Journal articles on the topic 'Bone inhibition'
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1
Ransjö, Maria, and Ulf H. Lerner. "Calcitonin causes a sustained inhibition of protein kinase C-stimulated bone resorption in contrast to the transient inhibition of parathyroid hormone-induced bone resorption." Acta Endocrinologica 123, no. 3 (September 1990): 251–56. http://dx.doi.org/10.1530/acta.0.1230251.
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Abstract. Calcitonin is a well known inhibitor of osteoclastic bone resorption, both in vivo and in vitro. However, it is also known that calcitonin has only a transient inhibitory effect on bone resorption. The mechanism for this so-called "escape from inhibition" phenomenon is not clear. In the present study, the inhibitory effect of calcitonin on phorbol ester-induced bone resorption was examined in cultured neonatal mouse calvaria. Bone resorption was assessed as the release of radioactivity from bones prelabelled in vivo with 45Ca. Two protein kinase C-activating phorbol esters, phorbol-12-myristate-13-acetate and phorbol-12,13-dibutyrate, both stimulated 45Ca release in 120-h cultures at a concentration of 10 nmol/l. Calcitonin (30 nmol/l) inhibited phorbol esterstimulated bone resorption without any "escape from inhibition". This was in contrast to the transient inhibitory effect of calcitonin on bone resorption stimulated by parathyroid hormone (10 nmol/l), prostaglandin E2 (2 μmol/l), and bradykinin (1 μmol/l). Our results suggest that activation of protein kinase C produces a sustained inhibitory effect of calcitonin on bone resorption.
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Zhou, Jiabao, Jennifer M. Down, Christopher N. George, Jessica Murphy, Diane V. Lefley, Claudia Tulotta, Marwa A. Alsharif, Michael Leach, and Penelope D. Ottewell. "Novel Methods of Targeting IL-1 Signalling for the Treatment of Breast Cancer Bone Metastasis." Cancers 14, no. 19 (October 1, 2022): 4816. http://dx.doi.org/10.3390/cancers14194816.
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Breast cancer bone metastasis is currently incurable. Evidence suggests that inhibiting IL-1 signalling with the IL1R antagonist, Anakinra, or the IL1β antibody, Canakinumab, prevents metastasis and almost eliminates breast cancer growth in the bone. However, these drugs increase primary tumour growth. We, therefore, investigated whether targeting other members of the IL-1 pathway (Caspase-1, IL1β or IRAK1) could reduce bone metastases without increasing tumour growth outside of the bone. Inhibition of IL-1 via MLX01 (IL1β secretion inhibitor), VRT043198/VX765 (Caspase-1 inhibitor), Pacritinib (IRAK1 inhibitor) or Anakinra (IL1R antagonist) on tumour cell viability, migration and invasion were assessed in mouse mammary E0771 and Py8119 cells in vitro and on primary tumour growth, spontaneous metastasis and metastatic outgrowth in vivo. In vitro, Inhibition of IL-1 signalling by MLX01, VRT043198 and Anakinra reduced migration of E0771 and Py8119 cells and reversed tumour-derived IL1β induced-increased invasion and migration towards bone cells. In vivo, VX765 and Anakinra significantly reduced spontaneous metastasis and metastatic outgrowth in the bone, whereas MLX01 reduced primary tumour growth and bone metastasis. Pacritinib had no effect on metastasis in vitro or in vivo. Targeting IL-1 signalling with small molecule inhibitors may provide a new therapeutic strategy for breast cancer bone metastasis.
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Deng, Jianhua, Jun Wu, and Yuchang Zhu. "Inhibition of MicroRNA-9 Improves Fracture Healing by Modulating the Bone Morphogenetic Protein-7 Pathway." Pharmacology 104, no. 5-6 (2019): 352–58. http://dx.doi.org/10.1159/000502402.
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We evaluated the effect of microRNA (miR)-9 inhibition on fracture healing in a rat model of femoral fracture. The rats were divided into sham, negative control and miR-9 inhibitor groups. The miR-9 inhibitor group received 30 pmol/mL inhibitor intrathecally for 8 consecutive weeks following surgery-induced femoral fracture. The effect of miR-9 inhibition on fracture healing was estimated by determining the bone mineral density (BMD) and by performing X-ray analysis of the fractured bone. The serum levels of markers of bone formation were estimated by enzyme-linked immunosorbent assay and reverse transcription polymerase chain reaction, and western blotting and immunohistochemical analysis were performed to assess the effect of miR-9 inhibition on fracture healing. The BMD at the fracture site was significantly higher in the miR-9 inhibitor group than in the negative control group. Inhibition of miR-9 blocked the fracture gap and resulted in new callus formation at the fracture site. The serum levels of osteocalcin and bone GLA protein were increased and that of alkaline phosphatase was decreased by inhibition of miR-9 compared to levels in the negative control. However, inhibition of miR-9 significantly increased the mRNA levels of runt-related transcription factor 2 (Runx2) and bone morphogenetic protein 7 (BMP-7) in the bone tissue at the fracture site compared to the negative control group; this result was confirmed by western blotting. In conclusion, miR-9 inhibition enhanced fracture healing by modulating the BMP-7/Runx2 signalling pathway in a rat model of femoral fracture.
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Banu, Jameela, Erika Varela, Ali N. Bahadur, Raheela Soomro, Nishu Kazi, and Gabriel Fernandes. "Inhibition of Bone Loss byCissus quadrangularisin Mice: A Preliminary Report." Journal of Osteoporosis 2012 (2012): 1–10. http://dx.doi.org/10.1155/2012/101206.
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Women drastically loose bone during and after menopause leading to osteoporosis, a disease characterized by low bone mass increasing the risk of fractures with minor trauma. Existing therapies mainly reduce bone resorption, however, all existing drugs have severe side effects. Recently, the focus is to identify alternative medicines that can prevent and treat osteoporosis with minimal or no side effects. We usedCissus quadrangularis(CQ), a medicinal herb, to determine its effects on bone loss after ovariectomy in C57BL/6 mice. Two-month old mice were either sham operated or ovariectomized and fed CQ diet. After eleven weeks, mice were sacrificed and the long bones scanned using pQCT andμCT. In the distal femoral metaphysis, femoral diaphysis, and proximal tibia, control mice had decreased cancellous and cortical bone, while CQ-fed mice showed no significant differences in the trabecular number, thickness, and connectivity density, between Sham and OVX mice, except for cortical bone mineral content in the proximal tibia. There were no changes in the bone at the tibio-fibular junction between groups. We conclude that CQ effectively inhibited bone loss in the cancellous and cortical bones of femur and proximal tibia in these mice.
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Vallet, Sonia, Kishan Patel, Nileshwari Vaghela, Mariateresa Fulciniti, Petter Veiby, Teru Hideshima, Samantha Pozzi, et al. "CCL3 Impairs Osteoblast Function Via Downregulation of Osteocalcin." Blood 114, no. 22 (November 20, 2009): 739. http://dx.doi.org/10.1182/blood.v114.22.739.739.
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Abstract Abstract 739 A common feature of bone disease in cancer is hyperactivity of osteoclasts (OC). However, osteoblast (OB) inhibition is critical to the development of osteolytic lesions. Tumor-OC interactions have been extensively studied, the mechanism of OB inhibition however still remains elusive. Several chemokines are upregulated in the multiple myeloma (MM)/bone microenvironment. CCL3 (MIP-1αa), in particular, mediates MM cell migration and stimulates OC differentiation, directly, by stimulating precursor cell fusion, and indirectly, by inducing OB secretion of RANKL. Here, we investigate whether CCL3 interferes with OB differentiation and activity. In vitro osteoblastogenesis consists of differentiation of alkaline phosphatase (ALP) positive cells, followed by secretion and mineralization of the extracellular matrix. We observed that ALP-positive cells express both CCL3 receptors, CCR1 and CCR5, late in differentiation (40% and 32%, respectively, isotype control 9%). No significant CCL3 secretion was detected in OB culture supernatant, suggesting that paracrine CCL3 may primarily affect matrix mineralization. Indeed, exogenous CCL3 (25 to 100 ng/ml) did not modify OB number, instead it decreased calcium deposition (10% decrease at 25ng/ml, 33% decrease at 50 and 100 ng/ml, p<0.05). We next assessed the expression levels of proteins critical to matrix formation and mineralization including osteopontin, bone-sialoprotein and osteocalcin. Osteopontin expression was not affected by CCL3, while both bone-sialoprotein and osteocalcin were downregulated. Importantly, either continuous exposure to CCL3 or 24h stimulation of mature OB impaired RNA expression of osteocalcin (30% to 80%) and bone-sialoprotein (26% to 60%) but not ALP, confirming that CCL3 interferes with OB function rather than formation. We also observed a correlation between osteocalcin expression by IHC on BM biopsies and CCL3 levels in BM serum of MM patients. These data suggest that MM-derived CCL3 interferes with bone mineralization by inhibiting osteocalcin expression. Using neutralizing antibodies against CCL3 we restored both osteocalcin and bone sialoprotein RNA expression levels in the presence of CCL3. Importantly, pretreatment with a small molecule CCR1 inhibitor, MLN3897 (Millennium Pharmaceuticals) completely abrogated the inhibition on osteocalcin and partially reversed bone-sialoprotein expression, suggesting CCR1 as the main mediator of CCL3 effects. We further verified these results in an in-vivo setting of MM bone disease, using the SCID-hu model. CB17 SCID mice bearing a human fetal bone implant were engrafted with CCL3-expressing INA6 MM cells and treated orally with MLN3897 for a total of 49 doses. After 4 weeks of treatment the bones were harvested and stained for TRAP activity, hematoxylin-eosin and osteocalcin. The number of OC/400x field was significantly reduced in the treated group (2.7 vs 1.9, p<0.05), thus confirming in vivo the anti-osteoclastogenic effect of CCR1 inhibition. Moreover, in the presence of INA6 MM cells osteocalcin levels were downregulated compared to non-injected bones and treatment with the CCR1 inhibitor partially restored osteocalcin expression. These results suggest a new role for the CCL3/CCR1 pathway in the development of osteolytic lesions in MM, as inhibitor of OB function other than OC growth factor. Targeting this pathway represents a promising strategy for the treatment of bone disease. Disclosures: Veiby: Millennium Pharmaceuticals: Employment. Anderson:Millennium: Research Funding. Raje:Astrazeneca, Novartis, Celgene: Research Funding.
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Wada, Teiji. "RANKL inhibition in bone metastases." Folia Pharmacologica Japonica 141, no. 1 (2013): 22–26. http://dx.doi.org/10.1254/fpj.141.22.
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Takayanagi, Hiroshi. "RANKL inhibition -Bone and beyond-." Proceedings for Annual Meeting of The Japanese Pharmacological Society WCP2018 (2018): SY42–1. http://dx.doi.org/10.1254/jpssuppl.wcp2018.0_sy42-1.
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Momenzadeh, Mahnaz, Maryam Khosravian, and Bhaskar VKS Lakkakula. "Potential of renin-angiotensin system inhibition to improve metabolic bone disorders." Journal of Nephropharmacology 10, no. 2 (October 17, 2020): e16-e16. http://dx.doi.org/10.34172/npj.2021.16.
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Metabolic bone disorder is an abnormality of bones indicated by reduced bone mass and high risk of fractures. Several lines of evidence have demonstrated that the local bone tissue renin-angiotensin system (RAS) is directly involved in bone metabolism and influences the bone health. This review aimed to assess the role of RAS in bone metabolism and comparative effectiveness of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) in reducing the bone fractures. In summary, the clinical trials, in vivo studies, and functional - pharmacological experiments suggested that the RAS regulates bone marrow metabolism and influences the bone health. Hence, it warrants further investigation on the role of ACEIs and ARBs in reducing risk fractures.
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Fraser, Christopher C., Kumiko Nagashima, Vito Sasseville, Jim Deeds, Alice McDonald, Chris Simpson, and Yajun Xu. "Selective Rapid B-Cell Depletion In Vivo by Pharmacologic IKK2 Inhibition." Blood 104, no. 11 (November 16, 2004): 2481. http://dx.doi.org/10.1182/blood.v104.11.2481.2481.
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Abstract Studies using genetically deficient mice have revealed that members of the NF-kB family play key roles in B-cell development. IKK2 which activates NF-kB by targeting degradation of IkB, is also required for B-cell development. We have studied the role of IKK2 in hematopoiesis using a chemical specific inhibitor (ML120B). Mice given daily oral dosing of ML120B for 4 days had severe B-cell depletion in spleen and bone marrow. B-cells at all stages (pro-B, pre-B, immature and mature B) were depleted 10 fold in the bone marrow while granulocyte numbers were largely unaffected. IKK2 inhibition in vivo showed selective sensitivity of B-cell progenitors (4 fold decrease) in the marrow compared to myeloid progenitors which were unaffected at an equivalent dose. Foci of cells with an apoptotic morphology were visible in bone marrow and spleen within 6 hours of a single oral dose. Apoptotic cells detected by labeling fragmented DNA were increased within splenic follicles (6 fold) and bone marrow. Also an increase in B220+ / annexin V+ cells and a decrease in pre-B (B220+/IgM−) cells in the marrow were observed. RNA expression studies in the marrow 6 hours after a single oral dose revealed a decrease in IL-7 and increased GM-CSF expression. Image analysis of B220 in spleens within 18 hours of a single dose of an IKK inhibitor revealed decreased follicle size. In order to evaluate hematopoietic progenitor sensitivity to NF-kB inhibition, dose responses to ML120B, panepoxydone (PPD) and proteasome inhibitor Lactacystin (Lcyst) were evaluated in B-cell and myeloid bone marrow colony assays. Inhibitors PPD and Lcyst were more effective at inhibiting B-cell colony growth than myeloid colony growth. In summary, pharmacologic inhibition of IKK2 results in a rapid induction of apoptosis with preferential depletion of B-cells and retention of myeloid cells and progenitors within the bone marrow.
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Kaipatur, N. R., M. Murshed, and M. D. McKee. "Matrix Gla Protein Inhibition of Tooth Mineralization." Journal of Dental Research 87, no. 9 (September 2008): 839–44. http://dx.doi.org/10.1177/154405910808700907.
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Extracellular matrix (ECM) mineralization is regulated by mineral ion availability, proteins, and other molecular determinants. To investigate protein regulation of mineralization in tooth dentin and cementum, and in alveolar bone, we expressed matrix Gla protein (MGP) ectopically in bones and teeth in mice, using an osteoblast/odontoblast-specific 2.3-kb Col1a1 promoter. Mandibles were analyzed by radiography, micro-computed tomography, light microscopy, histomorphometry, and transmission electron microscopy. While bone and tooth ECMs were established in the Col1a1-Mgp mice, extensive hypomineralization was observed, with values of unmineralized ECM from four- to eight-fold higher in dentin and alveolar bone when compared with that in wild-type tissues. Mineralization was virtually absent in tooth root dentin and cellular cementum, while crown dentin showed “breakthrough” areas of mineralization. Acellular cementum was lacking in Col1a1-Mgp teeth, and unmineralized osteodentin formed within the pulp. These results strengthen the view that bone and tooth mineralization is critically regulated by mineralization inhibitors.
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Nakayama, Takayuki, Noriko Mutsuga, and Giovanna Tosato. "FGF2 posttranscriptionally down-regulates expression of SDF1 in bone marrow stromal cells through FGFR1 IIIc." Blood 109, no. 4 (October 31, 2006): 1363–72. http://dx.doi.org/10.1182/blood-2006-06-028217.
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AbstractThe chemokine stromal cell–derived factor-1 (SDF-1) is constitutively expressed by bone marrow stromal cells and plays key roles in hematopoiesis. Fibroblast growth factor 2 (FGF2), a member of the FGF family that plays important roles in developmental morphogenic processes, is abnormally elevated in the bone marrow from patients with clonal myeloid disorders and other disorders where normal hematopoiesis is impaired. Here, we report that FGF2 reduces SDF-1 secretion and protein content in bone marrow stromal cells. By inhibiting SDF-1 production, FGF2 compromises stromal cell support of hematopoietic progenitor cells. Reverse-transcriptase–polymerase chain reaction (RT-PCR) analysis revealed that bone marrow stromal cells express 5 FGF receptors (FGFRs) among the 7 known FGFR subtypes. Blocking experiments identified FGFR1 IIIc as the receptor mediating FGF2 inhibition of SDF-1 expression in bone marrow stromal cells. Analysis of the mechanisms underlying FGF2 inhibition of SDF-1 production in bone marrow stromal cells revealed that FGF2 reduces the SDF-1 mRNA content by posttranscriptionally accelerating SDF-1 mRNA decay. Thus, we identify FGF2 as an inhibitor of SDF-1 production in bone marrow stromal cells and a regulator of stromal cell supportive functions for hematopoietic progenitor cells.
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Mamedova, Elizaveta O., Tatiana A. Grebennikova, Zhanna E. Belaya, and Liudmila Y. Rozhinskaya. "Sclerostin antibodies as novel anabolic therapy for osteoporosis." Osteoporosis and Bone Diseases 21, no. 3 (April 8, 2019): 21–29. http://dx.doi.org/10.14341/osteo10127.
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Osteoporosis medications are divided into two groups: those inhibiting bone resorption and formation (bisphosphonates and denosumab), and those stimulating bone formation i.e. having an anabolic effect. The latter include teriparatide, parathyroid hormone 1-84 and abaloparatide, all of which stimulate bone resorption as well as bone formation, which limits their anabolic effect.
The discovery of sclerostin – the key inhibitor of bone formation – has led to development of the concept that inhibition of this protein could stimulate bone formation. Romosozumab is a human monoclonal antibody to sclerostin that binds to sclerostin and enables Wnt-signaling pathway ligands and their co-receptors to interact with each other, which, in turn, leads to increased bone formation and bone mineral density. Unlike classical anabolic drugs in osteoporosis treatment, romosozumab stimulates bone formation and inhibits bone resorption. In clinical trials, romosozumab showed marked increase in lumbar spine and hip bone mineral density. Presented article contains information about pre-clinical and clinical studies of romosozumab.
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Odes-Barth, Shlomit, Marina Khanin, Karin Linnewiel-Hermoni, Yifat Miller, Karina Abramov, Joseph Levy, and Yoav Sharoni. "Inhibition of Osteoclast Differentiation by Carotenoid Derivatives through Inhibition of the NF-κB Pathway." Antioxidants 9, no. 11 (November 23, 2020): 1167. http://dx.doi.org/10.3390/antiox9111167.
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The bone protective effects of carotenoids have been demonstrated in several studies, and the inhibition of RANKL-induced osteoclast differentiation by lycopene has also been demonstrated. We previously reported that carotenoid oxidation products are the active mediators in the activation of the transcription factor Nrf2 and the inhibition of the NF-κB transcription system by carotenoids. Here, we demonstrate that lycopene oxidation products are more potent than intact lycopene in inhibiting osteoclast differentiation. We analyzed the structure–activity relationship of a series of dialdehyde carotenoid derivatives (diapocarotene-dials) in inhibiting osteoclastogenesis. We found that the degree of inhibition depends on the electron density of the carbon atom that determines the reactivity of the conjugated double bond in reactions such as Michael addition to thiol groups in proteins. Moreover, the carotenoid derivatives attenuated the NF-κB signal through inhibition of IκB phosphorylation and NF-κB translocation to the nucleus. In addition, we show a synergistic inhibition of osteoclast differentiation by combinations of an active carotenoid derivative with the polyphenols curcumin and carnosic acid with combination index (CI) values < 1. Our findings suggest that carotenoid derivatives inhibit osteoclast differentiation, partially by inhibiting the NF-κB pathway. In addition, carotenoid derivatives can synergistically inhibit osteoclast differentiation with curcumin and carnosic acid.
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&NA;. "Imatinib: hypophosphataemia and bone remodelling inhibition." Reactions Weekly &NA;, no. 1102 (May 2006): 4. http://dx.doi.org/10.2165/00128415-200611020-00011.
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OʼDonovan, David A., Giorgio C. La Scala, Iona Leong, Maria Mendes, Marianne Rogers, Kenneth H. Pritzker, Ivan Yeung, Cho Y. Pang, Peter C. Neligan, and Christopher R. Forrest. "Radiation-Induced Craniofacial Bone Growth Inhibition." Plastic and Reconstructive Surgery 129, no. 4 (April 2012): 636e—645e. http://dx.doi.org/10.1097/prs.0b013e31824421b6.
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Seiffert, Martina. "Checkpoint inhibition in the bone marrow." Nature Biomedical Engineering 2, no. 11 (November 2018): 793–94. http://dx.doi.org/10.1038/s41551-018-0319-6.
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Vallet, Soni a., Nileshwari Vaghela, Mariateresa Fulciniti, Petter Veiby, Teru Hideshima, Samantha Pozzi, Loredana Santo, et al. "CCR1 Inhibition Targets Osteoclast-Myeloma Adhesion and Exerts in Vivo Anti-Osteoclast Activity." Blood 112, no. 11 (November 16, 2008): 2757. http://dx.doi.org/10.1182/blood.v112.11.2757.2757.
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Abstract Among the components of the tumor microenvironment, osteoclasts (OC) and bone marrow stromal cells (BMSC) play a key role in stimulating multiple myeloma (MM) cell proliferation via cell-to-cell contact and cytokine secretion. In a vicious loop, MM cells promote OC development and impair osteoblasts (OB) differentiation shaping the microenvironment to support tumor growth and chemoresistance. These effects translate in osteolytic lesions that negatively affect patient quality of life and survival. CCL3 is involved in the pathogenesis of MM bone disease. Indeed, high bone marrow plasma levels of CCL3 correlate with osteolytic lesions in MM and CCL3 has a pro-osteoclastogenic effect. We have previously shown that inhibition of CCL3 receptor, CCR1, results in impaired osteoclastogenesis and blocks the proliferative advantage conferred by OCs to MM cells in vitro. (Vallet et al, Blood 2007) Here, we extend our studies and demonstrate in an in-vivo SCID-hu mouse model the anti-OC effects of MLN3897, a small molecule CCR1 inhibitor (Millennium Pharmaceuticals, Cambridge). CB17 SCID mice bearing a human fetal bone implant engrafted with INA6 MM cells were treated orally with MLN3897 for a total of 49 doses. After 4 weeks of treatment the bones were harvested and stained for TRAP activity and hematoxylin-eosin. The number of OC/400x field was significantly reduced in the treated group (2.7 vs 1.9, p<0.05), thus confirming in vivo the anti-osteoclastogenic effect of CCR1 inhibition. Although a 2-fold inhibition of tumor growth in the treated group was noted, this difference did not reach statistical significance. Our previous data suggested that CCR1 inhibition impaired OC-MM cell adhesion with subsequent reduced MM cell proliferation. Here, we observed a specific effect of CCR1 inhibition on MM cell/OC adhesion rather than BMSCs and fibronectin. Interestingly, these effects translated in anti-proliferative effects of the CCR1 inhibitor in OC-MM cells coculture with no effects in BMSCs-MM coculture, suggesting a specific inhibitory effect on the OC compartment. Ongoing studies to characterize the underlying mechanism of CCR1 inhbition on OC-MM cell adhesion will be presented. Combination approaches to study whether forced OB differentiation by the proteasome inhibitor, bortezomib, will improve BMSC sensitivity to CCR1 inhibition are being studied. These data confirm the specific in vivo anti-OC effects of CCR1 inhibition and will highlight the role of novel combinations by using anti-OC agents like MLN3897 and anabolic drugs like Bortezomib.
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Yaccoby, Shmuel, Wen Ling, Fenghuang Zhan, Ronald Walker, Bart Barlogie, and John D. Shaughnessy. "Antibody-based inhibition of DKK1 suppresses tumor-induced bone resorption and multiple myeloma growth in vivo." Blood 109, no. 5 (October 26, 2006): 2106–11. http://dx.doi.org/10.1182/blood-2006-09-047712.
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Abstract Dickkopf-1 (DKK1), a soluble inhibitor of Wnt signaling secreted by multiple myeloma (MM) cells contributes to osteolytic bone disease by inhibiting the differentiation of osteoblasts. In this study, we tested the effect of anti-DKK1 therapy on bone metabolism and tumor growth in a SCID-rab system. SCID-rab mice were engrafted with primary MM cells expressing varying levels of DKK1 from 11 patients and treated with control and DKK1-neutralizing antibodies for 4 to 6 weeks. Whereas bone mineral density (BMD) of the implanted myelomatous bone in control mice was reduced during the experimental period, the BMD in mice treated with anti-DKK1 increased from pretreatment levels (P < .001). Histologic examination revealed that myelomatous bones of anti-DKK1–treated mice had increased numbers of osteocalcin-expressing osteoblasts and reduced number of multinucleated TRAP-expressing osteoclasts. The bone anabolic effect of anti-DKK1 was associated with reduced MM burden (P < .04). Anti-DKK1 also significantly increased BMD of the implanted bone and murine femur in nonmyelomatous SCID-rab mice, suggesting that DKK1 is physiologically an important regulator of bone remodeling in adults. We conclude that DKK1 is a key player in MM bone disease and that blocking DKK1 activity in myelomatous bones reduces osteolytic bone resorption, increases bone formation, and helps control MM growth.
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Weaver, Samantha R., Hannah P. Fricke, Cynthia Xie, Robert J. Aiello, Julia F. Charles, and Laura L. Hernandez. "Peripartum dietary supplementation of a small-molecule inhibitor of tryptophan hydroxylase 1 compromises infant, but not maternal, bone." American Journal of Physiology-Endocrinology and Metabolism 315, no. 6 (December 1, 2018): E1133—E1142. http://dx.doi.org/10.1152/ajpendo.00198.2018.
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Long-term effects of breastfeeding on maternal bone are not fully understood. Excessive maternal bone loss stimulated by serotonin signaling during lactation may increase bone fragility later in life. We hypothesized that inhibiting nonneuronal serotonin activity by feeding a small-molecule inhibitor of the rate-limiting enzyme in serotonin synthesis [tryptophan hydroxylase 1 (TPH1)] would preserve maternal bone postweaning without affecting neonatal bone. Chow supplemented with the small-molecule TPH1 inhibitor LP778902 (~100 mg/kg) or control chow was fed to C57BL/6 dams throughout pregnancy and lactation, and blood was collected on days 1 and 21 of lactation. Dams returned to a common diet postweaning and were aged to 3 or 9 mo postweaning. Pups were euthanized at weaning. The effect of TPH1 inhibition on dam and pup femoral bone was determined by micro-computed tomography. Peripartum dietary supplementation with LP778902 decreased maternal serum serotonin concentrations ( P = 0.0007) and reduced bone turnover, indicated by serum NH2-terminal propeptide of type I collagen ( P = 0.01) and COOH-terminal collagen cross-links ( P = 0.02) concentrations, on day 21 of lactation. Repressed bone turnover from TPH1 inhibition was not associated with structural changes in maternal femur at 3 or 9 mo postweaning. By contrast, neonates exposed to peripartum LP778902 demonstrated differences in trabecular and cortical femoral bone compared with pups from control dams, with fewer ( P = 0.02) and thinner ( P = 0.001) trabeculae as well as increased trabecular spacing ( P = 0.04). Additionally, cortical porosity was increased ( P = 0.007) and cortical tissue mineral density was decreased ( P = 0.005) in pups of LP778902-treated dams. Small-molecule TPH1 inhibitors should be carefully considered in pregnant and lactating women, given potential risks to neonatal bone development.
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Terpos, Evangelos, Orhan Sezer, Peter Croucher, and Meletios-Athanassios Dimopoulos. "Myeloma bone disease and proteasome inhibition therapies." Blood 110, no. 4 (August 15, 2007): 1098–104. http://dx.doi.org/10.1182/blood-2007-03-067710.
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AbstractBone disease is one of the most debilitating manifestations of multiple myeloma. A complex interdependence exists between myeloma bone disease and tumor growth, creating a vicious circle of extensive bone destruction and myeloma progression. Proteasome inhibitors have recently been shown to promote bone formation in vitro and in vivo. Preclinical studies have demonstrated that proteasome inhibitors, including bortezomib, which is the first-in-class such agent, stimulate osteoblast differentiation while inhibiting osteoclast formation and bone resorption. Clinical studies are confirming these observations. Bortezomib counteracts the abnormal balance of osteoclast regulators (receptor activator of nuclear factor-κB ligand and osteoprotegerin), leading to osteoclast inhibition and decreased bone destruction, as measured by a reduction in markers of bone resorption. In addition, bortezomib stimulates osteoblast function, possibly through the reduction of dickkopf-1, leading to increased bone formation, as indicated by the elevation in bone-specific alkaline phosphatase and osteocalcin. The effect of bortezomib on bone disease is thought to be direct and not only a consequence of the agent's antimyeloma properties, making it an attractive agent for further investigation, as it may combine potent antimyeloma activity with beneficial effects on bone. However, the clinical implication of these effects requires prospective studies with specific clinical end points.
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Komatsu, Koichiro, Akemi Shimada, Tatsuya Shibata, Satoshi Wada, Hisashi Ideno, Kazuhisa Nakashima, Norio Amizuka, Masaki Noda, and Akira Nifuji. "Alendronate promotes bone formation by inhibiting protein prenylation in osteoblasts in rat tooth replantation model." Journal of Endocrinology 219, no. 2 (November 2013): 145–58. http://dx.doi.org/10.1530/joe-13-0040.
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Bisphosphonates (BPs) are a major class of antiresorptive drug, and their molecular mechanisms of antiresorptive action have been extensively studied. Recent studies have suggested that BPs target bone-forming cells as well as bone-resorbing cells. We previously demonstrated that local application of a nitrogen-containing BP (N-BP), alendronate (ALN), for a short period of time increased bone tissue in a rat tooth replantation model. Here, we investigated cellular mechanisms of bone formation by ALN. Bone histomorphometry confirmed that bone formation was increased by local application of ALN. ALN increased proliferation of bone-forming cells residing on the bone surface, whereas it suppressed the number of tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts in vivo. Moreover, ALN treatment induced more alkaline phosphatase-positive and osteocalcin-positive cells on the bone surface than PBS treatment. In vitro studies revealed that pulse treatment with ALN promoted osteocalcin expression. To track the target cells of N-BPs, we applied fluorescence-labeled ALN (F-ALN) in vivo and in vitro. F-ALN was taken into bone-forming cells both in vivo and in vitro. This intracellular uptake was inhibited by endocytosis inhibitors. Furthermore, the endocytosis inhibitor dansylcadaverine (DC) suppressed ALN-stimulated osteoblastic differentiation in vitro and it suppressed the increase in alkaline phosphatase-positive bone-forming cells and subsequent bone formation in vivo. DC also blocked the inhibition of Rap1A prenylation by ALN in the osteoblastic cells. These data suggest that local application of ALN promotes bone formation by stimulating proliferation and differentiation of bone-forming cells as well as inhibiting osteoclast function. These effects may occur through endocytic incorporation of ALN and subsequent inhibition of protein prenylation.
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Teramachi, Jumpei, Masahiro Hiasa, Asuka Oda, Hirofumi Tenshin, Ryota Amachi, Takeshi Harada, Derek Hanson, et al. "Pim Inhibition Suppresses Osteoclastogenesis and Tumor Growth in Myeloma." Blood 126, no. 23 (December 3, 2015): 4203. http://dx.doi.org/10.1182/blood.v126.23.4203.4203.
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Abstract Devastating bone destruction in multiple myeloma (MM) still remains a significant clinical problem. In pursuing factors responsible for MM tumor expansion and bone destruction, we found that the serine/threonine kinase Pim-2 is constitutively over-expressed as an anti-apoptotic mediator, and further up-regulated in MM cells when cocultured with bone marrow stromal cells or osteoclasts (OCs) (Leukemia, 2011). We also demonstrated that Pim inhibition is able to induce bone formation while suppressing MM tumor growth (Leukemia, 2015). However, the impact of Pim inhibition on MM-induced bone resorption remains unknown. Therefore, the present study was undertaken to clarify the role of Pim-2 in osteoclastogenesis enhanced in MM and the therapeutic effects of Pim inhibition on mutual interaction between MM cells and OCs. Pim-2 was highly expressed almost exclusively in cathepsin K-positive mature OCs on the surface of bone but not in other bone marrow cells in normal mouse bone tissues. RANK ligand and TNF-α induced the expression of Pim-2 in monocytes and RAW264.7 preosteoclastic cells at mRNA and protein levels. Inhibitors of the classical NF-κB pathway, SN50 or IMG2001, abolished Pim-2 up-regulation in RAW264.7 cells by RANK ligand or TNF-α, while Pim inhibition marginally affected the nuclear translocation of NF-κB subunits, p50 and p65, as well as the promoter activity of NF-κB, suggesting Pim-2 up-regulation downstream of the NF-κB pathway. Pim-2 appeared to be up-regulated along with c-fos, NFATc1 and cathepsin K during osteoclastogenesis. The Pim inhibitor SMI-16a potently suppressed the RANK ligand-induced expression of c-fos, NFATc1 and cathepsin K in RAW264.7 cells, and abolished osteoclastogenesis and bone resorption enhanced by MM cell conditioned media on hydroxyapatite-coated dishes. Furthermore, the Pim inhibition was found to suppress [Ca2+ ]i oscillation and thereby nuclear translocation of NFATc1, a critical transcription factor for osteoclastogenesis. MM cells and acid-producing OCs are mutually interacted in bone lesions to enhance MM tumor growth and bone destruction while creating an acidic milieu, thereby forming a progressive vicious cycle. Pim-2 was also up-regulated in MM cells when cocultured with OCs as well as bone marrow stromal cells, and to lesser extent merely by acidic conditions. Interestingly, acidic conditions rather preferentially enhanced the cytotoxic effects of the Pim inhibitor SMI-16a on MM cells even in cocultures with OCs or bone marrow stromal cells. Finally, treatment with SMI-16a reduced OC numbers in bone lesions together with tumor reduction and the restoration of bone formation in mouse MM models with intra-tibial injection of murine 5TGM1 MM cells. These results collectively demonstrated that Pim-2 play a critical role in osteoclastogenesis and tumor growth in acidic bone lesions in MM, and further corroborated that Pim-2 is a pivotal therapeutic target for MM bone disease and tumor progression. Disclosures Abe: Novartis Pharma K.K.: Speakers Bureau; Takeda Pharmaceutical Company Limited: Research Funding; Kyowa Hakko Kirin Company, Limited: Research Funding; Astellas Pharma Inc.: Research Funding; Ono Pharmaceutical Co.,Ltd.: Research Funding; GlaxoSmithKline plc: Research Funding.
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Lee, Yongjin, Vipada Kantayos, Jin-Suk Kim, Eui-Shik Rha, Young-Jin Son, and So-Hyeon Baek. "Inhibitory Effects of Protopanaxadiol-Producing Transgenic Rice Seed Extracts on RANKL-Induced Osteoclast Differentiation." Life 12, no. 11 (November 14, 2022): 1886. http://dx.doi.org/10.3390/life12111886.
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(1) Background: Osteoporosis is a disease in which bones are weakened and fractured easily because of various factors. It is mainly observed in elderly and postmenopausal women, and it continues to carry high economic costs in aging societies. Normal bone maintains a healthy state through a balanced process of osteoclast suppression and osteoblast activation; (2) Methods: In this study, osteoclast inhibition was induced by inhibiting osteoclast differentiation using ginseng protopanaxadiol-enriched rice (PPD-rice) seed extract. To analyze the effect of PPD-rice extract on the inhibition of osteoclast differentiation, bone marrow macrophages extracted from mice were treated with PPD-rice and Dongjin seed (non-transformed rice) extracts and analyzed for the inhibition of osteoclast differentiation; (3) Results: The results illustrated that PPD-rice extract reduced the transcription and translation of NFATc1, a modulator of osteoclast formation, decreased the mRNA expression of various osteoclast differentiation marker genes, and reduced osteoclast activity. Moreover, the bone resorptive activity of osteoclasts was diminished by PPD-rice extract on Osteo Assay plates; (4) Conclusions: Based on these results, PPD-rice extract is a useful candidate therapeutic agent for suppressing osteoclasts, an important component of osteoporosis, and it could be used as an ingredient in health supplements.
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Feng, Rentian, Xiangao Huang, G. David Roodman, Selina Chen-Kiang, and Suzanne Lentzsch. "Inhibition of Cdk4/6 by PD 0332991 Results in Abrogation of Osteoclast Formation." Blood 112, no. 11 (November 16, 2008): 3676. http://dx.doi.org/10.1182/blood.v112.11.3676.3676.
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Abstract Multiple myeloma (MM) is characterized by increased osteoclast activity resulting in bone destruction and development of lytic lesions. Despite overall survival achieved by new treatment modalities, new drugs are required to specifically and effectively inhibit bone destruction. PD 0332991 is a selective small molecule inhibitor of cyclin-dependent kinase (Cdk)4 and Cdk6 with oral bioavailability. We have demonstrated recently that inhibition of Cdk4/6 by PD 0332991 effectively controls MM tumor expansion in animal models and sensitizes chemoresistant MM tumor cells to bortezomib killing despite protection by bone marrow stromal cells. Currently clinical phase I/II trials are ongoing to test the efficacy of the combination of PD 0332991 and bortezomib. Selective inhibition of Cdk4/6 by PD 0332991 leads to sustained G1 arrest but not apoptosis, and this appears to be cell type-specific. Consistent with these findings, PD 0332991 is well tolerated in MM patients. On this basis, we address the possibility that PD 0332991, alone and in combination with bortezomib, may inhibit osteoclastogenesis, by culturing non-adherent mononuclear bone marrow cells from MM patients cultured in the presence of M-CSF and RANKL for three weeks. Treatment of human osteoclast cultures with PD 0332991 for 3 weeks decreased osteoclast formation in a dose-dependent manner with an IC50 50 nM. The combination of PD 0332991 and bortezomib led to synergistic inhibition of osteoclast formation and completely abrogated osteoclastogenesis with low dose PD 0332991 (25 nM) and bortezomib (2 nM). Furthermore, we show in a time course study that treatment with PD 0332991 for the first week, but not the second or third week, was sufficient to inhibit osteoclast formation. PD 0332991 is the only known selective inhibitor of Cdk4 and Cdk6, which at concentration below 5 uM does not cross react with at least 38 kinases or induce apoptosis. Taken together, our data suggest that by inducing G1 arrest and inhibiting progenitor expansion, PD 0332991 is a powerful and selective inhibitor for osteoclastogenesis. We propose that targeting Cdk4/6 with PD 0332291 in combination therapy is a promising therapeutic strategy to improve bone integrity in MM.
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Zhao, Ming, Seon-Yle Ko, Jin-Hua Liu, Di Chen, Jianghong Zhang, Baolin Wang, Stephen E. Harris, Babatunde O. Oyajobi, and Gregory R. Mundy. "Inhibition of Microtubule Assembly in Osteoblasts Stimulates Bone Morphogenetic Protein 2 Expression and Bone Formation through Transcription Factor Gli2." Molecular and Cellular Biology 29, no. 5 (December 22, 2008): 1291–305. http://dx.doi.org/10.1128/mcb.01566-08.
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ABSTRACT Bone morphogenetic protein 2 (BMP-2) is essential for postnatal bone formation and fracture repair. By screening chemical libraries for BMP-2 mimics using a cell-based assay, we identified inhibitors of microtubule assembly as stimulators of BMP-2 transcription. These microtubule inhibitors increased osteoblast differentiation in vitro, stimulated periosteal bone formation when injected locally over murine calvaria, and enhanced trabecular bone formation when administered systemically in vivo. To explore molecular mechanisms mediating these responses, we examined effects of microtubule inhibitors on the hedgehog (Hh) pathway, since this pathway is known to regulate BMP-2 transcription in osteoblasts and microtubules have been shown to be involved in Hh signaling in Drosophila. Here we show that in osteoblasts, inhibition of microtubule assembly increased cytoplasmic levels and transcriptional activity of Gli2, a transcriptional mediator of Hh signaling that we have previously shown to enhance BMP-2 expression in osteoblasts (M. Zhao et al., Mol. Cell. Biol. 26:6197-6208, 2006). Microtubule inhibition blocked β-TrCP-mediated proteasomal processing of Gli2 in osteoblasts. In summary, inhibition of microtubule assembly enhances BMP-2 gene transcription and subsequent bone formation, in part, through inhibiting proteasomal processing of Gli2 and increasing intracellular Gli2 concentrations.
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Gebru, Yoseph, Teng-Yue Diao, Hai Pan, Emmanuel Mukwaya, and Yan Zhang. "Potential of RAS Inhibition to Improve Metabolic Bone Disorders." BioMed Research International 2013 (2013): 1–6. http://dx.doi.org/10.1155/2013/932691.
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Metabolic bone disorder is usually caused by abnormalities of minerals and hormones metabolism. Recently, it has been proved by several studies that the renin-angiotensin system (RAS) in local bone tissue is directly involved in bone metabolism. Activation of skeletal RAS plays an important role in bone metabolic disorders. Based onin vitro,in vivo, and clinical studies, this review explains the roles of RAS in bone metabolism and also covers the potential approaches and beneficial effects of RAS inhibition on bone health. Differential strategies for inhibiting RAS can be employed to maintain bone health, which are attributed primarily to the reduced level of angiotensin II (AngII) and suppressed stimulation of the AngII signaling pathway. The use of renin inhibitors, angiotensin-converting enzyme inhibitors, and AngII receptor blockers either individually or in combination with each other could have promising results in fighting bone metabolic disorders associated with other cardiovascular diseases as well as independent bone injuries.
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Knowles. "The Adenosine A2B Receptor Drives Osteoclast-Mediated Bone Resorption in Hypoxic Microenvironments." Cells 8, no. 6 (June 21, 2019): 624. http://dx.doi.org/10.3390/cells8060624.
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Osteoclast-mediated bone destruction is amplified in the hypoxic synovial microenvironment of rheumatoid arthritis (RA). This increased bone resorption is driven by the hypoxia-inducible transcription factor HIF. We identified hypoxic induction of the HIF-regulated adenosine A2B receptor in primary human osteoclasts (mRNA, 3.8-fold increase, p < 0.01) and sought to identify the role(s) of purinergic signaling via this receptor in the bone resorption process. Primary human osteoclasts were differentiated from CD14+ monocytes and exposed to hypoxia (2% O2) and A2B receptor inhibitors (MRS1754, PSB603). The hypoxic increase in bone resorption was prevented by the inhibition of the A2B receptor, at least partly by the attenuation of glycolytic and mitochondrial metabolism via inhibition of HIF. A2B receptor inhibition also reduced osteoclastogenesis in hypoxia by inhibiting early cell fusion (day 3–4, p < 0.05). The A2B receptor is only functional in hypoxic or inflammatory environments when the extracellular concentrations of adenosine (1.6-fold increase, p < 0.05) are sufficient to activate the receptor. Inhibition of the A2B receptor under normoxic conditions therefore did not affect any parameter tested. Reciprocal positive regulation of HIF and the A2B receptor in a hypoxic microenvironment thus enhances glycolytic and mitochondrial metabolism in osteoclasts to drive increased bone resorption. A2B receptor inhibition could potentially prevent the pathological osteolysis associated with hypoxic diseases such as rheumatoid arthritis.
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Dayyani, Farshid, Nila Parikh, Jian H. Song, John C. Araujo, Joan M. Carboni, Marco M. Gottardis, Geralyn C. Trudel, Christopher Logothetis, and Gary E. Gallick. "Inhibition of Src and insulin/insulin-like growth factor-1 receptor (IR/IGF-1R) on tumors and bone turnover in prostate cancer (PCa) models in vivo compared with inhibition of either kinase alone." Journal of Clinical Oncology 30, no. 5_suppl (February 10, 2012): 61. http://dx.doi.org/10.1200/jco.2012.30.5_suppl.61.
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61 Background: The Src and IGF-1R axes are aberrantly activated in both PCa and the microenvironment of bone metastases. Dasatinib and BMS-754807 are clinically promising small molecule inhibitors with high potency against Src family kinases (SFK) and IR/IGF-1R, respectively. Based on a phase I/II clinical trial in which 9/19 pts treated with docetaxel + dasatinib were increased in serum IGF-1 levels after one cycle, the aim of this study was to establish potential antitumor cooperativity of inhibiting both IGF-1R and Src in experimental PCa models in vitro and in mice. Methods: Inhibition of Src and IGF-1R pathways was accomplished by pharmacologic agents (dasatinib against Src and BMS-754807 against IR/IGF-1R) as well as by shRNA, in PC3 and LNCaP cells. In vivo studies were done after orthotopic and intratibial injection of PC3 cells in nude mice. Results: SFK inhibition decreased proliferation and migration of PCa cells whereas IGF-1R blockade induced apoptosis. All anti-tumor effects were enhanced by dual blockade. IGF-1 induced phosphorylation of Akt1 and 2. Only Akt 1 phosphorylation was decreased by dasatinib; whereas Akt 1 and 2 phosphorylation were completely abrogated by the combination. Dasatinib and BMS-754807 inhibited orthotopic in vivo tumor growth of PC3 cells more potently than either inhibitor alone. Similarly, intratibial tumor growth and bone destruction was significantly reduced with the drug combination, accompanied by a decrease in serum bone turnover markers alkaline phosphatase and N-telopeptide. Conclusions: Dual inhibition of Src and IGF-1R has greater anti-tumor effect in PCa cells compared to inhibiting either alone. In the presence of IGF-1, dasatinib and BMS-754807 are necessary to inhibit IGF-1-induced phosphorylation of Akt1 and 2 in tumor cells in culture. In intratibial models, decreased bone turnover markers in serum support the concept of targeting both the epithelial and bone microenvironment. The combination of dasatinib and BMS-754807 may be a rational therapeutic approach in PCa by blocking complementary processes of tumor growth and progression.
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Kim, Tae-Ho, Eui Kyun Park, Man-Il Huh, Hong Kyun Kim, Shin-Yoon Kim, and Sang-Han Lee. "Rhus javanicaGall Extract Inhibits the Differentiation of Bone Marrow-Derived Osteoclasts and Ovariectomy-Induced Bone Loss." Evidence-Based Complementary and Alternative Medicine 2016 (2016): 1–7. http://dx.doi.org/10.1155/2016/3284704.
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Inhibition of osteoclast differentiation and bone resorption is a therapeutic strategy for the management of postmenopausal bone loss. This study investigated the effects ofRhus javanica(R. javanica) extracts on bone marrow cultures to develop agents from natural sources that may prevent osteoclastogenesis. Extracts ofR. javanica(eGr) cocoons spun byRhus javanica(Bell.) Baker inhibited the osteoclast differentiation and bone resorption. The effects of aqueous extract (aeGr) or 100% ethanolic extract (eeGr) on ovariectomy- (OVX-) induced bone loss were investigated by various biochemical assays. Furthermore, microcomputed tomography (µCT) was performed to study bone remodeling. Oral administration of eGr (30 mg or 100 mg/kg/day for 6 weeks) augmented the inhibition of femoral bone mineral density (BMD), bone mineral content (BMC), and other factors involved in bone remodeling when compared to OVX controls. Additionally, eGr slightly decreased bone turnover markers that were increased by OVX. Therefore, it may be suggested that the protective effects of eGr could have originated from the suppression of OVX-induced increase in bone turnover. Collectively, the findings of this study indicate that eGr has potential to activate bone remodeling by inhibiting osteoclast differentiation and bone loss.
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Lung, Hsuan, Tania Moody, Kelly Wentworth, Misun Kang, Sunita Ho, and Edward Hsiao. "Global Wnt Inhibition With a Porcupine Inhibitor Decreases Established Trabecular Bone in a Mouse Model of Fibrous Dysplasia." Journal of the Endocrine Society 5, Supplement_1 (May 1, 2021): A234. http://dx.doi.org/10.1210/jendso/bvab048.475.
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Abstract Background: G protein-coupled receptors (GPCRs) mediate a wide spectrum of physiological functions, including bone development and remodeling. Fibrous dysplasia (FD) is a common skeletal dysplasia caused by increased Gs-GPCR signaling and characterized by fibrotic expansile bone lesions. FD has no effective medical treatments. Our prior studies used the ColI(2.3)+/Rs1+ mouse model where osteoblastic-cell Gs signaling induced a dramatic FD-like phenotype and increased Wnt signaling, which we hypothesized is a major driver of the phenotype. Furthermore, we previously showed that blocking Rs1 expression could reverse the abnormal bone phenotype, providing proof-of-concept for finding therapies for FD. Methods: Long bone stromal cells from wildtype and ColI(2.3)+/Rs1+ 9-week-old male mice were analyzed by single-cell RNAseq to identify potential cellular sources of Wnt ligands. We compared these findings with global inhibition of Wnt activity by oral administration of the porcupine inhibitor LGK974 to ColI(2.3)+/Rs1+ mice. These mice were analyzed by histology and micro-computed tomography (micro-CT). Results: Control and ColI(2.3)+/Rs1+ bones showed similar scRNAseq results, except for a large expansion of osteoblastic lineage cells and increased differential expression (DE) genes in this cluster. Expression of Gi-GPCRs was increased, potentially as compensation for the strong Gs-GPCR pathway activation induced by Rs1 expression. We also found increased GH/IGF1 pathway activation in the osteoblastic cluster, and expression of multiple Wnt ligands within multiple cell clusters. We also identified a cell population unique to the ColI(2.3)+/Rs1+ FD-like bone lesions. Broad Wnt production inhibition of porcupine by LGK974 induced dose-dependent resorption of the abnormal FD bone shown by decreased bone volume and trabecular thickness; however, the fibrocellular infiltrate in the ColI(2.3)+/Rs1+ mice was still present. Conclusions: FD-like bones of ColI(2.3)+/Rs1+ mice showed broad activation of Wnt signaling in multiple cell types, suggesting both cell autonomous and non-cell autonomous activity. Broad Wnt inhibition decreased established FD-like trabecular bone, but the fibrocellular infiltrate did not fully reverse. These results suggest distinct roles of Gs-GPCR and Wnt signaling in FD pathogenesis.
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Muñoz-Garcia, Javier, Jorge William Vargas-Franco, Bénédicte Brounais-Le Royer, Denis Cochonneau, Jérôme Amiaud, Marie-Françoise Heymann, Dominique Heymann, and Frédéric Lézot. "Inhibiting Endothelin Receptors with Macitentan Strengthens the Bone Protective Action of RANKL Inhibition and Reduces Metastatic Dissemination in Osteosarcoma." Cancers 14, no. 7 (March 30, 2022): 1765. http://dx.doi.org/10.3390/cancers14071765.
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Current treatments for osteosarcoma, combining conventional polychemotherapy and surgery, make it possible to attain a five-year survival rate of 70% in affected individuals. The presence of chemoresistance and metastases significantly shorten the patient’s lifespan, making identification of new therapeutic tools essential. Inhibiting bone resorption has been shown to be an efficient adjuvant strategy impacting the metastatic dissemination of osteosarcoma, tumor growth, and associated bone destruction. Unfortunately, over-apposition of mineralized matrix by normal and tumoral osteoblasts was associated with this inhibition. Endothelin signaling is implicated in the functional differentiation of osteoblasts, raising the question of the potential value of inhibiting it alone, or in combination with bone resorption repression. Using mouse models of osteosarcoma, the impact of macitentan, an endothelin receptor inhibitor, was evaluated regarding tumor growth, metastatic dissemination, matrix over-apposition secondary to RANKL blockade, and safety when combined with chemotherapy. The results showed that macitentan has no impact on tumor growth or sensitivity to ifosfamide, but significantly reduces tumoral osteoid tissue formation and the metastatic capacity of the osteosarcoma. To conclude, macitentan appears to be a promising therapeutic adjuvant for osteosarcoma alone or associated with bone resorption inhibitors.
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Lin, Neng-Yu, Chih-Wei Chen, Rosebeth Kagwiria, Ruifang Liang, Christian Beyer, Alfiya Distler, Julia Luther, Klaus Engelke, Georg Schett, and Jörg HW Distler. "Inactivation of autophagy ameliorates glucocorticoid-induced and ovariectomy-induced bone loss." Annals of the Rheumatic Diseases 75, no. 6 (June 25, 2015): 1203–10. http://dx.doi.org/10.1136/annrheumdis-2015-207240.
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ObjectivesAutophagy has recently been shown to regulate osteoclast activity and osteoclast differentiation. Here, we aim to investigate the impact of autophagy inhibition as a potential therapeutic approach for the treatment of osteoporosis in preclinical models.MethodsSystemic bone loss was induced in mice by glucocorticoids and by ovariectomy (OVX). Autophagy was targeted by conditional inactivation of autophagy-related gene 7 (Atg7) and by treatment with chloroquine (CQ). Bone density was evaluated by microCT. The role of autophagy on osteoclastogenesis was analysed by osteoclastogenesis and bone resorption assays. The quantification of receptor activator of nuclear factor κ B ligand and osteoprotegerin proteins in cocultures was performed using ELISA whereas that of osteoclast and osteoblast differentiation markers was by qPCR.ResultsSelective deletion of Atg7 in monocytes from Atg7fl/fl_x_LysM-Cre mice mitigated glucocorticoid-induced and OVX-induced osteoclast differentiation and bone loss compared with Atg7fl/fl littermates. Pharmacological inhibition of autophagy by treatment with CQ suppressed glucocorticoid-induced osteoclastogenesis and protected mice from bone loss. Similarly, inactivation of autophagy shielded mice from OVX-induced bone loss. Inhibition of autophagy led to decreased osteoclast differentiation with lower expression of osteoclast markers such as NFATc1, tartrate-resistant acid phosphatase, OSCAR and cathepsin K and attenuated bone resorption in vitro. In contrast, osteoblast differentiation was not affected by inhibition of autophagy.ConclusionsPharmacological or genetic inactivation of autophagy ameliorated glucocorticoid-induced and OVX-induced bone loss by inhibiting osteoclastogenesis. These findings may have direct translational implications for the treatment of osteoporosis, since inhibitors of autophagy such as CQ are already in clinical use.
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Zang, Y., J. H. Song, S. H. Oh, J. W. Kim, M. N. Lee, X. Piao, J. W. Yang, et al. "Targeting NLRP3 Inflammasome Reduces Age-Related Experimental Alveolar Bone Loss." Journal of Dental Research 99, no. 11 (June 12, 2020): 1287–95. http://dx.doi.org/10.1177/0022034520933533.
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The cause of chronic inflammatory periodontitis, which leads to the destruction of periodontal ligament and alveolar bone, is multifactorial. An increasing number of studies have shown the clinical significance of NLRP3-mediated low-grade inflammation in degenerative disorders, but its causal linkage to age-related periodontitis has not yet been elucidated. In this study, we investigated the involvement of the NLRP3 inflammasome and the therapeutic potential of NLRP3 inhibition in age-related alveolar bone loss by using in vivo and in vitro models. The poor quality of alveolar bones in aged mice was correlated with caspase-1 activation by macrophages and elevated levels of IL-1β, which are mainly regulated by the NLRP3 inflammasome, in periodontal ligament and serum, respectively. Aged mice lacking Nlrp3 showed better bone mass than age-matched wild-type mice via a way that affects bone resorption rather than bone formation. In line with this finding, treatment with MCC950, a potent inhibitor of the NLRP3 inflammasome, significantly suppressed alveolar bone loss with reduced caspase-1 activation in aged mice but not in young mice. In addition, our in vitro studies showed that the addition of IL-1β encourages RANKL-induced osteoclastogenesis from bone marrow–derived macrophages and that treatment with MCC950 significantly suppresses osteoclastic differentiation directly, irrelevant to the inhibition of IL-1β production. Our results suggest that the NLRP3 inflammasome is a critical mediator in age-related alveolar bone loss and that targeting the NLRP3 inflammasome could be a novel option for controlling periodontal degenerative changes with age.
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Lillard, James, Rajesh Singh, Praveen Sharma, and Shailesh Singh. "CXCL13 inhibition prevents bone metastasis in hormone-refractory prostate cancer (133.8)." Journal of Immunology 184, no. 1_Supplement (April 1, 2010): 133.8. http://dx.doi.org/10.4049/jimmunol.184.supp.133.8.
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Abstract We have recently reported, chemokine receptor CXCR5 and its ligand CXCL13 expression positively correlates with prostate tumor staging. We have also noted differential expression of CXCR5 by prostate cancer (PCa) cell lines. By virtue of the presence of elevated CXCL13 levels in patient serum, CXCL13 secretion by bone marrow endothelium, and expression of CXCR5 on the surface of PCa cells, we hypothesized that gradient-dependent CXCR5-CXCL13 interactions are responsible in part for PCa cell bone metastases and inhibition of this axis may prove beneficial for prevention of bone metastasis and tumor progression. Luciferase-expressing PC3 cells were injected into the right carotid artery or directly into the tibia of nude mice. Before and after the development of bone metastases, groups were treated with control or anti-CXCL13 antibodies every third day and monitored for tumor progression or regression by non-invasive bioluminescent and microCT in vivo imaging. We demonstrate CXCL13 is present in bone marrow of xenograft tumor-bearing mice following intra-cardiac /intra-tibial injection of PC3 cells. This hormone-refractory PCa cell line established skeletal (osteolytic) metastases and tumor growth, but CXCL13 blockade significantly delayed prostate tumor formation, osteolysis, and spread to bones as well as growth, than compared to mice treated with control antibody. In conclusion, our study shows that the CXCL13-CXCR5 axis supports PCa bone metastasis and growth.
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Vanderkerken, Karin, Satya Medicherla, Les Coulton, Benjamin Van Camp, Andy Protter, Linda Higgins, Eline Menu, and Peter Croucher. "Inhibition of p38α MAPK Reduces Tumor Burden, Prevents the Development of Myeloma Bone Disease, and Increases Survival in the 5T2 and 5T33 Murine Models of Myeloma." Blood 108, no. 11 (November 16, 2006): 3436. http://dx.doi.org/10.1182/blood.v108.11.3436.3436.
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Abstract The bone microenvironment plays a critical role in supporting the growth and survival of myeloma cells and the development of osteolytic bone disease. Signalling through p38 α MAPK mediates synthesis of myeloma cell survival factors by stromal cells; whereas, inhibiting p38 α MAPK reduces myeloma cell proliferation and inhibits osteoclast formation in vitro. However, it is unclear whether p38 α MAPK inhibition will prevent the growth and survival of myeloma cells and the bone disease in vivo. The aim of this study was to determine whether SCIO-469, a selective p38 α MAPK inhibitor, would inhibit myeloma growth and prevent the development of bone disease in the 5TMM syngeneic models of myeloma. Treatment of 5TMM cells, in vitro, with SCIO-469 resulted in a clear inhibition of p38 phosphorylation, as assessed by Western blotting and an inhibition up to 35% of stromal cell induced 5T33MM proliferation. Injection of 5T2MM murine myeloma cells into C57Bl/KaLwRij mice resulted in the growth of myeloma in bone and the development of bone disease characterized by increased osteoclast surface (p<0.05), a reduction in cancellous bone (p<0.01) and the presence of osteolytic bone lesions on x-ray (p<0.01). Treatment of 5T2MM-bearing mice with SCIO-469 (150mg/kg in the diet, therapeutical treatment from paraprotein detection) resulted in a 42% decrease in serum paraprotein and prevented development of osteolytic lesions (p<0.01). Injection of 5T33MM cells into C57Bl/KaLwRij mice also resulted in the development of myeloma but not associated bone disease. Treatment of 5T33MM-bearing mice from the time of tumor cell injection with SCIO-469 resulted in a decrease in serum paraprotein (8.8+/−1.4g/dl to 0.04+/− 0.03g/dl, p<0.001) and a reduction in the proportion of tumor cells in the bone marrow (67 +/− 8.1% to 1.09 +/− 0.58%, p<0.001). Kaplan-Meier analysis demonstrated an increase in disease-free survival (veh=27.5 days vs 96 days, p<0.001) after treatment of the mice with SCIO-469. These data demonstrate that targeting p38 α MAPK with SCIO-469 is associated with an anti-myeloma effect, which indirectly prevents the development of myeloma bone disease.
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Zhang, Junhe, Licheng Zhang, Meng Xu, Lihai Zhang, Peifu Tang, and Chuanlu Jiang. "Murine RANK Protein’s Inhibition of Bone Resorption." Journal of Craniofacial Surgery 22, no. 6 (November 2011): 2084–89. http://dx.doi.org/10.1097/scs.0b013e3182326d99.
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Wang, Chenchao, Bharti Bisht, Jia Shen, Soonchu Lee, Yulong Zhang, Hsin Chuan Pan, Justine Tanjaya, Emily A. Berthiaume, Andrew L. Da Lio, and Chia Soo. "PPARγ Inhibition Impairs BMP2-Mediated Bone Repair." Journal of the American College of Surgeons 225, no. 4 (October 2017): e37-e38. http://dx.doi.org/10.1016/j.jamcollsurg.2017.07.618.
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Nassar, Carlos Augusto, Patrícia Oehlmeyer Nassar, Patrícia Maria Nassar, and Luis Carlos Spolidorio. "Selective cyclooxygenase-2 inhibition prevents bone resorption." Brazilian Oral Research 19, no. 1 (March 2005): 36–40. http://dx.doi.org/10.1590/s1806-83242005000100007.
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The aim of the present work was to evaluate the effect of a selective cyclooxygenase-2 (COX-2) inhibitor (meloxicam) on the alveolar bone loss progression in experimentally induced periodontitis. Forty (40) Wistar rats were separated into 8 experimental groups (n = 5). Cotton ligatures were placed at the gingival margin level of the lower right first molars of some rats. Four groups were treated for 5 or 15 days with an oral dose of 15 mg/kg of body weight/day of the selective COX-2 inhibitor. The other groups were used as positive control (sham) or negative control in each experimental period. Standardized digital radiographs were taken after sacrifice at 5 and 15 days to measure the amount of bone loss at the mesial root surface of the first molar tooth in each rat. The treatment with meloxicam did not induce weight alteration or other visible systemic manifestations. One way analysis of variance (ANOVA) indicated that groups treated with meloxicam, after 5 days, had significantly less alveolar bone loss (p < 0.05) when compared with control groups. On the other hand, no significant differences in bone loss were observed after 15 days of treatment with meloxicam. These data provide evidence that systemic therapy with meloxicam can modify the progression of experimentally induced periodontitis in rats during the initial experimental period.
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Tajima, Kosuke, Hironari Takaishi, Jiro Takito, Takahide Tohmonda, Masaki Yoda, Norikazu Ota, Naoto Kosaki, et al. "Inhibition of STAT1 accelerates bone fracture healing." Journal of Orthopaedic Research 28, no. 7 (January 8, 2010): 937–41. http://dx.doi.org/10.1002/jor.21086.
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Adachi, K., R. A. Chole, and J. Yee. "Indomethacin Inhibition of Middle Ear Bone Resorption." Archives of Otolaryngology - Head and Neck Surgery 117, no. 3 (March 1, 1991): 267–69. http://dx.doi.org/10.1001/archotol.1991.01870150035002.
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Horowitz, Stephen M., Sheila A. Algan, and Marie A. Purdon. "Pharmacologic inhibition of particulate-induced bone resorption." Journal of Biomedical Materials Research 31, no. 1 (May 1996): 91–96. http://dx.doi.org/10.1002/(sici)1097-4636(199605)31:1<91::aid-jbm11>3.0.co;2-p.
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Dudakovic, Amel, Rebekah M. Samsonraj, Christopher R. Paradise, Catalina Galeano-Garces, Merel O. Mol, Daniela Galeano-Garces, Pengfei Zan, et al. "Inhibition of the epigenetic suppressor EZH2 primes osteogenic differentiation mediated by BMP2." Journal of Biological Chemistry 295, no. 23 (April 24, 2020): 7877–93. http://dx.doi.org/10.1074/jbc.ra119.011685.
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Bone-stimulatory therapeutics include bone morphogenetic proteins (e.g. BMP2), parathyroid hormone, and antibody-based suppression of WNT antagonists. Inhibition of the epigenetic enzyme enhancer of zeste homolog 2 (EZH2) is both bone anabolic and osteoprotective. EZH2 inhibition stimulates key components of bone-stimulatory signaling pathways, including the BMP2 signaling cascade. Because of high costs and adverse effects associated with BMP2 use, here we investigated whether BMP2 dosing can be reduced by co-treatment with EZH2 inhibitors. Co-administration of BMP2 with the EZH2 inhibitor GSK126 enhanced differentiation of murine (MC3T3) osteoblasts, reflected by increased alkaline phosphatase activity, Alizarin Red staining, and expression of bone-related marker genes (e.g. Bglap and Phospho1). Strikingly, co-treatment with BMP2 (10 ng/ml) and GSK126 (5 μm) was synergistic and was as effective as 50 ng/ml BMP2 at inducing MC3T3 osteoblastogenesis. Similarly, the BMP2–GSK126 co-treatment stimulated osteogenic differentiation of human bone marrow–derived mesenchymal stem/stromal cells, reflected by induction of key osteogenic markers (e.g. Osterix/SP7 and IBSP). A combination of BMP2 (300 ng local) and GSK126 (5 μg local and 5 days of 50 mg/kg systemic) yielded more consistent bone healing than single treatments with either compound in a mouse calvarial critical-sized defect model according to results from μCT, histomorphometry, and surgical grading of qualitative X-rays. We conclude that EZH2 inhibition facilitates BMP2-mediated induction of osteogenic differentiation of progenitor cells and maturation of committed osteoblasts. We propose that epigenetic priming, coupled with bone anabolic agents, enhances osteogenesis and could be leveraged in therapeutic strategies to improve bone mass.
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Giuliani, Nicola, Vittorio Rizzoli, and G. David Roodman. "Multiple myeloma bone disease: pathophysiology of osteoblast inhibition." Blood 108, no. 13 (December 15, 2006): 3992–96. http://dx.doi.org/10.1182/blood-2006-05-026112.
Full textAbstract:
Abstract Multiple myeloma (MM) is a plasma cell malignancy characterized by a high capacity to induce osteolytic bone lesions. Bone destruction in MM results from increased osteoclast formation and activity that occur in close proximity to myeloma cells. However, histomorphometric studies have demonstrated that MM patients with osteolytic bone lesions have lower numbers of osteoblasts and decreased bone formation. This impaired bone formation plays a critical role in the bone-destructive process. Recently, the biologic mechanisms involved in the osteoblast inhibition induced by MM cells have begun to be elucidated. In this article, the pathophysiology underlying osteoblast inhibition in MM is reviewed.
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Sasaki, T., N. S. Ramamurthy, and L. M. Golub. "Long-Term Therapy with a New Chemically Modified Tetracycline (CMT-8) Inhibits Bone Loss in Femurs of Ovariectomized Rats." Advances in Dental Research 12, no. 1 (November 1998): 76–81. http://dx.doi.org/10.1177/08959374980120012501.
Full textAbstract:
The effect of a new non-antimicrobial analog of tetracycline (CMT-8) on bone loss in ovariectomized (OVX) rats was examined. Three-month-old female rats were ovariectomized, and one week later, were distributed into 3 groups: sham-operated non-OVX controls, vehicle-treated OVX controls, and CMT-8-treated OVX rats. After 145 days of daily CMT-8 administration, the intact femurs were dissected and examined by several histological and histomorphometric techniques. OVX significantly (p < 0.01) decreased trabecular bone volume by 53.4% in the metaphyses compared with sham-operated controls. CMT-8 therapy produced a significant (p < 0.05) inhibition of trabecular bone loss and also induced bone formation in the OVX rats. Of interest, the newly synthesized bone in the CMT-treated OVX rats was found to increase the "connectivity" of the trabecular "struts" by bridging the adjacent longitudinal bone trabeculae, forming dense, platelike bone trabeculae. These results strongly suggest that long-term CMT-8 therapy effectively inhibits bone loss after OVX, not only by inhibiting bone resorption but also by inducing new bone formation in the trabecular areas of long bones.
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Sun, Qi, Yuanzhen Zhang, Yilan Ding, Wenqing Xie, Hengzhen Li, Shaohua Li, Yusheng Li, and Ming Cai. "Inhibition of PGE2 in Subchondral Bone Attenuates Osteoarthritis." Cells 11, no. 17 (September 5, 2022): 2760. http://dx.doi.org/10.3390/cells11172760.
Full textAbstract:
Aberrant subchondral bone architecture is a crucial driver of the pathological progression of osteoarthritis, coupled with increased sensory innervation. The sensory PGE2/EP4 pathway is involved in the regulation of bone mass accrual by the induction of differentiation of mesenchymal stromal cells. This study aimed to clarify whether the sensory PGE2/EP4 pathway induces aberrant structural alteration of subchondral bone in osteoarthritis. Destabilization of the medial meniscus (DMM) using a mouse model was combined with three approaches: the treatment of celecoxib, capsaicin, and sensory nerve-specific prostaglandin E2 receptor 4 (EP4)-knockout mice. Cartilage degeneration, subchondral bone architecture, PGE2 levels, distribution of sensory nerves, the number of osteoprogenitors, and pain-related behavior in DMM mice were assessed. Serum and tissue PGE2 levels and subchondral bone architecture in a human sample were measured. Increased PGE2 is closely related to subchondral bone’s abnormal microstructure in humans and mice. Elevated PGE2 concentration in subchondral bone that is mainly derived from osteoblasts occurs in early-stage osteoarthritis, preceding articular cartilage degeneration in mice. The decreased PGE2 levels by the celecoxib or sensory denervation by capsaicin attenuate the aberrant alteration of subchondral bone architecture, joint degeneration, and pain. Selective EP4 receptor knockout of the sensory nerve attenuates the aberrant formation of subchondral bone and facilitates the prevention of cartilage degeneration in DMM mice. Excessive PGE2 in subchondral bone caused a pathological alteration to subchondral bone in osteoarthritis and maintaining the physiological level of PGE2 could potentially be used as an osteoarthritis treatment.
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Yaccoby, Shmuel, Wen Ling, Rinku Saha, Fenghuang Zhan, Ron Walker, Guido Tricot, Bart Barlogie, and John D. Shaughnessy. "Inhibition of DKK1 Activity Is Associated with Increased Osteoblast Numbers and Bone Formation, Reduced Osteoclast Activity and Inhibition of Tumor Growth in the SCID-rab Model for Primary Myeloma." Blood 106, no. 11 (November 16, 2005): 638. http://dx.doi.org/10.1182/blood.v106.11.638.638.
Full textAbstract:
Abstract We have previously demonstrated that myeloma (MM) cells produce the Wnt signaling antagonist, Dickkopf-1 (DKK1), and that DKK1 inhibits differentiation of osteoblasts (Tian et al. NEJM 2003). This is thought to result in an uncoupling process that may lead to induction of lytic bone disease in MM and possibly promote tumor growth. The aim of this study was to investigate the role of DKK1 in our established SCID-rab model for primary MM. Growth of primary MM in this system is restricted to the implanted bone and associated with typical disease manifestations including increased osteoclast activity, reduced osteoblast numbers and induction of osteolytic bone disease (Yata & Yaccoby, Leukemia 2004). In this study, SCID-rab mice were engrafted with MM cells expressing DKK1 (assessed by global gene expression profiling) from 8 patients. The level of DKK1 expression was correlated with numbers of MRI and x-ray focal lesions in these patients. Following establishment of MM growth, as monitored by weekly measurement of human monoclonal immunoglobulins (hIg) in mouse sera and radiographically, mice were injected subcutaneously into the surrounding area of the implanted bone with neutralizing antibody (AB, R&D) against DKK1 (polyclonal AB: n=4, 50 μg/injection/2 days; monoclonal AB: n=4, 100 μg/injection/day) or control IgG AB, for 4–6 weeks. Whereas bone mineral density (BMD) in control mice was reduced by 7.1%±4.6% from pre-treatment levels, BMD in mice treated with anti-DKK1 was increased by 5.6%±6.7% from pre-treatment levels (p<0.03). The bone anabolic effect of DKK1 AB was also visualized on x-rays and was detected in mice transplanted with cells from patients with low and high degree of bone disease. Histological examination revealed that myelomatous bones of DKK1 AB-treated mice had increased numbers of osteocalcin-expressing osteoblasts (45±5 vs. 16±2 per mm bone in control mice, p<0.02) and reduced number of multinucleated TRAP-expressing multinucleated osteoclasts (5±3 vs. 13±2 per mm bone in control mice, p<0.004). These results support recent reports demonstrating the critical involvement of Wnt signaling in osteoblasts in regulation of osteoclastogenesis as well (Glass et al., Dev. Cell 2005). Whereas in control mice myeloma burden increased in all experiments, anti-DKK1 treatment was associated with reduced tumor growth from pre-treatment levels in 4 of 8 experiments. Overall, myeloma tumor burden increased by 325%±122% and 165%±53% from pre-treatment levels in control and DKK1 AB-treated mice, respectively (p<0.03). Furthermore, bone marrow areas with locally high numbers of differentiated osteoblasts were depleted of myeloma cells in DKK1 AB-treated hosts. We conclude that DKK1 is a key player in myeloma bone disease and that blocking DKK1 activity in myelomatous bones reduces osteolytic bone resorption, increases bone formation and helps control myeloma progression.
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Lundy, M. W., K. H. Lau, H. C. Blair, and D. J. Baylink. "Chick osteoblasts contain fluoride-sensitive acid phosphatase activity." Journal of Histochemistry & Cytochemistry 36, no. 9 (September 1988): 1175–80. http://dx.doi.org/10.1177/36.9.3403968.
Full textAbstract:
We used histological and biochemical methods to determine the cellular origin of bone matrix fluoride-sensitive acid phosphatase in chicken bone. Embryonic chicken calvariae were embedded in plastic and sections stained for acid phosphatase at various concentrations of substrate and fluoride. Acid phosphatase activity was observed in osteoblasts and osteoclasts but not in fibroblasts. Striking inhibition of osteoblastic acid phosphatase occurred at 100 microM fluoride, a concentration that had no apparent effect on osteoclastic acid phosphatase. Inhibition of osteoblastic and osteoclastic acid phosphatase by fluoride was also examined using extracts of embryonic chicken calvarial cells, mouse osteoblasts (MC3T3-El cell line), and purified chick osteoclasts, respectively. Fluoride is a partial competitive inhibitor of both chicken and mouse osteoblastic acid phosphatases, with apparent inhibition constants of 10-100 microM. These concentrations of fluoride correspond to those that increase bone formation in vitro and in vivo. In contrast, the apparent inhibition constant for fluoride of osteoclastic acid phosphatase was much higher (i.e., 0.5 mM). In summary, this study demonstrates that chicken osteoblasts contain an acid phosphatase that is sensitive to inhibition by low concentrations (i.e., microM) of fluoride.
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Hideshima, Teru, Pierfrancesco Tassone, Dharminder Chauhan, Kenji Ishitsuka, Constantine Mitsiades, Noopur Raje, Shaji Kumar, et al. "Targeting IKK Inhibits Multiple Myeloma (MM) Cell Growth in the Bone Marrow Microenvironment." Blood 104, no. 11 (November 16, 2004): 2351. http://dx.doi.org/10.1182/blood.v104.11.2351.2351.
Full textAbstract:
Abstract NF-κB is a transcriptional factor promoting tumor cell growth and inhibition of apoptosis via regulating expression of proteins modulating cell cycle and anti-apoptosis. NF-κB is constitutively associated with an inhibitor (IκB), which is phosphorylated by IκB kinase (IKK) upon cell stimulation (ie, TNFα) and subsequently degraded by ubiquitin-proteasome pathway, thereby allowing NF-κB to translocate to nucleus. We have previously shown that an IKK inhibitor PS-1145 partially (20–50%) inhibits MM cell proliferation; however, it inhibits both IL-6 secretion from BMSCs triggered by MM cell adhesion and proliferation of MM cells adherent to BMSCs. Targeting IKKβ is therefore a possible therapeutic option for inhibition of MM cell growth in the bone marrow microenvironment by downregulating NF-κB activity. In this study, we further delineated the biologic significance of IKK inhibition in MM cells using IKKβ specific inhibitor MLN120B (Millennium Pharmaceuticals, Cambridge, MA). MLN120B induced 60–90% growth inhibition in cells from the MM cell lines RPMI8226, RPMI/Dox40, RPMI/LR5, U266, and INA-6; on the other hand, it induced only 25–30% inhibition in MM.1S and MM.1R cells, assessed by 72 h tritiated-thymidine uptake. Importantly, neither IL-6 nor IGF-1 overcomes the growth inhibitory effect of MLN120B in both MM.1S and U266 cells. Interestingly, MLN120B significantly augmented TNFα-induced cytotoxicity in MM.1S cells. We next examined whether MLN120B could enhance the cytotoxicity of other agents. MLN120B augmented growth inhibition triggered by doxorubicin and melphalan in RPMI8226 and IL-6 dependent INA-6 cell line. We therefore studied growth inhibitory effect of MLN120B in the presence of bone marrow stromal cells (BMSCs). MLN120B inhibited 70–80% of constitutive IL-6 secretion from BMSCs, without toxicity. Importantly, MLN120B almost completely blocked stimulation of MM.1S, U266 and INA-4 cell growth and IL-6 secretion from BMSCs induced by binding of tumor cells to BMSCs. Finally, MLN120B overcame the protective effect of BMSCs, cell adhesion mediated drug resistance, against dexamethasone in MM.1S cells. Taken together, our data demonstrate that an IKKβ inhibitor induces cytotoxicity in MM cells in the BM milieu, providing the framework for clinical trials of these novel agents to improve patient outcome in MM.
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Kameda, Takashi, Hiroshi Mano, Tatsuhisa Yuasa, Yoshihisa Mori, Koshi Miyazawa, Miho Shiokawa, Yukiya Nakamaru, et al. "Estrogen Inhibits Bone Resorption by Directly Inducing Apoptosis of the Bone-resorbing Osteoclasts." Journal of Experimental Medicine 186, no. 4 (August 18, 1997): 489–95. http://dx.doi.org/10.1084/jem.186.4.489.
Full textAbstract:
Estrogen deficiency causes bone loss, which can be prevented by estrogen replacement therapy. Using a recently developed technique for isolation of highly purified mammalian osteoclasts, we showed that 17 β-estradiol (E2) was able to directly inhibit osteoclastic bone resorption. At concentrations effective for inhibiting bone resorption, E2 also directly induced osteoclast apoptosis in a dose- and time-dependent manner. ICI164,384 and tamoxifen, as pure and partial antagonists, respectively, completely or partially blocked the effect of E2 on both inhibition of osteoclastic bone resorption and induction of osteoclast apoptosis. These data suggest that the protective effects of estrogen against postmenopausal osteoporosis are mediated in part by the direct induction of apoptosis of the bone-resorbing osteoclasts by an estrogen receptor– mediated mechanism.
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Steinbicker, Andrea U., Chetana Sachidanandan, Ashley J. Vonner, Rushdia Z. Yusuf, Donna Y. Deng, Carol S. Lai, Kristen M. Rauwerdink, et al. "Inhibition of bone morphogenetic protein signaling attenuates anemia associated with inflammation." Blood 117, no. 18 (May 5, 2011): 4915–23. http://dx.doi.org/10.1182/blood-2010-10-313064.
Full textAbstract:
Abstract Anemia of inflammation develops in settings of chronic inflammatory, infectious, or neoplastic disease. In this highly prevalent form of anemia, inflammatory cytokines, including IL-6, stimulate hepatic expression of hepcidin, which negatively regulates iron bioavailability by inactivating ferroportin. Hepcidin is transcriptionally regulated by IL-6 and bone morphogenetic protein (BMP) signaling. We hypothesized that inhibiting BMP signaling can reduce hepcidin expression and ameliorate hypoferremia and anemia associated with inflammation. In human hepatoma cells, IL-6–induced hepcidin expression, an effect that was inhibited by treatment with a BMP type I receptor inhibitor, LDN-193189, or BMP ligand antagonists noggin and ALK3-Fc. In zebrafish, the induction of hepcidin expression by transgenic expression of IL-6 was also reduced by LDN-193189. In mice, treatment with IL-6 or turpentine increased hepcidin expression and reduced serum iron, effects that were inhibited by LDN-193189 or ALK3-Fc. Chronic turpentine treatment led to microcytic anemia, which was prevented by concurrent administration of LDN-193189 or attenuated when LDN-193189 was administered after anemia was established. Our studies support the concept that BMP and IL-6 act together to regulate iron homeostasis and suggest that inhibition of BMP signaling may be an effective strategy for the treatment of anemia of inflammation.