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1
Sneddon, W. Bruce, Yanmei Yang, Jianming Ba, Lisa M. Harinstein, and Peter A. Friedman. "Extracellular signal-regulated kinase activation by parathyroid hormone in distal tubule cells." American Journal of Physiology-Renal Physiology 292, no. 3 (March 2007): F1028—F1034. http://dx.doi.org/10.1152/ajprenal.00288.2006.
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The PTH receptor (PTH1R) activates multiple signaling pathways, including extracellular signal-regulated kinases 1 and 2 (ERK1/2). The role of epidermal growth factor receptor (EGFR) transactivation in ERK1/2 activation by PTH in distal kidney cells, a primary site of PTH action, was characterized. ERK1/2 phosphorylation was stimulated by PTH and blocked by the EGFR inhibitor, AG1478. Upon PTH stimulation, metalloprotease cleavage of membrane-bound heparin-binding fragment (HB-EGF) induced EGFR transactivation of ERK. Conditioned media from PTH-treated distal kidney cells activated ERK in HEK-293 cells. AG1478 added to HEK-293 cells ablated transactivation by conditioned media. HB-EGF directly activated ERK1/2 in HEK-293 cells. Pretreatment of distal kidney cells with the metalloprotease inhibitor GM-6001 abolished transactivation of ERK1/2 by PTH. The role of the PTH1R COOH terminus in PTX-sensitive ERK1/2 activation was characterized in HEK-293 cells transfected with wild-type PTH1R, with a PTH1R mutated at its COOH terminus, or with PTH1R truncated at position 480. PTH stimulated ERK by wild-type, mutated and truncated PTH1Rs 21-, 27- and 57-fold, respectively. Thus, the PTH1R COOH terminus exerts an inhibitory effect on ERK activation. EBP50, a scaffolding protein that binds to the PDZ recognition domain of the PTH1R, impaired PTH but not isoproterenol or calcitonin-induced ERK activation. Pertussis toxin inhibited PTH-stimulated ERK1/2 by mutated and truncated PTH1Rs and abolished ERK1/2 activation by wild-type PTH1R. We conclude that ERK phosphorylation in distal kidney cells by PTH requires PTH1R activation of Gi, which leads to stimulation of metalloprotease-mediated cleavage of HB-EGF and transactivation of the EGFR and is regulated by EBP50.
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Bhattacharya, Poulomi, Yi Lin Yan, John Postlethwait, and David A. Rubin. "Evolution of the vertebrate pth2 (tip39) gene family and the regulation of PTH type 2 receptor (pth2r) and its endogenous ligand pth2 by hedgehog signaling in zebrafish development." Journal of Endocrinology 211, no. 2 (August 31, 2011): 187–200. http://dx.doi.org/10.1530/joe-10-0439.
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In mammals, parathyroid hormone (PTH), secreted by parathyroid glands, increases calcium levels in the blood from reservoirs in bone. While mammals have two PTH receptor genes, PTH1R and PTH2R, zebrafish has three receptors, pth1r, pth2r, and pth3r. PTH can activate all three zebrafish Pthrs while PTH2 (alias tuberoinfundibular peptide 39, TIP39) preferentially activates zebrafish and mammalian PTH2Rs. We know little about the roles of the PTH2/PTH2R system in the development of any animal. To determine the roles of PTH2 and PTH2R during vertebrate development, we evaluated their expression patterns in developing zebrafish, observed their phylogenetic and conserved synteny relationships with humans, and described the genomic organization of pth2, pth2r, and pth2r splice variants. Expression studies showed that pth2 is expressed in cells adjacent to the ventral part of the posterior tuberculum in the diencephalon, whereas pth2r is robustly expressed throughout the central nervous system. Otic vesicles express both pth2 and pth2r, but heart expresses only pth2. Analysis of mutants showed that hedgehog (Hh) signaling regulates the expression of pth2 transcripts more than that of nearby gnrh2-expressing cells. Genomic analysis showed that a lizard, chicken, and zebra finch lack a PTH2 gene, which is associated with an inversion breakpoint. Likewise, chickens lack PTH2R, while humans lack PTH3R, a case of reciprocally missing ohnologs (paralogs derived from a genome duplication). The considerable evolutionary conservation in genomic structure, synteny relationships, and expression of zebrafish pth2 and pth2r provides a foundation for exploring the endocrine roles of this system in developing vertebrate embryos.
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Atchison, Douglas K., Pamela Harding, M. Cecilia Ortiz-Capisano, Edward L. Peterson, and William H. Beierwaltes. "Parathyroid hormone stimulates juxtaglomerular cell cAMP accumulation without stimulating renin release." American Journal of Physiology-Renal Physiology 303, no. 8 (October 15, 2012): F1157—F1165. http://dx.doi.org/10.1152/ajprenal.00269.2012.
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Parathyroid hormone (PTH) is positively coupled to the generation of cAMP via its actions on the PTH1R and PTH2R receptors. Renin secretion from juxtaglomerular (JG) cells is stimulated by elevated intracellular cAMP, and every stimulus that increases renin secretion is thought to do so via increasing cAMP. Thus we hypothesized that PTH increases renin release from primary cultures of mouse JG cells by elevating intracellular cAMP via the PTH1R receptor. We found PTH1R, but not PTH2R, mRNA expressed in JG cells. While PTH increased JG cell cAMP content from (log10 means ± SE) 3.27 ± 0.06 to 3.92 ± 0.12 fmol/mg protein ( P < 0.001), it did not affect renin release. The PTH1R-specific agonist, parathyroid hormone-related protein (PTHrP), also increased JG cell cAMP from 3.13 ± 0.09 to 3.93 ± 0.09 fmol/mg protein ( P < 0.001), again without effect on renin release. PTH2R receptor agonists had no effect on cAMP or renin release. PTHrP increased cAMP in the presence of both low and high extracellular calcium from 3.31 ± 0.17 to 3.83 ± 0.20 fmol/mg protein ( P < 0.01) and from 3.29 ± 0.18 to 3.63 ± 0.22 fmol/mg protein ( P < 0.05), respectively, with no effect on renin release. PTHrP increased JG cell cAMP in the presence of adenylyl cyclase-V inhibition from 2.85 ± 0.17 to 3.44 ± 0.14 fmol/mg protein ( P < 0.001) without affecting renin release. As a positive control, forskolin increased JG cell cAMP from 3.39 ± 0.13 to 4.48 ± 0.07 fmol/mg protein ( P < 0.01) and renin release from 2.96 ± 0.10 to 3.29 ± 0.08 ng ANG I·mg prot−1·h−1 ( P < 0.01). Thus PTH increases JG cell cAMP via non-calcium-sensitive adenylate cyclases without affecting renin release. These data suggest compartmentalization of cAMP signaling in JG cells.
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Gensure, Robert C., Bhaskar Ponugoti, Yasemin Gunes, Madhusudhan R. Papasani, Beate Lanske, Murat Bastepe, David A. Rubin, and Harald Jüppner. "Identification and Characterization of Two Parathyroid Hormone-Like Molecules in Zebrafish." Endocrinology 145, no. 4 (April 1, 2004): 1634–39. http://dx.doi.org/10.1210/en.2003-0964.
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Abstract Zebrafish (Danio rerio) have receptors homologous to the human PTH (hPTH)/PTHrP receptor (PTH1R) and PTH-2 receptor (PTH2R) and an additional receptor (PTH3R) with high homology to the PTH1R. To find natural ligands for zPTH1R and zPTH3R, we searched the zebrafish genomic database and discovered two distinct regions that, when translated (zPTH1 and zPTH2), showed high homology to hPTH. Isolation of cDNAs and determination of the intron/exon boundaries revealed genomic structures which were similar to known PTHs. Peptides consisting of the first 34 amino acids after the pre- and prosequences of the zebrafish PTHs (zPTHs) were synthesized and were shown to be fully active at the hPTH1R. zPTH2(1–34) was, however, approximately 30-fold less potent at the zPTH1R than hPTH(1–34), hPTHrP(1–36), and zPTH1(1–34). When tested with zPTH3R, zPTH1(1–34) and hPTHrP(1–36) showed similar potencies, whereas the potency of zPTH2(1–34) was moderately (3-fold) reduced. To determine whether other fishes have multiple PTHs, we searched the genomic database of the Japanese pufferfish (Takifugu rubripes) and identified zPTH1 and zPTH2 homologs. Phylogenetic analysis showed that PTHs from zebrafish and pufferfish are more closely related to each other than to known mammalian PTH homologs or to PTHrP and tuberoinfundibular peptide of 39 residues. This is consistent with evolution of two teleost PTH-like peptides occurring after the evolutionary divergence between fishes and mammals. Overall, the PTH system appears more complex in fishes than in mammals, providing evidence of continued evolution in nontetrapod species. The availability of multiple forms of fish PTH and their receptors provide additional tools for PTH ligand/receptor structure-function studies.
5
Mannstadt, Michael, Harald Jüppner, and Thomas J. Gardella. "Receptors for PTH and PTHrP: their biological importance and functional properties." American Journal of Physiology-Renal Physiology 277, no. 5 (November 1, 1999): F665—F675. http://dx.doi.org/10.1152/ajprenal.1999.277.5.f665.
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The type 1 receptor (PTH1R) for parathyroid hormone (PTH) and parathyroid hormone-related peptide (PTHrP) is a G protein-coupled receptor that is highly expressed in bone and kidney and mediates in these tissues the PTH-dependent regulation of mineral ion homeostasis. The PTH1R also mediates the paracrine actions of PTHrP, which play a particularly vital role in the process of endochondral bone formation. These important functions, the likely involvement of the PTH1R in certain genetic diseases affecting skeletal development and calcium homeostasis, and the potential utility of PTH in treating osteoporosis have been the driving force behind intense investigations of both the receptor and its peptide ligands. Recent lines of work have led to the identification of constitutively active PTH1Rs in patients with Jansen's metaphyseal chondrodysplasia, the demonstration of inverse agonism by certain ligand analogs, and the discovery of the PTH-2 receptor subtype that responds to PTH but not PTHrP. As reviewed herein, a detailed exploration of the receptor-ligand interaction process is currently being pursued through the use of site-directed mutagenesis and photoaffinity cross-linking methods; ultimately, such work could enable the development of novel PTH receptor ligands that have therapeutic value in treating diseases such as osteoporosis and certain forms of hypercalcemia.
6
Miedlich, Susanne U., and Abdul B. Abou-Samra. "Eliminating phosphorylation sites of the parathyroid hormone receptor type 1 differentially affects stimulation of phospholipase C and receptor internalization." American Journal of Physiology-Endocrinology and Metabolism 295, no. 3 (September 2008): E665—E671. http://dx.doi.org/10.1152/ajpendo.00036.2008.
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The parathyroid hormone (PTH)/PTH-related peptide (PTHrP) receptor (PTH1R) belongs to family B of seven-transmembrane-spanning receptors and is activated by PTH and PTHrP. Upon PTH stimulation, the rat PTH1R becomes phosphorylated at seven serine residues. Elimination of all PTH1R phosphorylation sites results in prolonged cAMP accumulation and impaired internalization in stably transfected LLC-PK1 cells. The present study explores the role of individual PTH1R phosphorylation sites in PTH1R signaling through phospholipase C, agonist-dependent receptor internalization, and regulation by G protein-coupled receptor kinases. By means of transiently transfected COS-7 cells, we demonstrate that the phosphorylation-deficient (pd) PTH1R confers dramatically enhanced coupling to Gq/11 proteins upon PTH stimulation predominantly caused by elimination of Ser491/492/493, Ser501, or Ser504. Reportedly, impaired internalization of the pd PTH1R, however, is not dependent on a specific phosphorylation site. In addition, we show that G protein-coupled receptor kinase 2 interferes with pd PTH1R signaling to Gq/11 proteins at least partially by direct binding to Gq/11 proteins.
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Sneddon, W. Bruce, and Peter A. Friedman. "β-Arrestin-Dependent Parathyroid Hormone-Stimulated Extracellular Signal-Regulated Kinase Activation and Parathyroid Hormone Type 1 Receptor Internalization." Endocrinology 148, no. 8 (August 1, 2007): 4073–79. http://dx.doi.org/10.1210/en.2007-0343.
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PTH regulates renal calcium homeostasis by actions on the distal nephron. PTH-induced calcium transport in mouse distal convoluted tubule (DCT) cells requires activation of ERK1/2. ERK activation by β-adrenergic receptors occurs in a biphasic manner and involves receptor internalization. An early rapid phase is β-arrestin (βAr) independent, whereas prolonged activation is βAr dependent. We characterized PTH-stimulated ERK activation and the involvement of receptor internalization and βAr dependence. In DCT cells, PTH transiently activated ERK maximally at 5 min and then returned to baseline. βAr dependence of PTH receptor (PTH1R)-mediated ERK stimulation was assessed using mouse embryonic fibroblasts (MEFs) from βAr1- and -2-null mice. In wild-type MEFs, PTH(1–34)-stimulated ERK activation peaked after 5 min, was 50% maximal after 15 min, and then recovered to 80% of maximal stimulation by 30 min. In MEFs null for βAr1 and -2, PTH-stimulated ERK activation peaked by 5 min and returned to baseline. The effect was identical in βAr2-null MEFs. In βAr1-null MEFs, ERK exhibited delayed activation and remained elevated. PTH-stimulated ERK activation and receptor endocytosis were not inhibited by the clathrin-binding domain of βAr1 [Ar(319–418)]. Coexpression of the sodium proton exchanger regulatory factor 1 (NHERF1) with Ar(319–418) blocked PTH1R internalization. We conclude that PTH-stimulated ERK activation in DCT cells proceeds with a rapid but transient phase that may involve βAr1. Furthermore, the βAr-dependent late phase of ERK activation by PTH requires the participation of βAr2 and PTH1R internalization.
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Izquierdo-Lahuerta, Adriana. "The Parathyroid Hormone-Related Protein/Parathyroid Hormone 1 Receptor Axis in Adipose Tissue." Biomolecules 11, no. 11 (October 22, 2021): 1570. http://dx.doi.org/10.3390/biom11111570.
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Adipose tissue is an organ that shows great plasticity and is able to adapt to the conditions to which the body is subdued. It participates in the regulation of energetic homeostasis and has endocrine functions. Recent studies have shown how the parathyroid hormone-related protein (PTHrP)/Parathyroid Hormone Receptor 1 (PTH1R) axis participates in the regulation of adipogenesis, opposing the action of Peroxisome proliferator-activated receptor gamma (PPARγ). In addition to this, PTHrP is overexpressed in adipose tissue in situations of wear and tear of the body, favoring browning and lipolysis in this tissue. It is also overexpressed in adipose tissue in stressful situations but in the opposite direction, in obesity, metabolic syndrome, type 2 diabetes mellitus (T2DM) and gestational diabetes mellitus (GDM). In conclusion, the PTHrP/PTH1R axis has a main role in adipose tissue, participating in its differentiation and remodeling. PTHrP might be used in obesity treatment and its complications for its ability to reprogram adipogenesis and adipose tissue expansion, WAT browning and for the improvement of the insulin sensitivity. In addition, PTHrP could even be used as a marker of placental status and maternal adaptations to prevent future metabolic problems in mothers and children, as well as in the treatment of bone-related diseases such as osteoporosis.
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Danz, Jan. "Zahneruption und Zahnbewegung bei kongenitaler Retention mit Mutation des PTH1-Rezeptor-Gens." Informationen aus Orthodontie & Kieferorthopädie 50, no. 03 (September 2018): 169–75. http://dx.doi.org/10.1055/a-0648-8013.
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ZusammenfassungDie primäre kongenitale Retention von Zähnen des Typs heterozygote Mutation von Parathyroid hormone receptor type 1 (PTH1R) mit autosomal dominanter Vererbung ist eine Regulationsstörung des Knochenumbaus, welche die Zahneruption und die Zahnbewegungen stark behindert oder verhindert. Bei beginnender Zahneruption und bei Zahnbewegung wird PTHrP (Parathyroid hormone-related protein) ausgeschüttet, welches durch Osteozyten den Knochenumbau Richtung Knochenresorption entkoppelt. Bei PTH1R-Mutation mit Funktionsverlust dieses Rezeptors fehlt einerseits die Verringerung der Osteoprotegerin (OPG)- und der Sclerostin-Ausschüttung durch Osteozyten und andererseits die erhöhte Expression und Ausschüttung von Soluble receptor activator of nuclear factor κB (sRANKL) durch Osteozyten und Osteoblasten, was zu einer ausbleibenden Osteoklastenaktivierung führt. Ohne Knochenresorption durch Osteoklasten sind sowohl die Zahneruption als auch die Zahnbewegung gestört. Durch das als kompetitiver Antagonist des wnt-Rezeptor-Komplexes (kanonischer-wnt-Signalweg) und der BMP-I/BMP-II-Rezeptoren wirkende Sclerostin modulieren Osteozyten auch die Osteoblastenaktivität. Bei Verdacht auf kongenitale Retention ist eine humangenetische Abklärung zum Test einer PTH1-Rezeptor-Mutation ein wichtiges diagnostisches Mittel, um nicht erfolgsversprechende kieferorthopädische Therapien zu vermeiden und Behandlungsalternativen planen zu können.
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Zhang, Yan-Liang, John A. Frangos, and Mirianas Chachisvilis. "Mechanical stimulus alters conformation of type 1 parathyroid hormone receptor in bone cells." American Journal of Physiology-Cell Physiology 296, no. 6 (June 2009): C1391—C1399. http://dx.doi.org/10.1152/ajpcell.00549.2008.
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The molecular mechanisms by which bone cells transduce mechanical stimuli into intracellular biochemical responses have yet to be established. There is evidence that mechanical stimulation acts synergistically with parathyroid hormone PTH(1-34) in mediating bone growth. Using picosecond time-resolved fluorescence microscopy and G protein-coupled receptor conformation-sensitive fluorescence resonance energy transfer (FRET), we investigated conformational transitions in parathyroid hormone type 1 receptor (PTH1R). 1) A genetically engineered PTH1R sensor containing an intramolecular FRET pair was constructed that enabled detection of conformational activity of PTH1R in single cells. 2) The nature of ligand-dependent conformational change of PTH1R depends on the type of ligand: stimulation with the PTH(1-34) leads to conformational transitions characterized by decrease in FRET efficiency while NH2-terminal truncated ligand PTH(3-34) stimulates conformational transitions characterized by higher FRET efficiencies. 3) Stimulation of murine preosteoblastic cells (MC3T3-E1) with fluid shear stress (FSS) leads to significant changes in conformational equilibrium of the PTH1R in MC3T3-E1 cells, suggesting that mechanical perturbation of the plasma membrane leads to ligand-independent response of the PTH1R. Conformational transitions induced by mechanical stress were characterized by an increase in FRET efficiency, similar to those induced by the NH2-terminal truncated ligand PTH(3-34). The response to the FSS stimulation was inhibited in the presence of PTH(1-34) in the flow medium. These results indicate that the FSS can modulate the action of the PTH(1-34) ligand. 4) Plasma membrane fluidization using benzyl alcohol or cholesterol extraction also leads to conformational transitions characterized by increased FRET levels. We therefore suggest that PTH1R is involved in mediating primary mechanochemical signal transduction in MC3T3-E1 cells.
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Liu, Caojie, Qiwen Li, Qingyue Xiao, Ping Gong, and Ning Kang. "CHD7 Regulates Osteogenic Differentiation of Human Dental Follicle Cells via PTH1R Signaling." Stem Cells International 2020 (September 21, 2020): 1–10. http://dx.doi.org/10.1155/2020/8882857.
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Chromodomain helicase DNA-binding protein 7 (CHD7) is an ATP-dependent chromatin remodeling enzyme, functioning as chromatin reader to conduct epigenetic modification. Its effect on osteogenic differentiation of human dental follicle cells (hDFCs) remains unclear. Here, we show the CHD7 expression increases with osteogenic differentiation. The knockdown of CHD7 impairs the osteogenic ability of hDFCs, characterized by reduced alkaline phosphatase activity and mineralization, and the decreased expression of osteogenesis-related genes. Conversely, the CHD7 overexpression enhances the osteogenic differentiation of hDFCs. Mechanically, RNA-seq analyses revealed the downregulated enrichment of PTH (parathyroid hormone)/PTH1R (parathyroid hormone receptor-1) signaling pathway after CHD7 knockdown. We found the expression of PTH1R positively correlates with CHD7. Importantly, the overexpression of PTH1R in CHD7-knockdown hDFCs partially rescued the impaired osteogenic differentiation. Our research demonstrates that CHD7 regulates the osteogenic differentiation of hDFCs by regulating the transcription of PTH1R.
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Shimada, Masako, Matthew J. Mahon, Peter A. Greer, and Gino V. Segre. "The Receptor for Parathyroid Hormone and Parathyroid Hormone-Related Peptide Is Hydrolyzed and Its Signaling Properties Are Altered by Directly Binding the Calpain Small Subunit." Endocrinology 146, no. 5 (May 1, 2005): 2336–44. http://dx.doi.org/10.1210/en.2004-1637.
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Abstract We show calcium-dependent, direct binding between the N-terminal portion of the PTH/PTHrP receptor (PTH1R) C-terminal intracellular tail and the calpain small subunit. Binding requires, but may not be limited to, amino acids W474, S475, and W477. The wild-type, full-length rat (r) PTH1R, but not rPTH1R with W474A/W477A substitutions, copurifies with the endogenous calpain small subunit in HEK293 cells. Calpain hydrolyzes ΔNt-rPTH1R, a receptor with a 156-amino acid N-terminal deletion, in a calcium-dependent manner in vitro and in intact cells. Most importantly, PTH stimulation increases the cleavage of ΔNt-rPTH1R and rPTH1R-yellow fluorescent protein in HEK293 cells, and of talin in HEK293 cells expressing rPTH1R-yellow fluorescent protein and in ROS17/2.8 osteoblast-like cells that express rPTH1R endogenously. The absence of calpain in Capn4-null embryonic fibroblasts and the lowered calpain activity in MC3T3-E1 osteoblastic cells due to stable expression of the calpain inhibitor, calpastatin, reduce PTH-stimulated cAMP accumulation. The calpain small subunit is the second protein, in addition to the sodium-hydrogen exchanger regulatory factor, and the first enzyme that binds the PTH1R; PTH1R bound to both of these proteins results in altered PTH signaling.
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Selim, A. A., M. Mahon, H. Juppner, F. R. Bringhurst, and P. Divieti. "Role of calcium channels in carboxyl-terminal parathyroid hormone receptor signaling." American Journal of Physiology-Cell Physiology 291, no. 1 (July 2006): C114—C121. http://dx.doi.org/10.1152/ajpcell.00566.2005.
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Parathyroid hormone (PTH), an 84-amino acid polypeptide, is a major systemic regulator of calcium homeostasis that activates PTH/PTHrP receptors (PTH1Rs) on target cells. Carboxyl fragments of PTH (CPTH), secreted by the parathyroids or generated by PTH proteolysis in the liver, circulate in blood at concentrations much higher than intact PTH-(1–84) but cannot activate PTH1Rs. Receptors specific for CPTH fragments (CPTHRs), distinct from PTH1Rs, are expressed by bone cells, especially osteocytes. Activation of CPTHRs was previously reported to modify intracellular calcium within chondrocytes. To further investigate the mechanism of action of CPTHRs in osteocytes, cytosolic free calcium concentration ([Ca2+]i) was measured in the PTH1R-null osteocytic cell line OC59, which expresses abundant CPTHRs but no PTH1Rs. [Ca2+]i was assessed by single-cell ratiometric microfluorimetry in fura-2-loaded OC59 cells. A rapid and transient increase in [Ca2+]i was observed in OC59 cells in response to the CPTH fragment hPTH-(53–84) (250 nM). No [Ca2+]i signal was observed in COS-7 cells, in which CPTHR binding also cannot be detected. Neither hPTH-(1–34) nor a mutant CPTH analog, [Ala55–57]hPTH-(53–84), that does not to bind to CPTHRs, increased [Ca2+]i in OC59 cells. The [Ca2+]i response to hPTH-(53–84) required the presence of extracellular calcium and was blocked by inhibitors of voltage-dependent calcium channels (VDCCs), including nifedipine (100 nM), ω-agatoxin IVA (10 nM), and ω-conotoxin GVIA (100 nM). We conclude that activation of CPTHRs in OC59 osteocytic cells leads to a rapid increase in influx of extracellular calcium, most likely through the opening of VDCCs.
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Bhandi, Shilpa, Ahmed Alkahtani, Rodolfo Reda, Mohammed Mashyakhy, Nezar Boreak, Prabhadevi C. Maganur, Satish Vishwanathaiah, et al. "Parathyroid Hormone Secretion and Receptor Expression Determine the Age-Related Degree of Osteogenic Differentiation in Dental Pulp Stem Cells." Journal of Personalized Medicine 11, no. 5 (April 27, 2021): 349. http://dx.doi.org/10.3390/jpm11050349.
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Objective: To demonstrate the levels of parathyroid hormone secretion and genetic expressions of parathyroid hormone (PTH) and PTH1 receptor (PTH1R) genes in the dental pulp stem cells (DPSCs) from different age groups before and after induction of osteogenic differentiation. In addition, we also wanted to check their correlation with the degree of osteogenic differentiation. Methods: Human primary DPSCs from three age groups (milk tooth (SHEDs), 7–12 years old; young DPSCs (yDPSCs), 20–40 years old; old DPSCs (oDPSCs), 60+ years old) were characterized for mesenchymal stem cell (MSC) markers. DPSCs were subjected to osteogenic differentiation and functional staining. Gene expression levels were analyzed by qRT-PCR. Surface receptor analysis was done by flow cytometry. Comparative protein levels were evaluated by ELISA. Results: All SHEDs, yDPSCs, and oDPSCs were found to be expressing mesenchymal stem cell markers. SHEDs showed more mineralization than yDPSCs and oDPSCs after osteogenic induction. SHEDs exhibited higher expression of PTH and PTH1R before and after osteogenic induction, and after osteogenic induction, SHEDs showed more expression for RUNX2, ALPL, and OCN. Higher levels of PTH were observed in SHEDs and yDPSCs, and the number of PTH1R positive cells was relatively lower in yDPSCs and oDPSCs than in SHEDs. After osteogenic induction, SHEDs were superior in the secretion of OPG, and the secretions of ALPL and PTH and the number of PTH1R positive cells were relatively low in the oDPSCs. Conclusions: The therapeutic quality of dental pulp stem cells is largely based on their ability to retain their stemness characteristics. This study emphasizes the criterion of aging, which affects the secretion of PTH by these cells, which in turn attenuates their osteogenic potential.
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Wang, Bin, Yanmei Yang, and Peter A. Friedman. "Na/H Exchange Regulatory Factor 1, a Novel AKT-associating Protein, Regulates Extracellular Signal-regulated Kinase Signaling through a B-Raf–Mediated Pathway." Molecular Biology of the Cell 19, no. 4 (April 2008): 1637–45. http://dx.doi.org/10.1091/mbc.e07-11-1114.
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Na/H exchange regulatory factor 1 (NHERF1) is a scaffolding protein that regulates signaling and trafficking of several G protein-coupled receptors (GPCRs), including the parathyroid hormone receptor (PTH1R). GPCRs activate extracellular signal-regulated kinase (ERK)1/2 through different mechanisms. Here, we characterized NHERF1 regulation of PTH1R-stimulated ERK1/2. Parathyroid hormone (PTH) stimulated ERK1/2 phosphorylation by a protein kinase A (PKA)-dependent, but protein kinase C-, cyclic adenosine 5′-monophosphate-, and Rap1-independent pathway in Chinese hamster ovary cells stably transfected with the PTH1R and engineered to express NHERF1 under the control of tetracycline. NHERF1 blocked PTH-induced ERK1/2 phosphorylation downstream of PKA. This suggested that NHERF1 inhibitory effects on ERK1/2 occur at a postreceptor locus. Forskolin activated ERK1/2, and this effect was blocked by NHERF1. NHERF1 interacted with AKT and inhibited ERK1/2 activation by decreasing the stimulatory effect of 14-3-3 binding to B-Raf, while increasing the inhibitory influence of AKT negative regulation on ERK1/2 activation. This novel regulatory mechanism provides a new model by which cytoplasmic adapter proteins modulate ERK1/2 activation through a receptor-independent mechanism involving B-Raf.
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Ortega, Arantxa, Ma Teresa Pérez de Prada, Petra J. Mateos-Cáceres, Priscila Ramos Mozo, Juan J. González-Armengol, Juan M. González del Castillo, Javier Martín Sánchez, et al. "Effect of parathyroid-hormone-related protein on human platelet activation." Clinical Science 113, no. 7 (September 3, 2007): 319–27. http://dx.doi.org/10.1042/cs20070010.
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Evidence suggests that PTHrP [PTH (parathyroid hormone)-related protein] can act as an inflammatory mediator in several pathological settings including cardiovascular disease. The aim of the present study was to determine whether PTHrP might be involved in human platelet activation. We used a turbidimetric method to determine platelet aggregation. The expression of PTH1R (PTH type 1 receptor) in human platelets was analysed by Western blot and flow cytometry analyses. PTHrP-(1–36) (10−7 mol/l) by itself failed to modify the activation of platelets. However, it significantly enhanced ADP-induced platelet activation, and also increased the ability of other agonists (thrombin, collagen and arachidonic acid) to induce platelet aggregation. H89 (10−6 mol/l) and 25×10−6 mol/l Rp-cAMPS (adenosine 3′,5′-cyclic monophosphorothioate Rp-isomer), two protein kinase A inhibitors, and 25×10−9 mol/l bisindolylmaleimide I, a protein kinase C inhibitor, partially decreased the enhancing effect of PTHrP-(1–36) on ADP-induced platelet activation. Meanwhile, 10−6 mol/l PTHrP-(7–34), a PTH1R antagonist, as well as 10−5 mol/l PD098059, a MAPK (mitogen-activated protein kinase) inhibitor, or a farnesyltransferase inhibitor abolished this effect of PTHrP-(1–36). Moreover, 10−7 mol/l PTHrP-(1–36) increased (2-fold over control) MAPK activation in human platelets. PTH1R was detected in platelets, and the number of platelets expressing it on their surface in patients during AMI (acute myocardial infarction) was not different from that in a group of patients with similar cardiovascular risk factors without AMI. Western blot analysis showed that total PTH1R protein levels were markedly higher in platelets from control than those from AMI patients. PTH1R was found in plasma, where its levels were increased in AMI patients compared with controls. In conclusion, human platelets express the PTH1R. PTHrP can interact with this receptor to enhance human platelet activation induced by several agonists through a MAPK-dependent mechanism.
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Zhao, Li-Hua, Shanshan Ma, Ieva Sutkeviciute, Dan-Dan Shen, X. Edward Zhou, Parker W. de Waal, Chen-Yao Li, et al. "Structure and dynamics of the active human parathyroid hormone receptor-1." Science 364, no. 6436 (April 11, 2019): 148–53. http://dx.doi.org/10.1126/science.aav7942.
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The parathyroid hormone receptor-1 (PTH1R) is a class B G protein–coupled receptor central to calcium homeostasis and a therapeutic target for osteoporosis and hypoparathyroidism. Here we report the cryo–electron microscopy structure of human PTH1R bound to a long-acting PTH analog and the stimulatory G protein. The bound peptide adopts an extended helix with its amino terminus inserted deeply into the receptor transmembrane domain (TMD), which leads to partial unwinding of the carboxyl terminus of transmembrane helix 6 and induces a sharp kink at the middle of this helix to allow the receptor to couple with G protein. In contrast to a single TMD structure state, the extracellular domain adopts multiple conformations. These results provide insights into the structural basis and dynamics of PTH binding and receptor activation.
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Tetzlaff, S., S. Ponsuksili, E. Murani, K. Schellander, and K. Wimmers. "SNP analysis, genotyping and mapping of the porcine <i>PTHR1</i> gene to chromosome 13 (Brief report)." Archives Animal Breeding 50, no. 3 (October 10, 2007): 320–21. http://dx.doi.org/10.5194/aab-50-320-2007.
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Abstract. The parathyroid hormone/parathyroid hormone like hormone type I receptor (PTHR1) belongs to the family of G protein-coupled receptors for peptide hormones, including parathyroid hormone (PTH) and parathyroid hormone like hormone (PTHLH), which participate in epithelial-mesenchymal interactions during the formation and differentiation of epithelial organs (FOLEY et al., 2001; CHOMDEJ et al., 2004). The function of PTHR1 and its ligands suggest its candidacy for traits related to the development of bones and joints but also of mammary gland. The porcine gene was screened for SNPs and assigned to SSC13.
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Pickard, Bryce W., Anthony B. Hodsman, Laurence J. Fraher, and Patricia H. Watson. "Type 1 Parathyroid Hormone Receptor (PTH1R) Nuclear Trafficking: Association of PTH1R with Importin α1and β." Endocrinology 147, no. 7 (July 2006): 3326–32. http://dx.doi.org/10.1210/en.2005-1408.
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Zangari, Maurizio, Caleb K. Stein, Shmuel Yaccoby, Donghoon Yoon, Christoph Heuck, Yogesh Jethava, Donald Johann, et al. "Higher Expressions of PTH Receptor Type 1 and/or 2 in Bone Marrow Is Associated to Longer Survival in Newly Diagnosed Myeloma Patients Enrolled in Total Therapy 3." Blood 124, no. 21 (December 6, 2014): 3409. http://dx.doi.org/10.1182/blood.v124.21.3409.3409.
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Abstract Higher Expressions of PTH Receptor Type 1 and/or 2 in Bone Marrow is Associated to Longer Survival in Newly Diagnosed Myeloma Patients Enrolled in Total Therapy 3 INTRODUCTION: The Total Therapy 3 enrolled 303 newly diagnosed multiple myeloma patients at Myeloma Institute for Research and Therapy. Protocol included 2 cycles of VTD-PACE (bortezomib, thalidomide, and dexamethasone and 4-day continuous infusions of cisplatin, doxorubicin, cyclophosphamide, and etoposide) as induction and consolidation therapy after melphalan-based tandem transplantation, which is followed by 3 years of intended maintenance with VTD in year 1 and thalidomide/dexamethasone in years 2 and 3. As part of the protocol, gene expression profiling was performed from baseline bone marrow biopsy samples in 178 individuals. We have previously reported the clinical correlation between response to bortezomib and serum parathyroid hormone variations in myeloma patients as well as the interaction between receptor 1 and proteasome inhibitors function in cell line and myeloma mouse model. In this study we examine the PTH receptor 1 and 2 expression levels and their correlation to survival in total therapy 3 enrolled patients. METHOD: Gene expression profiling was performed using Affymetrix U133 plus 2.0 Microarrays (Santa Clara, CA) in baseline bone marrow biopsy samples from 178 patients enrolled on total therapy 3. Of these 178 patients, 108 were male. The overall median age of these patients was 59 years old at enrollment; 10 % of patients were considered to have high risk disease by 70 GEP model. Cox proportional hazards analysis was performed on the MAS5 normalized log 2 expression values of PTH1R and PTH2R using overall survival as the end point. Optimal dichotomous break points were found for PTH1R and PTH2R that corresponded to the maximum log rank test statistic from all cox proportional hazard models examined. To confirm PTH receptor expression in bone marrow, we performed real-time PCR using Taqman probes (PTH1R: Assay ID Hs00174895_m1 and PTH2R: Assay ID Hs00175044_m1) on subset of samples. RESULTS: Based on cox proportional hazards regression of PTH1R and PTH2R expression values, patients with higher PTH1R and PTH2R expression demonstrated better survival compared to lower expressing patients. PTH1R expression above optimal break point of 8.92 had a hazard ratio of 0.583 with a 95% confidence interval of (0.351, 0.969) and logrank test p-value of 0.035. PTH2R expression above optimal break point of 6.85 had a hazard ratio of 0.541 with a 95% confidence interval of (0.323, 0.905) and logrank test p-value of 0.018. Furthermore, the patients that were lower expressed in both PTH1R and PTH2R performed significantly poorer in outcome (n= 24 and median survival of 4.52 years logrank p-value+5.71e-05). Real-time PCR using Taqman probes was able to demonstrate relatively high levels of PTH1R and PTHR2 transcripts at bone marrow level. Figure 1 Figure 1. CONCLUSIONS: This is the first report indicating that PTH receptors type 1 and 2 gene expression levels are positively associated to overall survival in symptomatic multiple myeloma patients. Also we describe the presence of PTH2R at bone marrow level which function appear associated to myeloma control. These data confirm the correlation and close interaction between the survival of multiple myeloma patients and the parathyroid hormone axis. Disclosures Zangari: Norvartis: Membership on an entity's Board of Directors or advisory committees; Onyx: Research Funding; Millennium: Research Funding. Heuck:Celgene: Honoraria; Foundation Medicine: Honoraria; Millennium: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. van Rhee:Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees. Morgan:Celgene Corp: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Myeloma UK: Membership on an entity's Board of Directors or advisory committees; International Myeloma Foundation: Membership on an entity's Board of Directors or advisory committees; The Binding Site: Membership on an entity's Board of Directors or advisory committees; MMRF: Membership on an entity's Board of Directors or advisory committees.
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Li, Mengrong, Yiqiong Bao, Ran Xu, Miaomiao Li, Lili Xi, and Jingjing Guo. "Understanding the Allosteric Modulation of PTH1R by a Negative Allosteric Modulator." Cells 12, no. 1 (December 22, 2022): 41. http://dx.doi.org/10.3390/cells12010041.
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The parathyroid hormone type 1 receptor (PTH1R) acts as a canonical class B G protein-coupled receptor, regulating crucial functions including calcium homeostasis and bone formation. The identification and development of PTH1R non-peptide allosteric modulators have obtained widespread attention. It has been found that a negative allosteric modulator (NAM) could inhibit the activation of PTH1R, but the implied mechanism remains unclear. Herein, extensive molecular dynamics simulations together with multiple analytical approaches are utilized to unravel the mechanism of PTH1R allosteric inhibition. The results suggest that the binding of NAM destabilizes the structure of the PTH1R–PTH–spep/qpep (the C terminus of Gs/Gq proteins) complexes. Moreover, the presence of NAM weakens the binding of PTH/peps (spep and qpep) and PTH1R. The intra- and inter-molecular couplings are also weakened in PTH1R upon NAM binding. Interestingly, compared with our previous study of the positive allosteric effects induced by extracellular Ca2+, the enhanced correlation between the PTH and G-protein binding sites is significantly reduced by the replacement of this negative allosteric regulator. Our findings might contribute to the development of new therapeutic agents for diseases caused by the abnormal activation of PTH1R.
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Pickard, Bryce W., Anthony B. Hodsman, Laurence J. Fraher, and Patricia H. Watson. "Type 1 Parathyroid Hormone Receptor (PTH1R) Nuclear Trafficking: Regulation of PTH1R Nuclear-Cytoplasmic Shuttling by Importin-α/β and Chromosomal Region Maintenance 1/Exportin 1." Endocrinology 148, no. 5 (May 1, 2007): 2282–89. http://dx.doi.org/10.1210/en.2007-0157.
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The type 1 PTH/PTH-related peptide receptor (PTH1R) is a class B G protein-coupled receptor that demonstrates immunoreactivity in the nucleus as well as cytoplasm of target cells. Our previous studies on the PTH1R have shown that it associates with the importin family of transport regulatory proteins. To investigate the role of the importins in PTH1R nuclear import, we used small interfering (si)RNA technology to knock down the expression of importin-β in the mouse osteoblast-like cell line, MC3T3-E1. Immunofluorescence microscopy as well as ligand blotting for PTH1R in nuclear fractions of importin-β siRNA-treated cells demonstrated a decrease in nuclear localization of the PTH1R in comparison with control cells. Under normal culture conditions, PTH1R is present in both the nucleus and cytoplasm of cells. Serum starvation favors nuclear localization of PTH1R, whereas returning cells to serum or treatment with PTH-related peptide induced its cytoplasmic localization. To address the nuclear export of PTH1R, interactions between PTH1R and chromosomal region maintenance 1 (CRM1) were investigated. PTH1R and CRM1 coimmunoprecipitated from MC3T3-E1 cells, suggesting that CRM1 and PTH1R form a complex in vivo. After treatment with leptomycin B, a specific inhibitor of CRM1-mediated nuclear export, PTH1R accumulated in the nucleus. Taken together, our studies show that PTH1R shuttles from the nucleus to the cytoplasm under normal physiological conditions and that this nuclear-cytoplasmic transport is dependent upon importin-α/β and CRM1.
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Calvi, Laura M., Olga Bromberg, Yumie Rhee, Jonathan M. Weber, Julianne N. P. Smith, Miles J. Basil, Benjamin J. Frisch, and Teresita Bellido. "Osteoblastic expansion induced by parathyroid hormone receptor signaling in murine osteocytes is not sufficient to increase hematopoietic stem cells." Blood 119, no. 11 (March 15, 2012): 2489–99. http://dx.doi.org/10.1182/blood-2011-06-360933.
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Abstract Microenvironmental expansion of hematopoietic stem cells (HSCs) is induced by treatment with parathyroid hormone (PTH) or activation of the PTH receptor (PTH1R) in osteoblastic cells; however, the osteoblastic subset mediating this action of PTH is unknown. Osteocytes are terminally differentiated osteoblasts embedded in mineralized bone matrix but are connected with the BM. Activation of PTH1R in osteocytes increases osteoblastic number and bone mass. To establish whether osteocyte-mediated PTH1R signaling expands HSCs, we studied mice expressing a constitutively active PTH1R in osteocytes (TG mice). Osteoblasts, osteoclasts, and trabecular bone were increased in TG mice without changes in BM phenotypic HSCs or HSC function. TG mice had progressively increased trabecular bone but decreased HSC function. In severely affected TG mice, phenotypic HSCs were decreased in the BM but increased in the spleen. TG osteocytes had no increase in signals associated with microenvironmental HSC support, and the spindle-shaped osteoblastic cells that increased with PTH treatment were not present in TG bones. These findings demonstrate that activation of PTH1R signaling in osteocytes does not expand BM HSCs, which are instead decreased in TG mice. Therefore, osteocytes do not mediate the HSC expansion induced by PTH1R signaling. Further, osteoblastic expansion is not sufficient to increase HSCs.
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Rubin, David A., and Harald Jüppner. "Zebrafish Express the Common Parathyroid Hormone/Parathyroid Hormone-related Peptide Receptor (PTH1R) and a Novel Receptor (PTH3R) That Is Preferentially Activated by Mammalian and Fugufish Parathyroid Hormone-related Peptide." Journal of Biological Chemistry 274, no. 40 (October 1, 1999): 28185–90. http://dx.doi.org/10.1074/jbc.274.40.28185.
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Izumida, E., T. Suzawa, Y. Miyamoto, A. Yamada, M. Otsu, T. Saito, T. Yamaguchi, et al. "Functional Analysis of PTH1R Variants Found in Primary Failure of Eruption." Journal of Dental Research 99, no. 4 (January 27, 2020): 429–36. http://dx.doi.org/10.1177/0022034520901731.
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Although many variants of the parathyroid hormone 1 receptor (PTH1R) gene are known to be associated with primary failure of eruption (PFE), the mechanisms underlying the link remains poorly understood. We here performed functional analyses of PTH1R variants reported in PFE patients—namely, 356C>T (P119L), 395C>T (P132L), 439C>T (R147C), and 1148G>A (R383Q)—using HeLa cells with a lentiviral vector-mediated genetic modification. Two particular variants, P119L and P132L, had severe reduction in a level of N-linked glycosylation when compared with wild-type PTH1R, whereas the other 2 showed modest alteration. PTH1R having P119L or P132L showed marked decrease in the affinity to PTH1-34, which likely led to severely impaired cAMP accumulation upon stimulation in cells expressing these mutants, highlighting the importance of these 2 amino acid residues for ligand-mediated proper functioning of PTH1R. To further gain insights into PTH1R functions, we established the induced pluripotent stem cell (iPSC) lines from a patient with PFE and the heterozygous P132L mutation. When differentiated into osteoblastic-lineage cells, PFE-iPSCs showed no abnormality in mineralization. The mRNA expression of RUNX2, SP7, and BGLAP, the osteoblastic differentiation-related genes, and that of PTH1R were augmented in both PFE-iPSC-derived cells and control iPSC-derived cells in the presence of bone morphogenetic protein 2. Also, active vitamin D3 induced the expression of RANKL, a major key factor for osteoclastogenesis, equally in osteoblastic cells derived from control and PFE-iPSCs. In sharp contrast, exposure to PTH1-34 resulted in no induction of RANKL mRNA expression in the cells expressing P132L variant PTH1R, consistent with the idea that a type of heterozygous PTH1R gene mutation would spoil PTH-dependent response in osteoblasts. Collectively, this study demonstrates a link between PFE-associated genetic alteration and causative functional impairment of PTH1R, as well as a utility of iPSC-based disease modeling for future elucidation of pathogenesis in genetic disorders, including PFE.
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Massfelder, Thierry, Nathalie Taesch, Samuel Fritsch, Anne Eichinger, Mariette Barthelmebs, Andrew F. Stewart, and Jean-Jacques Helwig. "Type 1 Parathyroid Hormone Receptor Expression Level Modulates Renal Tone and Plasma Renin Activity in Spontaneously Hypertensive Rat." Journal of the American Society of Nephrology 13, no. 3 (March 2002): 639–48. http://dx.doi.org/10.1681/asn.v133639.
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ABSTRACT. These studies examine whether PTHrP(1-36), a vasodilator, modulates BP and renal vascular resistance (RVR) in spontaneously hypertensive rat (SHR). Within the kidney of normotensive rats, PTHrP(1-36) was enriched in vessels. In vessels of SHR, PTHrP was upregulated by 40% and type 1 PTH receptor (PTH1R) was downregulated by 65% compared with normotensive rats. To investigate the role of endogenous PTHrP in the regulation of BP and RVR, SHR were subjected to somatic human (h)PTH1R gene delivery. Three weeks after a single intravenous injection of pcDNA1.1 plasmid containing the hPTH1R gene under the control of the cytomegalovirus promoter, hPTH1R mRNA was detected in all of the main organs. Within the kidney, the transgene was enriched in vessels. In the isolated perfused kidney, RVR was reduced by 23% and PTHrP(1-36)–induced vasodilation, which is depressed in SHR, was restored and a vasoconstrictory response to PTH(3-34), a PTH1R antagonist, was revealed. These effects were not observed in control SHR treated with empty plasmid. BP remained unchanged, and plasma renin activity increased by 60%. Thus, in SHR renal vessels, a reduced number of PTH1R contributes to the high RVR, despite the higher expression of vasodilatory PTHrP. Moreover, these studies provide evidence for a direct link between the density of PTH1R and plasma renin activity, which might be responsible for the absence of effect of PTH1R gene delivery on BP in SHR. Overall, PTHrP significantly contributes to the homeostasis of renal and systemic hemodynamics in SHR.
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Zindel, Diana, Sandra Engel, Andrew R. Bottrill, Jean-Philippe Pin, Laurent Prézeau, Andrew B. Tobin, Moritz Bünemann, Cornelius Krasel, and Adrian J. Butcher. "Identification of key phosphorylation sites in PTH1R that determine arrestin3 binding and fine-tune receptor signaling." Biochemical Journal 473, no. 22 (November 10, 2016): 4173–92. http://dx.doi.org/10.1042/bcj20160740.
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The parathyroid hormone receptor 1 (PTH1R) is a member of family B of G-protein-coupled receptors (GPCRs), predominantly expressed in bone and kidney where it modulates extracellular Ca2+ homeostasis and bone turnover. It is well established that phosphorylation of GPCRs constitutes a key event in regulating receptor function by promoting arrestin recruitment and coupling to G-protein-independent signaling pathways. Mapping phosphorylation sites on PTH1R would provide insights into how phosphorylation at specific sites regulates cell signaling responses and also open the possibility of developing therapeutic agents that could target specific receptor functions. Here, we have used mass spectrometry to identify nine sites of phosphorylation in the C-terminal tail of PTH1R. Mutational analysis revealed identified two clusters of serine and threonine residues (Ser489–Ser495 and Ser501–Thr506) specifically responsible for the majority of PTH(1–34)-induced receptor phosphorylation. Mutation of these residues to alanine did not affect negatively on the ability of the receptor to couple to G-proteins or activate extracellular-signal-regulated kinase 1/2. Using fluorescence resonance energy transfer and bioluminescence resonance energy transfer to monitor PTH(1–34)-induced interaction of PTH1R with arrestin3, we show that the first cluster Ser489–Ser495 and the second cluster Ser501–Thr506 operated in concert to mediate both the efficacy and potency of ligand-induced arrestin3 recruitment. We further demonstrate that Ser503 and Thr504 in the second cluster are responsible for 70% of arrestin3 recruitment and are key determinants for interaction of arrestin with the receptor. Our data are consistent with the hypothesis that the pattern of C-terminal tail phosphorylation on PTH1R may determine the signaling outcome following receptor activation.
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Leonard, Anthony P., Kathryn M. Appleton, Louis M. Luttrell, and Yuri K. Peterson. "A High-Content, Live-Cell, and Real-Time Approach to the Quantitation of Ligand-Induced β-Arrestin2 and Class A/Class B GPCR Mobilization." Microscopy and Microanalysis 19, no. 1 (January 28, 2013): 150–70. http://dx.doi.org/10.1017/s1431927612014067.
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AbstractWe report the development of a method to analyze receptor and β-arrestin2 mobilization between Class A and B GPCRs via time-resolved fluorescent microscopy coupled with semiautomated high-content multiparametric analysis. Using transiently expressed, tagged β2-adrenergic receptor (β2-AR) or parathyroid hormone receptor type 1 (PTH1R), we quantified trafficking of the receptors along with the mobilization and colocalization of coexpressed tagged β-arrestin2. This classification system allows for exclusion of cells with nonoptimal characteristics and calculation of multiple morphological and spatial parameters including receptor endosome formation, β-arrestin mobilization, colocalization, areas, and shape. Stimulated Class A and B receptors demonstrate dramatically different patterns with regard to β-arrestin interactions. The method provides high kinetic resolution measurement of receptor translocation, which allows for the identification of the fleeting β-arrestin interaction found with β2-AR agonist stimulation, in contrast to stronger mobilization and receptor colocalization with agonist stimulation of the PTH1R. Though especially appropriate for receptor kinetic studies, this method is generalizable to any dual fluorescence probe system in which quantification of object formation and movement is desired. These methodologies allow for quantitative, unbiased measurement of microscopy data and are further enhanced by providing real-time kinetics.
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Sims, Natalie A. "VPS35: Two Ways to Recycle the Parathyroid Hormone Receptor (PTH1R) in Osteoblasts." EBioMedicine 9 (July 2016): 3–4. http://dx.doi.org/10.1016/j.ebiom.2016.06.029.
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Martin, T. John, Natalie A. Sims, and Ego Seeman. "Physiological and Pharmacological Roles of PTH and PTHrP in Bone Using Their Shared Receptor, PTH1R." Endocrine Reviews 42, no. 4 (February 10, 2021): 383–406. http://dx.doi.org/10.1210/endrev/bnab005.
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Abstract Parathyroid hormone (PTH) and the paracrine factor, PTH-related protein (PTHrP), have preserved in evolution sufficient identities in their amino-terminal domains to share equivalent actions upon a common G protein-coupled receptor, PTH1R, that predominantly uses the cyclic adenosine monophosphate-protein kinase A signaling pathway. Such a relationship between a hormone and local factor poses questions about how their common receptor mediates pharmacological and physiological actions of the two. Mouse genetic studies show that PTHrP is essential for endochondral bone lengthening in the fetus and is essential for bone remodeling. In contrast, the main postnatal function of PTH is hormonal control of calcium homeostasis, with no evidence that PTHrP contributes. Pharmacologically, amino-terminal PTH and PTHrP peptides (teriparatide and abaloparatide) promote bone formation when administered by intermittent (daily) injection. This anabolic effect is remodeling-based with a lesser contribution from modeling. The apparent lesser potency of PTHrP than PTH peptides as skeletal anabolic agents could be explained by lesser bioavailability to PTH1R. By contrast, prolongation of PTH1R stimulation by excessive dosing or infusion, converts the response to a predominantly resorptive one by stimulating osteoclast formation. Physiologically, locally generated PTHrP is better equipped than the circulating hormone to regulate bone remodeling, which occurs asynchronously at widely distributed sites throughout the skeleton where it is needed to replace old or damaged bone. While it remains possible that PTH, circulating within a narrow concentration range, could contribute in some way to remodeling and modeling, its main physiological role is in regulating calcium homeostasis.
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Sato, Tadatoshi, Marie Courbebaisse, Noriko Ide, Yi Fan, Jun-ichi Hanai, Jovana Kaludjerovic, Michael J. Densmore, et al. "Parathyroid hormone controls paracellular Ca2+ transport in the thick ascending limb by regulating the tight-junction protein Claudin14." Proceedings of the National Academy of Sciences 114, no. 16 (April 3, 2017): E3344—E3353. http://dx.doi.org/10.1073/pnas.1616733114.
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Renal Ca2+ reabsorption is essential for maintaining systemic Ca2+ homeostasis and is tightly regulated through the parathyroid hormone (PTH)/PTHrP receptor (PTH1R) signaling pathway. We investigated the role of PTH1R in the kidney by generating a mouse model with targeted deletion of PTH1R in the thick ascending limb of Henle (TAL) and in distal convoluted tubules (DCTs): Ksp-cre;Pth1rfl/fl. Mutant mice exhibited hypercalciuria and had lower serum calcium and markedly increased serum PTH levels. Unexpectedly, proteins involved in transcellular Ca2+ reabsorption in DCTs were not decreased. However, claudin14 (Cldn14), an inhibitory factor of the paracellular Ca2+ transport in the TAL, was significantly increased. Analyses by flow cytometry as well as the use of Cldn14-lacZ knock-in reporter mice confirmed increased Cldn14 expression and promoter activity in the TAL of Ksp-cre;Pth1rfl/fl mice. Moreover, PTH treatment of HEK293 cells stably transfected with CLDN14-GFP, together with PTH1R, induced cytosolic translocation of CLDN14 from the tight junction. Furthermore, mice with high serum PTH levels, regardless of high or low serum calcium, demonstrated that PTH/PTH1R signaling exerts a suppressive effect on Cldn14. We therefore conclude that PTH1R signaling directly and indirectly regulates the paracellular Ca2+ transport pathway by modulating Cldn14 expression in the TAL. Finally, systemic deletion of Cldn14 completely rescued the hypercalciuric and lower serum calcium phenotype in Ksp-cre;Pth1rfl/fl mice, emphasizing the importance of PTH in inhibiting Cldn14. Consequently, suppressing CLDN14 could provide a potential treatment to correct urinary Ca2+ loss, particularly in patients with hypoparathyroidism.
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Dean, Thomas, Thomas Gardella, Harald Jüppner, Sophia Savransky, Jean-Pierre Vilardaga, and Ignacio Portales-Castillo. "OR21-3 Spatial Signaling Bias of a Gain-of-Function PTH1R Mutant Associated with Delayed Ossification in Eiken Syndrome." Journal of the Endocrine Society 6, Supplement_1 (November 1, 2022): A194. http://dx.doi.org/10.1210/jendso/bvac150.400.
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Abstract Skeletal development is orchestrated by the interaction of the parathyroid hormone related peptide (PTHrP) with the parathyroid hormone receptor type 1 (PTH1R). Knock-out or severe deficiency of either PTH1R or PTHrP by homozygous loss-of-function mutations results in premature hypertrophy of chondrocytes and accelerated bone mineralization, leading to neonatal death. In contrast, patients with a heterozygous gain-of-function PTH1R mutation (H223R, T410P/R or I458K/R) present with Jansen metaphyseal chondrodysplasia (JMC), characterized by delayed bone mineralization, hypercalcemia, hypercalciuria and hypophosphatemia. Eiken syndrome is also characterized by markedly delayed bone mineralization but lacks the biochemical abnormalities of JMC. Eiken syndrome has been described for three unrelated families, in which there are one of three homozygous PTH1R mutations: R485X, E35K or Y134S. As the functional properties of these PTH1R mutants have not been studied, we assessed their characteristics in cell-based assays. GS22A cells (HEK293/Glosensor) were transiently transfected to express the WT or a mutant PTH1R. Cell surface expression levels assessed by extracellular HA tag-directed immunofluorescence flow cytometry and normalized to PTH1R-WT (100%) were 50% for PTH1R-R485X, 90% for PTH1R-E35K and 20% for PTH1R-Y134S. Dynamic cAMP measurements via the Glosensor reporter revealed that the basal activities of PTH1R-R485X and PTH1R-E35K were 7-fold and 1.5-fold higher than that of PTH1R-WT (p<0.005), while that of PTH1R-Y134S was comparable to PTH1R-WT. Stimulation with PTH(1-34) or PTHrP(1-36) yielded similar cAMP potencies for the three mutants and PTH1R-WT (EC50s ∼ 0.5 nM, p >0.05). Intracellular calcium signaling assessed by changes in FURA2 fluorescence after PTHrP(1-36) (100 nM) addition was more robust with PTH1R-R485X than for PTH1R-WT (AUCs over 2.5 mins. = 606±9 vs 551±10, p=0.0074) and similar to PTH1R-WT with PTH1R-E35K and PTH1R-Y134S (p ≥0.2). Both basal and agonist-activated cAMP signaling by the R485X mutant were reduced by addition of a dTrp12-PTHrP(7-36) antagonist/inverse agonist analog. Fluorescence microscopy of HEK293/βarrestin2YFP (GBR24) cells stimulated with TMRPTH(1-34) revealed a clear association of βarrestin2YFP with PTH1R-WT, as well as with PTH1R-E35K and PTH1R-Y134S in internalized complexes, but no such association with PTH1R-R485X. Nevertheless, over-expression of βarrestin2YFP in GS22A cells markedly reduced basal and ligand-stimulated cAMP generation by PTH1R-R485X, consistent with a residual capacity of PTH1R-485X to bind βarrestin2. Treatment with the endocytosis inhibitor Dyngo4A in GS22A cells transfected with PTH1R-R485X completely blocked TMRPTH(1-34) internalization assessed by fluorescent microscopy, and enhanced ∼5-fold the cAMP response potency to PTH(1-34) vs DMSO treatment. In contrast, treatment with Dyngo4A did not increase PTH(1-34) cAMP potency in the PTH1R-WT. Collectively these results suggest that PTH1R-R485X signals via cAMP predominantly from the cell surface. The data reveal distinct functional properties for the three PTH1R mutants associated with Eiken syndrome and suggest a novel correlation between excessive PTH1R cAMP signaling due to impaired βarrestin-mediated internalization and a delay in ossification. Presentation: Monday, June 13, 2022 11:30 a.m. - 11:45 a.m.
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Kamel, Suzan A., and John A. Yee. "Continuous and intermittent exposure of neonatal rat calvarial cells to PTHrP (1-36) inhibits bone nodule mineralization in vitro by downregulating bone sialoprotein expression via the cAMP signaling pathway." F1000Research 2 (June 13, 2013): 77. http://dx.doi.org/10.12688/f1000research.2-77.v2.
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The development and growth of the skeleton in the absence of parathyroid-hormone-related protein (PTHrP) is abnormal. The shortening of appendicular bones in PTHrP gene null mice is explained by an effect of PTHrP on endochondral bone growth. Whether or not PTHrP influences intramembranous ossification is less clear. The purpose of this study was to determine the effect of exogenous PTHrP on intramembranous ossificationin vitro. Neonatal rat calvarial cells maintained in primary cell culture conditions that permit spontaneous formation of woven bone nodules by intramembranous ossification were studied. The expression of PTHrP, parathyroid hormone 1 receptor (PTH1R), and alkaline phosphatase (AP) by osteogenic cells in developing nodules and the effects of PTHrP (1-36) on nodule development was determined over 3-18 days. PTHrP and PTH1R were detected colonies of osteogenic cells on culture day three, and AP was detected on day six. PTHrP and its receptor were localized in pre-osteoblasts, osteoblasts, and osteocytes, and AP activity was detected in pre-osteoblasts and osteoblasts but not osteocytes. Continuous and intermittent exposure to PTHrP (1-36) decreased the number of mineralized bone nodules and bone sialoprotein (BSP) mRNA and protein, but had no effect on the number of AP-positive osteogenic cell colonies, cell proliferation, apoptosis, or osteopontin (OPN) mRNA. These results demonstrate that osteogenic cells that participate in the formation of woven bone nodulesin vitroexhibit PTHrP and PTH1R before they demonstrate AP activity. Exogenous PTHrP (1-36) inhibits the mineralization of woven bone deposited during bone nodule formationin vitro,possibly by reducing the expression of BSP.
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Grippaudo, Cristina, Concetta Cafiero, Isabella D'Apolito, Beatrice Ricci, and Sylvia A. Frazier-Bowers. "Primary failure of eruption: Clinical and genetic findings in the mixed dentition." Angle Orthodontist 88, no. 3 (January 29, 2018): 275–82. http://dx.doi.org/10.2319/062717-430.1.
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ABSTRACT Objective: To test the hypothesis that mutations in the parathyroid hormone 1 receptor (PTH1R) include effects in both primary and permanent teeth. Materials and Methods: DNA was extracted from saliva samples of 29 patients (8 familial and 21 sporadic) who presented with clinical evidence of infraoccluded teeth, and their unaffected relatives (N = 22). Sequencing followed by mutational analysis of the coding regions of PTH1R gene was completed for all individuals (N = 29). Results: Eight of 29 cases revealed a heterozygous pathogenic variant in the PTH1R gene; five of eight variants represented distinct mutations based on comparison with the dbSNP, HGMD, and ESP databases. One mutation (c.1765 T>C p.Trp89Arg) was found to segregate within a family (n = 3). In silico analyses for all variants revealed a putative pathogenic effect. A genotype-phenotype correlation was reported as defined by a functional mutation in PTH1R and corresponding effects on one or more posterior teeth only; unilateral or bilateral involvement, infraoccluded primary teeth. Conclusions: Novel mutations were reported in the PTH1R gene that included PFE-affected primary molars, thus providing the basis for using a genetic diagnostic tool for early diagnosis leading to proper management.
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Datta, Nabanita S., Tareq A. Samra, Chandrika D. Mahalingam, Tanuka Datta, and Abdul B. Abou-Samra. "Role of PTH1R internalization in osteoblasts and bone mass using a phosphorylation-deficient knock-in mouse model." Journal of Endocrinology 207, no. 3 (October 7, 2010): 355–65. http://dx.doi.org/10.1677/joe-10-0227.
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Phosphorylation, internalization, and desensitization of G protein-coupled receptors, such as the parathyroid hormone (PTH) and PTH-related peptide (PTHrP) receptor (PTH1R), are well characterized and known to regulate the cellular responsiveness in vitro. However, the role of PTH1R receptor phosphorylation in bone formation and osteoblast functions has not yet been elucidated. In previous studies, we demonstrated impaired internalization and sustained cAMP stimulation of a phosphorylation-deficient (pd) PTH1R in vitro, and exaggerated cAMP and calcemic responses to s.c. PTH infusion in pdPTH1R knock-in mouse model. In this study, we examined the impact of impaired PTH1R phosphorylation on the skeletal phenotype of mice maintained on normal, low, and high calcium diets. The low calcium diet moderately reduced (P<0.05) bone volume and trabecular number, and increased trabecular spacing in both wild-type (WT) and pd mice. The effects, however, seem to be less pronounced in the female pd compared to WT mice. In primary calvarial osteoblasts isolated from 2-week-old pd or WT mice, PTH and PTHrP decreased phosphorylated extracellular signal-regulated kinases 1/2 (pERK1/2), a member of mitogen-activated protein kinase, and cyclin D1, a G1/S phase cyclin, in vitro. In contrast to WT osteoblasts, down-regulation of cyclin D1 was sustained for longer periods of time in osteoblasts isolated from the pd mice. Our results suggest that adaptive responses of intracellular signaling pathways in the pd mice may be important for maintaining bone homeostasis.
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Chauvin, Stephanie, Margaret Bencsik, Tom Bambino, and Robert A. Nissenson. "Parathyroid Hormone Receptor Recycling: Role of Receptor Dephosphorylation and β-Arrestin." Molecular Endocrinology 16, no. 12 (December 1, 2002): 2720–32. http://dx.doi.org/10.1210/me.2002-0049.
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Abstract The recovery of PTH receptor (PTHR) function after acute homologous receptor desensitization and down-regulation in bone and kidney cells has been attributed to receptor recycling. To determine the role of receptor dephosphorylation in PTHR recycling, we performed morphological and functional assays on human embryonic kidney 293 cells stably expressing wild-type (wt) or mutant PTHRs. Confocal microscopy and ligand binding assays revealed that the wt PTHR is rapidly recycled back to the plasma membrane after removal of the agonist. Receptors that were engineered to either lack the sites of phosphorylation or to resemble constitutively phosphorylated receptors were able to recycle back to the plasma membrane with the same kinetics as the wt PTHR. The PTHR was found to be dephosphorylated by an enzyme apparently distinct from protein phosphatases 1 or 2A. The PTHR and β-arrestin-2-green fluorescent protein (GFP) were found to stably colocalize during PTHR internalization, whereas after agonist removal and during receptor recycling, the colocalization slowly disappeared. Experiments using phosphorylation-deficient PTHRs and a dominant-negative form of β-arrestin showed that β-arrestin does not regulate the efficiency of PTHR recycling. These studies indicate that, unlike many G protein-coupled receptors, PTHR recycling does not require receptor dephosphorylation or its dissociation from β-arrestin.
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Meziani, Ferhat, Angela Tesse, Sandra Welsch, Hélène Kremer, Mariette Barthelmebs, Ramaroson Andriantsitohaina, Francis Schneider, and Alexis Gairard. "Expression and Biological Activity of Parathyroid Hormone-Related Peptide in Pregnant Rat Uterine Artery: Any Role for 8-Iso-Prostaglandin F2α?" Endocrinology 149, no. 2 (November 29, 2007): 626–33. http://dx.doi.org/10.1210/en.2007-0568.
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PTHrP is produced in vessels and acts as a local modulator of tone. We recently reported that PTHrP(1–34) is able to induce vasorelaxation in rat uterine arteries, but in pregnancy, this response is blunted and becomes strictly endothelium dependent. The present study aimed to get insights into the mechanisms involved in these changes because the adaptation of uterine blood flow is essential for fetal development. On d 20 of gestation, RT-PCR analysis of uterine arteries showed that PTH/PTHrP receptor (PTH1R) mRNA expression was decreased, whereas that of PTHrP mRNA was increased. This was associated with a redistribution of the PTHrP/PTH1R system, with both PTH1R protein and PTHrP peptide becoming concentrated in the intimal layer of arteries from pregnant rats. On the other hand, the blunted vasorelaxation induced by PTHrP(1–34) in uterine arteries from pregnant rats was specifically restored by indomethacin and a specific cyclooxygenase-2 inhibitor, NS 398. This was associated with an increase in cyclooxygenase-2 expression and in 8-iso-prostaglandin F2α release when uterine arteries from pregnant rats were exposed to high levels of PTHrP(1–34). Most interestingly, 8-iso-prostaglandin F2α itself was able to increase PTHrP expression and reduce PTH1R expression in cultured rat aortic smooth muscle cells. These results suggest a local regulation of uterine artery functions by PTHrP during pregnancy resulting from PTH1R redistribution. Moreover, they shed light on a potential role of 8-iso-prostaglandin F2α.
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Zhang, D., S. Zhang, J. Wang, Q. Li, H. Xue, R. Sheng, Q. Xiong, et al. "LepR-Expressing Stem Cells Are Essential for Alveolar Bone Regeneration." Journal of Dental Research 99, no. 11 (June 25, 2020): 1279–86. http://dx.doi.org/10.1177/0022034520932834.
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Stem cells play a critical role in bone regeneration. Multiple populations of skeletal stem cells have been identified in long bone, while their identity and functions in alveolar bone remain unclear. Here, we identified a quiescent leptin receptor–expressing (LepR+) cell population that contributed to intramembranous bone formation. Interestingly, these LepR+ cells became activated in response to tooth extraction and generated the majority of the newly formed bone in extraction sockets. In addition, genetic ablation of LepR+ cells attenuated extraction socket healing. The parabiosis experiments revealed that the LepR+ cells in the healing sockets were derived from resident tissue rather than peripheral blood circulation. Further studies on the mechanism suggested that these LepR+ cells were responsive to parathyroid hormone/parathyroid hormone 1 receptor (PTH/PTH1R) signaling. Collectively, we demonstrate that LepR+ cells, a postnatal skeletal stem cell population, are essential for alveolar bone regeneration of extraction sockets.
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Bosch, Ricardo J., Arantxa Ortega, Adriana Izquierdo, Ignacio Arribas, Jordi Bover, and Pedro Esbrit. "A Transgenic Mouse Model for Studying the Role of the Parathyroid Hormone-Related Protein System in Renal Injury." Journal of Biomedicine and Biotechnology 2011 (2011): 1–7. http://dx.doi.org/10.1155/2011/290874.
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Parathyroid hormone- (PTH-) related protein (PTHrP) and its receptor, the PTH1 receptor (PTH1R), are widely expressed in the kidney, where PTHrP exerts a modulatory action on renal function. PTHrP is known to be upregulated in several experimental nephropathies such as acute renal failure (ARF), obstructive nephropathy (ON) as well as diabetic nephropathy (DN). In this paper, we will discuss the functional consequences of chronic PTHrP overexpression in the damaged kidney using a transgenic mouse strain overexpressing PTHrP in the renal proximal tubule. In both ARF and ON, PTHrP displays proinflammatory and profibrogenic actions including the induction of epithelia to mesenquima transition. Moreover, PTHrP participates in the mechanisms of renal hypertrophy as well as proteinuria in experimental DN. Angiotensin II (Ang II), a critical factor in the progression of renal injury, appears to be, at least in part, responsible for endogenous PTHrP upregulation in these pathophysiological settings. These findings provide novel insights into the well-known protective effects of Ang II antagonists in renal diseases, paving the way for new therapeutic approaches.
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Yang, Hongxu, Mian Zhang, Qian Liu, Hongyun Zhang, Jing Zhang, Lei Lu, Mianjiao Xie, Di Chen, and Meiqing Wang. "Inhibition of Ihh Reverses Temporomandibular Joint Osteoarthritis via a PTH1R Signaling Dependent Mechanism." International Journal of Molecular Sciences 20, no. 15 (August 3, 2019): 3797. http://dx.doi.org/10.3390/ijms20153797.
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The temporomandibular joint (TMJ), which is biomechanically related to dental occlusion, is often insulted by osteoarthritis (OA). This study was conducted to clarify the relationship between Indian hedgehog (Ihh) and parathyroid hormone receptor 1 (PTH1R) signaling in modulating the enhanced chondrocyte terminal differentiation in dental stimulated TMJ osteoarthritic cartilage. A gain- and loss-of-function strategy was used in an in vitro model in which fluid flow shear stress (FFSS) was applied, and in an in vivo model in which the unilateral anterior cross-bite (UAC) stimulation was adopted. Ihh and PTH1R signaling was modulated through treating the isolated chondrocytes with inhibitor/activator and via deleting Smoothened (Smo) and/or Pth1r genes in mice with the promoter gene of type 2 collagen (Col2-CreER) in the tamoxifen-inducible pattern. We found that both FFSS and UAC stimulation promoted the deep zone chondrocytes to undergo terminal differentiation, while cells in the superficial zone were robust. We demonstrated that the terminal differentiation process in deep zone chondrocytes promoted by FFSS and UAC was mediated by the enhanced Ihh signaling and declined PTH1R expression. The FFSS-promoted terminal differentiation was suppressed by administration of the Ihh inhibitor or PTH1R activator. The UAC-promoted chondrocytes terminal differentiation and OA-like lesions were rescued in Smo knockout, but were enhanced in Pth1r knockout mice. Importantly, the relieving effect of Smo knockout mice was attenuated when Pth1r knockout was also applied. Our data suggest a chondrocyte protective effect of suppressing Ihh signaling in TMJ OA cartilage which is dependent on PTH1R signaling.
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Potts, John T. "Parathyroid hormone: past and present." Journal of Endocrinology 187, no. 3 (December 2005): 311–25. http://dx.doi.org/10.1677/joe.1.06057.
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Research on parathyroid hormone (PTH) has undergone four rather distinctive phases, beginning just before the turn of the 20th century. Early debates about the function of the parathyroids were resolved by 1925, when understanding the role of PTH led to comprehending the action of the glands in calcium physiology. Elucidation of the pathophysiology of hormone excess (severe bone loss) and deficiency (hypocalcemia) continued over the following decades. With the advent of advances in chemical and molecular biology, the structure of PTH and its principal receptor (PTHrP-receptor [PTHR1]) were established. Tests with purified hormonal peptide in humans led to the surprising, even paradoxical, finding that PTH can be used pharmacologically to build bone, providing a dramatic therapeutic impact on osteoporosis. These developments have stimulated the field of calcium and bone biology and posed new questions about the role of PTH as well as possible new directions in therapy.
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Cui, C., R. Bi, W. Liu, S. Guan, P. Li, D. Song, R. Xu, et al. "Role of PTH1R Signaling in Prx1+ Mesenchymal Progenitors during Eruption." Journal of Dental Research 99, no. 11 (June 25, 2020): 1296–305. http://dx.doi.org/10.1177/0022034520934732.
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Tooth eruption is a complex process requiring precise interaction between teeth and adjacent tissues. Molecular analysis demonstrates that bone remodeling plays an essential role during eruption, suggesting that a parathyroid hormone 1 receptor (PTH1R) gene mutation is associated with disturbances in bone remodeling and results in primary failure of eruption (PFE). Recent research reveals the function of PTH1R signaling in mesenchymal progenitors, whereas the function of PTH1R in mesenchymal stem cells during tooth eruption remains incompletely understood. We investigated the specific role of PTH1R in Prx1+ progenitor expression during eruption. We found that Prx1+-progenitors occur in mesenchymal stem cells residing in alveolar bone marrow surrounding incisors, at the base of molars and in the dental follicle and pulp of incisors. Mice with conditional deletion of PTH1R using the Prx1 promoter exhibited arrested mandibular incisor eruption and delayed molar eruption. Micro–computed tomography, histomorphometry, and molecular analyses revealed that mutant mice had significantly reduced alveolar bone formation concomitant with downregulated gene expression of key regulators of osteogenesis in PTH1R-deficient cells. Moreover, culturing orofacial bone-marrow-derived mesenchymal stem cells (OMSCs) from Prx1Cre;PTH1Rfl/fl mice or from transfecting Cre recombinase adenovirus in OMSCs from PTH1Rfl/fl mice suggested that lack of Pth1r expression inhibited osteogenic differentiation in vitro. However, bone resorption was not affected by PTH1R ablation, indicating the observed reduced alveolar bone volume was mainly due to impaired bone formation. Furthermore, we found irregular periodontal ligaments and reduced Periostin expression in mutant incisors, implying loss of PTH1R results in aberrant differentiation of periodontal ligament cells. Collectively, these data suggest that PTH1R signaling in Prx1+ progenitors plays a critical role in alveolar bone formation and periodontal ligament development during eruption. These findings have implications for our understanding of the physiologic and pathologic function of PTH1R signaling in tooth eruption and the progression of PFE.
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Ruiz-Jarabo, Ignacio, Silvia F. Gregório, and Juan Fuentes. "Regulation of Stanniocalcin Secretion by Calcium and PTHrP in Gilthead Seabream (Sparus aurata)." Biology 11, no. 6 (June 4, 2022): 863. http://dx.doi.org/10.3390/biology11060863.
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Calcium balance is of paramount importance for vertebrates. In fish, the endocrine modulators of calcium homeostasis include the stanniocalcin (STC), and some members of the parathyroid hormone (PTH) family, such as the PTH-related protein (PTHrP), acting as antagonists. STC is ubiquitously expressed in higher vertebrates. In turn, bony fish exhibit specific STC-producing glands named the corpuscles of Stannius (CS). Previous studies pointed to a calcium-sensing receptor (CaSR) involvement in the secretion of STC, but little is known of the involvement of other putative regulators. The CS provides a unique model to deepen the study of STC secretion. We developed an ex vivo assay to culture CS of fish and a competitive ELISA method to measure STC concentrations. As expected, STC released from the CS responds to CaSR stimulation by calcium, calcimimetics, and calcilytic drugs. Moreover, we uncover the presence (by PCR) of two PTHrP receptors in the CS, e.g., PTH1R and PTH3R. Thus, ex vivo incubations revealed a dose-response inhibition of STC secretion in response to PTHrP at basal Ca2+ concentrations. This inhibition is achieved through specific and reversible second messenger pathways (transmembrane adenylyl cyclases and phospholipase C), as the use of specific inhibitors highlights. Together, these results provide evidence for endocrine modulation between two antagonist hormones, STC and PTHrP.
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Ide, Noriko, Rui Ye, Marie Courbebaisse, Hannes Olauson, Michael J. Densmore, Tobias E. Larsson, Jun-ichi Hanai, and Beate Lanske. "In vivo evidence for an interplay of FGF23/Klotho/PTH axis on the phosphate handling in renal proximal tubules." American Journal of Physiology-Renal Physiology 315, no. 5 (November 1, 2018): F1261—F1270. http://dx.doi.org/10.1152/ajprenal.00650.2017.
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Phosphate homeostasis is primarily maintained in the renal proximal tubules, where the expression of sodium/phosphate cotransporters (Npt2a and Npt2c) is modified by the endocrine actions of both fibroblast growth factor 23 (FGF23) and parathyroid hormone (PTH). However, the specific contribution of each regulatory pathway in the proximal tubules has not been fully elucidated in vivo. We have previously demonstrated that proximal tubule-specific deletion of the FGF23 coreceptor Klotho results in mild hyperphosphatemia with little to no change in serum levels of FGF23, 1,25(OH)2D3, and PTH. In the present study, we characterized mice in which the PTH receptor PTH1R was specifically deleted from the proximal tubules, either alone or in combination with Klotho ( PT-PTH1R−/− and PT-PTH1R/KL−/−, respectively). PT-PTH1R−/− mice showed significant increases in serum FGF23 and PTH levels, whereas serum phosphate levels were maintained in the normal range, and Npt2a and Npt2c expression in brush border membrane (BBM) did not change compared with control mice. In contrast, PT-PTH1R/KL−/− mice displayed hyperphosphatemia and an increased abundance of Npt2a and Npt2c in the renal BBM, along with increased circulating FGF23 levels. While serum calcium was normal, 1,25(OH)2D3 levels were significantly decreased, leading to extremely high levels of PTH. Collectively, mice with a deletion of PTH1R alone in proximal tubules results in only minor changes in phosphate regulation, whereas deletion of both PTH1R and Klotho leads to a severe disturbance, including hyperphosphatemia with increased sodium/phosphate cotransporter expression in BBM. These results suggest an important interplay between the PTH/PTH1R and FGF23/Klotho pathways to affect renal phosphate handling in the proximal tubules.
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Sinha, Partha, Piia Aarnisalo, Rhiannon Chubb, Ingrid J. Poulton, Jun Guo, Gregory Nachtrab, Takaharu Kimura, et al. "Loss of Gsα in the Postnatal Skeleton Leads to Low Bone Mass and a Blunted Response to Anabolic Parathyroid Hormone Therapy." Journal of Biological Chemistry 291, no. 4 (November 23, 2015): 1631–42. http://dx.doi.org/10.1074/jbc.m115.679753.
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Parathyroid hormone (PTH) is an important regulator of osteoblast function and is the only anabolic therapy currently approved for treatment of osteoporosis. The PTH receptor (PTH1R) is a G protein-coupled receptor that signals via multiple G proteins including Gsα. Mice expressing a constitutively active mutant PTH1R exhibited a dramatic increase in trabecular bone that was dependent upon expression of Gsα in the osteoblast lineage. Postnatal removal of Gsα in the osteoblast lineage (P-GsαOsxKO mice) yielded markedly reduced trabecular and cortical bone mass. Treatment with anabolic PTH(1–34) (80 μg/kg/day) for 4 weeks failed to increase trabecular bone volume or cortical thickness in male and female P-GsαOsxKO mice. Surprisingly, in both male and female mice, PTH administration significantly increased osteoblast numbers and bone formation rate in both control and P-GsαOsxKO mice. In mice that express a mutated PTH1R that activates adenylyl cyclase and protein kinase A (PKA) via Gsα but not phospholipase C via Gq/11 (D/D mice), PTH significantly enhanced bone formation, indicating that phospholipase C activation is not required for increased bone turnover in response to PTH. Therefore, although the anabolic effect of intermittent PTH treatment on trabecular bone volume is blunted by deletion of Gsα in osteoblasts, PTH can stimulate osteoblast differentiation and bone formation. Together these findings suggest that alternative signaling pathways beyond Gsα and Gq/11 act downstream of PTH on osteoblast differentiation.
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Sarem, Melika, Miriam Heizmann, Andrea Barbero, Ivan Martin, and V. Prasad Shastri. "Hyperstimulation of CaSR in human MSCs by biomimetic apatite inhibits endochondral ossification via temporal down-regulation of PTH1R." Proceedings of the National Academy of Sciences 115, no. 27 (June 18, 2018): E6135—E6144. http://dx.doi.org/10.1073/pnas.1805159115.
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In adult bone injuries, periosteum-derived mesenchymal stem/stromal cells (MSCs) form bone via endochondral ossification (EO), whereas those from bone marrow (BM)/endosteum form bone primarily through intramembranous ossification (IMO). We hypothesized that this phenomenon is influenced by the proximity of MSCs residing in the BM to the trabecular bone microenvironment. Herein, we investigated the impact of the bone mineral phase on human BM-derived MSCs’ choice of ossification pathway, using a biomimetic bone-like hydroxyapatite (BBHAp) interface. BBHAp induced hyperstimulation of extracellular calcium-sensing receptor (CaSR) and temporal down-regulation of parathyroid hormone 1 receptor (PTH1R), leading to inhibition of chondrogenic differentiation of MSCs even in the presence of chondroinductive factors, such as transforming growth factor-β1 (TGF-β1). Interestingly rescuing PTH1R expression using human PTH fragment (1–34) partially restored chondrogenesis in the BBHAp environment. In vivo studies in an ectopic site revealed that the BBHAp interface inhibits EO and strictly promotes IMO. Furthermore, CaSR knockdown (CaSR KD) disrupted the bone-forming potential of MSCs irrespective of the absence or presence of the BBHAp interface. Our findings confirm the expression of CaSR in human BM-derived MSCs and unravel a prominent role for the interplay between CaSR and PTH1R in regulating MSC fate and the choice of pathway for bone formation.
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Bastepe, Murat, Serap Turan, and Qing He. "Heterotrimeric G proteins in the control of parathyroid hormone actions." Journal of Molecular Endocrinology 58, no. 4 (May 2017): R203—R224. http://dx.doi.org/10.1530/jme-16-0221.
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Parathyroid hormone (PTH) is a key regulator of skeletal physiology and calcium and phosphate homeostasis. It acts on bone and kidney to stimulate bone turnover, increase the circulating levels of 1,25 dihydroxyvitamin D and calcium and inhibit the reabsorption of phosphate from the glomerular filtrate. Dysregulated PTH actions contribute to or are the cause of several endocrine disorders. This calciotropic hormone exerts its actions via binding to the PTH/PTH-related peptide receptor (PTH1R), which couples to multiple heterotrimeric G proteins, including Gs and Gq/11. Genetic mutations affecting the activity or expression of the alpha-subunit of Gs, encoded by the GNAS complex locus, are responsible for several human diseases for which the clinical findings result, at least partly, from aberrant PTH signaling. Here, we review the bone and renal actions of PTH with respect to the different signaling pathways downstream of these G proteins, as well as the disorders caused by GNAS mutations.
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Maycas, Marta, Juan A. Ardura, Luis F. de Castro, Beatriz Bravo, Arancha R. Gortázar, and Pedro Esbrit. "Role of the Parathyroid Hormone Type 1 Receptor (PTH1R) as a Mechanosensor in Osteocyte Survival." Journal of Bone and Mineral Research 30, no. 7 (June 15, 2015): 1231–44. http://dx.doi.org/10.1002/jbmr.2439.
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Datta, Nabanita S., Tareq A. Samra, and Abdul B. Abou-Samra. "Parathyroid hormone induces bone formation in phosphorylation-deficient PTHR1 knockin mice." American Journal of Physiology-Endocrinology and Metabolism 302, no. 10 (May 15, 2012): E1183—E1188. http://dx.doi.org/10.1152/ajpendo.00380.2011.
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Activation of G protein-coupled receptors by agonists leads to receptor phosphorylation, internalization of ligand receptor complexes, and desensitization of hormonal response. The role of parathyroid hormone (PTH) receptor 1, PTHR1, is well characterized and known to regulate cellular responsiveness in vitro. However, the role of PTHR1 phosphorylation in bone formation is yet to be investigated. We have previously demonstrated that impaired internalization and sustained cAMP stimulation of phosphorylation-deficient (PD) PTHR1 leads to exaggerated cAMP response to subcutaneous PTH infusion in a PD knockin mouse model. To understand the physiological role of receptor internalization on PTH bone anabolic action, we examined bone parameters of wild-type (WT) and PD knockin female and male mice following PTH treatment. We found a decrease in total and diaphyseal bone mineral density in female but not in male PD mice compared with WT controls at 3–6 mo of age. This effect was attenuated at older age groups. PTH administration displayed increased bone volume and trabecular thickness in the vertebrae and distal femora of both WT and PD animals. These results suggest that PTHR1 phosphorylation does not play a major role in the anabolic action of PTH.
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Taylor, Colin W., and Stephen C. Tovey. "From parathyroid hormone to cytosolic Ca2+ signals." Biochemical Society Transactions 40, no. 1 (January 19, 2012): 147–52. http://dx.doi.org/10.1042/bst20110615.
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PTHR1 (type 1 parathyroid hormone receptors) mediate the effects of PTH (parathyroid hormone) on bone remodelling and plasma Ca2+ homoeostasis. PTH, via PTHR1, can stimulate both AC (adenylate cyclase) and increases in [Ca2+]i (cytosolic free Ca2+ concentration), although the relationship between the two responses differs between cell types. In the present paper, we review briefly the mechanisms that influence coupling of PTHR1 to different intracellular signalling proteins, including the G-proteins that stimulate AC or PLC (phospholipase C). Stimulus intensity, the ability of different PTH analogues to stabilize different receptor conformations (‘stimulus trafficking’), and association of PTHR1 with scaffold proteins, notably NHERF1 and NHERF2 (Na+/H+ exchanger regulatory factor 1 and 2), contribute to defining the interactions between signalling proteins and PTHR1. In addition, cAMP itself can, via Epac (exchange protein directly activated by cAMP), PKA (protein kinase A) or by binding directly to IP3Rs [Ins(1,4,5)P3 receptors] regulate [Ca2+]i. Epac leads to activation of PLCϵ, PKA can phosphorylate and thereby increase the sensitivity of IP3Rs and L-type Ca2+ channels, and cAMP delivered at high concentrations to IP3R2 from AC6 increases the sensitivity of IP3Rs to InsP3. The diversity of these links between PTH and [Ca2+]i highlights the versatility of PTHR1. This versatility allows PTHR1 to evoke different responses when stimulated by each of its physiological ligands, PTH and PTH-related peptide, and it provides scope for development of ligands that selectively harness the anabolic effects of PTH for more effective treatment of osteoporosis.