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Gene Review

Pth  -  parathyroid hormone

Mus musculus

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Disease relevance of Pth

  • PTH-deficient mice were dysmorphic but viable, whereas mice lacking PTHrP died at birth with dyschondroplasia [1].
  • Using F9 embryonal carcinoma (EC) cells and ES-5 embryonic stem (ES) cells as in vitro models, we demonstrate that during the differentiation of these cells towards primitive and parietal endoderm-like phenotypes, PTH/PTHrP-receptor mRNA is induced [2].
  • Although PTH and 1,25(OH)2D3 independently, but not additively, regulate osteoclastic bone resorption, they do affect the renal calcium transport pathway cooperatively [3].
  • Consequently, PTH and 1,25(OH)2D3 exhibit discrete and collaborative roles in modulating skeletal and calcium homeostasis and loss of the renal component of calcium conservation might be the major factor contributing to the lethal hypocalcemia in double mutants [3].
  • Although PTH-/- and 1alpha(OH)ase-/- mice displayed only moderate hypocalcemia, PTH-/-1alpha(OH)ase-/- mice died of tetany with severe hypocalcemia by 3 weeks of age [3].
  • These results suggest that atherogenic lipids inhibit osteogenic signaling induced by BMP-2 and PTH, raising the possibility that hyperlipidemia and atherogenic phospholipids may interfere with anabolic therapy [4].

High impact information on Pth


Chemical compound and disease context of Pth


Biological context of Pth

  • One recombinant clone isolated from a mouse genomic library contained 14 kb of DNA, encompassing the entire Pth gene [10].
  • Parathyroid hormone is essential for normal fetal bone formation [1].
  • These results indicate that coordinated action of both PTH and PTHrP are required to achieve normal fetal skeletal morphogenesis, and they demonstrate an essential function for PTH at the cartilage-bone interface [1].
  • Together these results indicate that the PTH/PTHrP-receptor signalling system serves as a para- or autocrine mechanism for parietal endoderm differentiation in the early mouse embryo, thus constituting the earliest hormone receptor system involved in embryogenesis defined to date [2].
  • While parathyroid hormone (PTH) gene expression appears to be limited to the parathyroid glands, PTHRP mRNA has been identified in a variety of normal tissues [11].

Anatomical context of Pth

  • The effect of PTH on fetal osteoblasts may be relevant to its postnatal anabolic effects on trabecular bone [1].
  • To investigate the apparent expression of the PTHRP in the central nervous system, we examined extracts of whole rat brain for PTHRP bioactivity by measuring adenylate cyclase-stimulating activity (ACSA) in a PTH-sensitive assay [11].
  • Unlike in the parathyroid cells, PTH expression in Th2 cells was not regulated by the fluctuation of calcium level, but rather it required the full activation of the T cells [12].
  • After prolonged exposure (24-48 h) in the presence of PTH, osteoclasts with low resorbing activity exhibited intermediate borders at their contact zone with the mineralized matrix [13].
  • Reduction of the PTH-induced anabolic actions on bone was associated with unloading, which was apparently related to suppression of c-fos mRNA expression in bone marrow [14].

Associations of Pth with chemical compounds

  • Addition of exogenous PTH or PTHrP to RA-treated EC or ES cells is an efficient replacement for dBcAMP in inducing full parietal endoderm differentiation [2].
  • ODF gene induction by parathyroid hormone or prostaglandin E is also dependent on NF-Y [15].
  • Cycloheximide did not block the effects of PTH on RANKL but did inhibit the suppression of OPG mRNA [16].
  • We investigated whether substitution of the sterically hindered and helix-promoting amino acid alpha-aminoisobutyric acid (Aib) in N-terminal PTH oligopeptides would improve the capacity of the peptide to activate the P1R [17].
  • Cyclic AMP measurements revealed no evidence of expression of alternate species of Gs-linked PTH receptors [18].

Physical interactions of Pth


Regulatory relationships of Pth

  • Skeletal unloading alleviates the anabolic action of intermittent PTH(1-34) in mouse tibia in association with inhibition of PTH-induced increase in c-fos mRNA in bone marrow cells [14].
  • PTH differentially regulates expression of RANKL and OPG [19].
  • The increase in alkaline phosphatase-positive colony-forming units-fibroblastic (CFU-f) colonies induced by PTH was maintained and that of TRACP+ multinucleated cells enhanced [14].
  • These findings establish a pivotal role for osteoblast-derived PTH-related protein (PTHrP) as a potent endogenous bone anabolic factor that potentiates bone formation by altering osteoblast recruitment and survival and whose level of expression in the bone microenvironment influences the therapeutic efficacy of exogenous PTH 1-34 [20].
  • To elucidate the role of endogenous FGF-2 in PTH responses, we examined PTH-induced OCL formation in bone marrow cultures from wild type and mice with a disruption of the Fgf2 gene [21].

Other interactions of Pth


Analytical, diagnostic and therapeutic context of Pth

  • In both animal models administration of PTH and calcitonin increased enzyme activity to levels greater than those obtained after maximal stimulation by either hormone alone, consistent with additive effects [25].
  • We analyzed the effect of unloading by tail suspension on the anabolic action of intermittent PTH in the tibia of growing mice [14].
  • In conclusion, PTH exerts an anabolic action at the tissue and cellular levels in intact mice and the magnitude and temporal pattern of this anabolic action, as assessed by densitometry and histomorphometry, are skeletal site specific [26].
  • Autoradiography of PTH-treated bones first showed [3H]thymidine label in osteoclast nuclei at 24 h, which increased markedly by 96 h [27].
  • In addition, Pthlh was localized to chromosome 6 band F-G and the mouse parathyroid hormone Pth was localized to chromosome 7 band F, by in situ hybridization [28].


  1. Parathyroid hormone is essential for normal fetal bone formation. Miao, D., He, B., Karaplis, A.C., Goltzman, D. J. Clin. Invest. (2002) [Pubmed]
  2. Parathyroid hormone-related peptide as an endogenous inducer of parietal endoderm differentiation. van de Stolpe, A., Karperien, M., Löwik, C.W., Jüppner, H., Segre, G.V., Abou-Samra, A.B., de Laat, S.W., Defize, L.H. J. Cell Biol. (1993) [Pubmed]
  3. Genetic models show that parathyroid hormone and 1,25-dihydroxyvitamin D3 play distinct and synergistic roles in postnatal mineral ion homeostasis and skeletal development. Xue, Y., Karaplis, A.C., Hendy, G.N., Goltzman, D., Miao, D. Hum. Mol. Genet. (2005) [Pubmed]
  4. Atherogenic phospholipids attenuate osteogenic signaling by BMP-2 and parathyroid hormone in osteoblasts. Huang, M.S., Morony, S., Lu, J., Zhang, Z., Bezouglaia, O., Tseng, W., Tetradis, S., Demer, L.L., Tintut, Y. J. Biol. Chem. (2007) [Pubmed]
  5. Vav3 regulates osteoclast function and bone mass. Faccio, R., Teitelbaum, S.L., Fujikawa, K., Chappel, J., Zallone, A., Tybulewicz, V.L., Ross, F.P., Swat, W. Nat. Med. (2005) [Pubmed]
  6. Genetic ablation of parathyroid glands reveals another source of parathyroid hormone. Günther, T., Chen, Z.F., Kim, J., Priemel, M., Rueger, J.M., Amling, M., Moseley, J.M., Martin, T.J., Anderson, D.J., Karsenty, G. Nature (2000) [Pubmed]
  7. Osteoclast differentiation factor mediates an essential signal for bone resorption induced by 1 alpha,25-dihydroxyvitamin D3, prostaglandin E2, or parathyroid hormone in the microenvironment of bone. Tsukii, K., Shima, N., Mochizuki, S., Yamaguchi, K., Kinosaki, M., Yano, K., Shibata, O., Udagawa, N., Yasuda, H., Suda, T., Higashio, K. Biochem. Biophys. Res. Commun. (1998) [Pubmed]
  8. Preferential inhibition of cytokine-stimulated bone resorption by recombinant interferon gamma. Gowen, M., Nedwin, G.E., Mundy, G.R. J. Bone Miner. Res. (1986) [Pubmed]
  9. Bone resorption in organ culture: inhibition by the divalent cation ionophores A23187 and X-537A. Ivey, J.L., Wright, D.R., Tashjian, A.H. J. Clin. Invest. (1976) [Pubmed]
  10. The murine gene encoding parathyroid hormone: genomic organization, nucleotide sequence and transcriptional regulation. He, B., Tong, T.K., Hiou-Tim, F.F., Al-Akad, B., Kronenberg, H.M., Karaplis, A.C. J. Mol. Endocrinol. (2002) [Pubmed]
  11. Parathyroid hormone-related peptide gene is expressed in the mammalian central nervous system. Weir, E.C., Brines, M.L., Ikeda, K., Burtis, W.J., Broadus, A.E., Robbins, R.J. Proc. Natl. Acad. Sci. U.S.A. (1990) [Pubmed]
  12. Differential regulation of osteoblast activity by Th cell subsets mediated by parathyroid hormone and IFN-gamma. Young, N., Mikhalkevich, N., Yan, Y., Chen, D., Zheng, W.P. J. Immunol. (2005) [Pubmed]
  13. Interferon gamma and calcitonin induce differential changes in cellular kinetics and morphology of osteoclasts in cultured neonatal mouse calvaria. Klaushofer, K., Hörandner, H., Hoffmann, O., Czerwenka, E., König, U., Koller, K., Peterlik, M. J. Bone Miner. Res. (1989) [Pubmed]
  14. Skeletal unloading alleviates the anabolic action of intermittent PTH(1-34) in mouse tibia in association with inhibition of PTH-induced increase in c-fos mRNA in bone marrow cells. Tanaka, S., Sakai, A., Tanaka, M., Otomo, H., Okimoto, N., Sakata, T., Nakamura, T. J. Bone Miner. Res. (2004) [Pubmed]
  15. NF-Y is essential for the recruitment of RNA polymerase II and inducible transcription of several CCAAT box-containing genes. Kabe, Y., Yamada, J., Uga, H., Yamaguchi, Y., Wada, T., Handa, H. Mol. Cell. Biol. (2005) [Pubmed]
  16. Parathyroid hormone stimulates receptor activator of NFkappa B ligand and inhibits osteoprotegerin expression via protein kinase A activation of cAMP-response element-binding protein. Fu, Q., Jilka, R.L., Manolagas, S.C., O'Brien, C.A. J. Biol. Chem. (2002) [Pubmed]
  17. Parathyroid hormone (PTH)-(1-14) and -(1-11) analogs conformationally constrained by alpha-aminoisobutyric acid mediate full agonist responses via the juxtamembrane region of the PTH-1 receptor. Shimizu, N., Guo, J., Gardella, T.J. J. Biol. Chem. (2001) [Pubmed]
  18. Conditionally immortalized murine osteoblasts lacking the type 1 PTH/PTHrP receptor. Divieti, P., Lanske, B., Kronenberg, H.M., Bringhurst, F.R. J. Bone Miner. Res. (1998) [Pubmed]
  19. PTH differentially regulates expression of RANKL and OPG. Huang, J.C., Sakata, T., Pfleger, L.L., Bencsik, M., Halloran, B.P., Bikle, D.D., Nissenson, R.A. J. Bone Miner. Res. (2004) [Pubmed]
  20. Osteoblast-derived PTHrP is a potent endogenous bone anabolic agent that modifies the therapeutic efficacy of administered PTH 1-34. Miao, D., He, B., Jiang, Y., Kobayashi, T., Sorocéanu, M.A., Zhao, J., Su, H., Tong, X., Amizuka, N., Gupta, A., Genant, H.K., Kronenberg, H.M., Goltzman, D., Karaplis, A.C. J. Clin. Invest. (2005) [Pubmed]
  21. Impaired osteoclast formation in bone marrow cultures of Fgf2 null mice in response to parathyroid hormone. Okada, Y., Montero, A., Zhang, X., Sobue, T., Lorenzo, J., Doetschman, T., Coffin, J.D., Hurley, M.M. J. Biol. Chem. (2003) [Pubmed]
  22. Stimulation of interleukin-6 production by either calcitonin gene-related peptide or parathyroid hormone in two phenotypically distinct bone marrow-derived murine stromal cell lines. Sakagami, Y., Girasole, G., Yu, X.P., Boswell, H.S., Manolagas, S.C. J. Bone Miner. Res. (1993) [Pubmed]
  23. Vitamin D receptor (VDR) knockout mice reveal VDR-independent regulation of intestinal calcium absorption and ECaC2 and calbindin D9k mRNA. Song, Y., Kato, S., Fleet, J.C. J. Nutr. (2003) [Pubmed]
  24. Neuropeptides of the vasoactive intestinal peptide/helodermin/pituitary adenylate cyclase activating peptide family elevate plasma cAMP in mice: comparison with a range of other regulatory peptides. Absood, A., Chen, D., Håkanson, R. Regul. Pept. (1992) [Pubmed]
  25. Calcitonin stimulation of renal 25-hydroxyvitamin D-1 alpha-hydroxylase activity in hypophosphatemic mice. Evidence that the regulation of calcitriol production is not universally abnormal in X-linked hypophosphatemia. Nesbitt, T., Lobaugh, B., Drezner, M.K. J. Clin. Invest. (1987) [Pubmed]
  26. Anabolic action of parathyroid hormone is skeletal site specific at the tissue and cellular levels in mice. Iida-Klein, A., Zhou, H., Lu, S.S., Levine, L.R., Ducayen-Knowles, M., Dempster, D.W., Nieves, J., Lindsay, R. J. Bone Miner. Res. (2002) [Pubmed]
  27. Effects of parathyroid hormone and calcitonin on osteoclast formation in vitro. Feldman, R.S., Krieger, N.S., Tashjian, A.H. Endocrinology (1980) [Pubmed]
  28. Localization of mouse parathyroid hormone-like peptide gene (Pthlh) to distal chromosome 6 using interspecific backcross mice and in situ hybridization. Seldin, M.F., Mattei, M.G., Hendy, G.N. Cytogenet. Cell Genet. (1992) [Pubmed]
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