest that these changes in BM are responsible for the arrest of B lymphopoiesis.
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Miyajima, Yurina, Kafi N. Ealey, Yasutaka Motomura, Miho Mochizuki, Natsuki Takeno, Motoko Yanagita, Aris N. Economides, Manabu Nakayama, Haruhiko Koseki, and Kazuyo Moro. "Effects of BMP7 produced by group 2 innate lymphoid cells on adipogenesis." International Immunology 32, no. 6 (March 9, 2020): 407–19. http://dx.doi.org/10.1093/intimm/dxaa013.
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Abstract Group 2 innate lymphoid cells (ILC2s) are type 2 cytokine-producing cells that have important roles in helminth infection and allergic inflammation. ILC2s are tissue-resident cells, and their phenotypes and roles are regulated by tissue-specific environmental factors. While the role of ILC2s in the lung, intestine and bone marrow has been elucidated in many studies, their role in adipose tissues is still unclear. Here, we report on the role of ILC2-derived bone morphogenetic protein 7 (BMP7) in adipocyte differentiation and lipid accumulation. Co-culture of fat-derived ILC2s with pluripotent mesenchymal C3H10T1/2 cells and committed white preadipocyte 3T3-L1 cells resulted in their differentiation to adipocytes and induced lipid accumulation. Co-culture experiments using BMP7-deficient ILC2s revealed that BMP7, produced by ILC2s, induces differentiation into brown adipocytes. Our results demonstrate that BMP7, produced by ILC2s, affects adipocyte differentiation, particularly in brown adipocytes.
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Li, Guan-Wu, Zheng Xu, Shi-Xin Chang, Lei Zhou, Xiao-Yan Wang, Hua Nian, and Xiao Shi. "Influence of Early Zoledronic Acid Administration on Bone Marrow Fat in Ovariectomized Rats." Endocrinology 155, no. 12 (December 1, 2014): 4731–38. http://dx.doi.org/10.1210/en.2014-1359.
Full textAbstract:
Although the primary target cell of bisphosphonates is the osteoclast, increasing attention is being given to other effector cells influenced by bisphosphonates, such as osteoblasts and marrow adipocytes. Early zoledronic acid (ZA) treatment to ovariectomized (OVX) rats has been found to fully preserve bone microarchitecture over time. However, little is known regarding the influence of ZA on marrow adipogenesis. The purpose of this study was to monitor the ability of early administration of ZA in restoring marrow adiposity in an estrogen-deficient rat model. Thirty female Sprague-Dawley rats were randomly divided into sham-operated (SHAM), OVX + vehicle, and OVX + ZA groups (n=10/group). Dual-energy x-ray absorptiometry and water/fat magnetic resonance imaging were performed at baseline, 6 weeks, and 12 weeks after treatment to assess bone mineral density and marrow fat fraction. Serum biochemical markers, bone remodeling, and marrow adipocyte parameters were analyzed using biochemistry, histomorphometry, and histopathology, respectively. The expression levels of osteoblast, adipocyte, and osteoclast-related genes in bone marrow were assessed using RT-PCR. The OVX rats showed marked bone loss, first detected at 12 weeks, but estrogen deficiency resulted in a remarked increase in marrow fat fraction, first detected at 6 weeks compared with the SHAM rats (all P < .001). Similarly, the OVX rats had a substantially larger percent adipocyte area (+163.0%), mean diameter (+29.5%), and higher density (+57.3%) relative to the SHAM rats. Bone histomorphometry, levels of osteoclast-related gene expression, and a serum resorption marker confirmed that ZA significantly suppressed bone resorption activities. Furthermore, ZA treatment returned adipocyte-related gene expression and marrow adipocyte parameters toward SHAM levels. These data suggest that a single dose of early ZA treatment acts to reverse marrow adipogenesis occurring during estrogen deficiency, which may contribute to its capacity to reduce bone loss.
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Marinelli Busilacchi, Elena, Erika Morsia, and Antonella Poloni. "Bone Marrow Adipose Tissue." Cells 13, no. 9 (April 23, 2024): 724. http://dx.doi.org/10.3390/cells13090724.
Full textAbstract:
Bone marrow (BM) acts as a dynamic organ within the bone cavity, responsible for hematopoiesis, skeletal remodeling, and immune system control. Bone marrow adipose tissue (BMAT) was long simply considered a filler of space, but now it is known that it instead constitutes an essential element of the BM microenvironment that participates in homeostasis, influences bone health and bone remodeling, alters hematopoietic stem cell functions, contributes to the commitment of mesenchymal stem cells, provides effects to immune homeostasis and defense against infections, and participates in energy metabolism and inflammation. BMAT has emerged as a significant contributor to the development and progression of various diseases, shedding light on its complex relationship with health. Notably, BMAT has been implicated in metabolic disorders, hematological malignancies, and skeletal conditions. BMAT has been shown to support the proliferation of tumor cells in acute myeloid leukemia and niche adipocytes have been found to protect cancer cells against chemotherapy, contributing to treatment resistance. Moreover, BMAT’s impact on bone density and remodeling can lead to conditions like osteoporosis, where high levels of BMAT are inversely correlated with bone mineral density, increasing the risk of fractures. BMAT has also been associated with diabetes, obesity, and anorexia nervosa, with varying effects on individuals depending on their weight and health status. Understanding the interaction between adipocytes and different diseases may lead to new therapeutic strategies.