Abstract
We have examined the role of parathyroid hormone (PTH) in the postnatal state in a mouse model of PTH-deficiency generated by targeting the Pth gene in ES cells. Mice homozygous for the ablated allele, when maintained on a normal calcium intake, developed hypocalcemia, hyperphosphatemia, and low circulating 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] levels consistent with primary hypoparathyroidism. Fertility in mutant females was diminished due to abnormal ovarian function manifested in part by impaired angiogenesis in the developing corpus luteum. Even in the presence of ovarian dysfunction, bone turnover was reduced and trabecular and cortical bone volume were increased in PTH-deficient mice. When placed on a low calcium diet, fertility in female mice was completely abolished. Moreover, renal 25-hydroxyvitamin D 1 alpha-hydroocylase (Cyp27bl) expression increased despite the absence of PTH, leading to a rise in circulating 1,25(OH)2D3 levels, marked osteodastogenesis, and profound bone resorption. These studies demonstrate the dependence of the reproductive and skeletal phenotype in animals with genetically depleted PTH on the external environment as well as on internal hormonal and ionic circulatory factors. They point to the importance of calcium balance in reproduction and show that while PTH action is the first defense against hypocalcemia, 1,25(OH)2D3 can be mobilized, even in the absence of PTH, to guard against extreme calcium deficiency.
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References
Juppner H, Abou-Samra AB, Freeman M et al. A G protein-linked receptor for parathyroid hormone and parathyroid hormone-related peptide. Science 1991; 254:1024–1026.
Schipani E, Karga H, Karaplis AC et al. Identical complementary deoxyribonucleic acids encode a human renal and bone parathyroid hormone (PTH)/PTH-related peptide receptor. Endocrinology 1993; 132:2157–2165.
Potts JT Jr, Kronenberg HM, Rosenblatt M. Parathyroid hormone: chemistry, biosynthesis, and mode of action. Adv Protein Chem 1982; 35:323–396.
Strewler GJ. The physiology of parathyroid hormone-related protein. N Engl J Med 2000; 342:177–185.
Karaplis AC, Luz A, Glowacki J et al. Lethal skeletal dysplasia from targeted disruption of the parathyroid hormone-related peptide gene. Genes Dev 1994; 8:277–289.
Lanske B, Karaplis AC, Lee K et al. PTH/PTHrP receptor in early development and Indian hedgehog-regulated bone growth. Science 1996; 273:663–666.
Jobert AS, Zhang P, Couvineau A et al. Absence of functional receptors for parathyroid hormone and parathyroid hormone-related peptide in Blomstrand chondrodysplasia. J Clin Invest 1998; 102:34–40.
Karaplis AC, He B, Nguyen MT et al. Inactivating mutation in the human parathyroid hormone receptor type 1 gene in Blomstrand chondrodysplasia. Endocrinology 1998; 139:5255–5258.
Usdin TB, Hilton J, Vertesi T et al. Distribution of the parathyroid hormone 2 receptor in rat: immunolocalization reveals expression by several endocrine cells. Endocrinology 1999; 140:3363–3371.
Usdin TB. The PTH2 receptor and TIP39: a new peptide-receptor system. Trends Pharmacol Sci 2000; 21:128–130.
Inomata N, Akiyama M, Kubota N et al. Characterization of a novel parathyroid hormone (PTH) receptor with specificity for the carboxyl-terminal region of PTH-(1–84). Endocrinology 1995; 136:4732–4740.
Divieti P, Inomata N, Chapin K et al. Receptors for the carboxyl-terminal region of PTH(1–84) are highly expressed in osteocytic cells. Endocrinology 2001; 142:916–925.
He B, Tong TK, Hiou-Tim FF et al. The murine gene encoding parathyroid hormone: genomic organization, nucleotide sequence and transcriptional regulation. J Mol Endocrinol 2002; 29:193–203.
Gunther T, Chen ZF, Kim J et al. Genetic ablation of parathyroid glands reveals another source of parathyroid hormone. Nature 2000; 406:199–203.
Miao D, He B, Karaplis AC et al. Parathyroid hormone is essential for normal fetal bone formation. J Clin Invest 2002; 109:1173–1182.
Jablonka-Shariff A, Grazul-Bilska AT, Redmer DA et al. Cellular proliferation and fibroblast growth factors in the corpus luteum during early pregnancy in ewes. Growth Factors 1997; 14:15–23.
Reynolds LP, Redmer DA. Expression of the angiogenic factors, basic fibroblast growth factor and vascular endothelial growth factor, in the ovary. J Anim Sci 1998; 76:1671–1681.
Johnson LE, DeLuca HF. Vitamin D receptor null mutant mice fed high levels of calcium are fertile. J Nutr 2001; 131:1787–1791.
Abugassa S, Nordenstrom J, Eriksson S et al. Bone mineral density in patients with chronic hypoparathyroidism. J Clin Endocrinol Metab 1993; 76:1617–1621.
Fujiyama K, Kiriyama T, Ito M et al. Attenuation of postmenopausal high turnover bone loss in patients with hypoparathyroidism. J Clin Endocrinol Metab 1995; 80:2135–2138.
Orr-Walker B, Harris R, Holdaway IM et al. High peripheral and axial bone densities in a postmenopausal woman with untreated hypoparathyroidism. Postgrad Med J 1990; 66:1061–1063.
Van Offel JF, De Gendt CM, De Clerck LS et al. High bone mass and hypocalcaemic myopathy in a patient with idiopathic hypoparathyroidism. Clin Rheumatol 2000; 19:64–66.
Ishii H, Wada M, Furuya Y et al. Daily intermittent decreases in serum levels of parathyroid hormone have an anabolic-like action on the bones of uremic rats with low-turnover bone and osteomalacia. Bone 2000; 26:175–182.
Olgaard K, and Lewin E. Prevention of uremic bone disease using calcimimetic compounds. Annu Rev Med 2001; 52:203–220.
Miller MA, Fox J. Daily transient decreases in plasma parathyroid hormone levels induced by the calcimimetic NPS R-568 slows the rate of bone loss but does not increase bone mass in ovariectomized rats. Bone 2000; 27:511–519.
Thomas GP, Baker SU, Eisman JA et al. Changing RANKL/OPG mRNA expression in differenti ating murine primary osteoblasts. J Endocrinol 2001; 170:451–460.
Weisinger JR, Favus MJ, Langman CB et al. Regulation of 1,25-dihydroxyvitamin D3 by calcium in the parathyroidectomized, parathyroid hormone-replete rat. J Bone Miner Res 1989; 4:929–935.
Bland R, Walker EA, Hughes SV et al. Constitutive expression of 25-hydroxyvitamin D3-lalpha-hydroxylase in a transformed human proximal tubule cell line: evidence for direct regulation of vitamin D metabolism by calcium. Endocrinology 1999; 140:2027–2034.
Vasicek TJ, McDevitt BE, Freeman MW et al. Nucleotide sequence of the human parathyroid hormone gene. Proc Natl Acad Sci USA 1983; 80:2127–2131.
Tybulewicz VL, Crawford CE, Jackson PK, et al. Neonatal lethality and lymphopenia in mice with a homozygous disruption of the c-abl proto-oncogene. Cell 1991; 65:1153–1163.
Bai X, Miao D, Panda D et al. Partial rescue of the Hyp phenotype by osteoblast-targeted PHEX (Phosphate-regulating gene with Homologies to Endopeptidases on the X chromosome) expression. Mol Endocrinol 2002; 16:2913–2925.
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Miao, D. et al. (2005). Skeletal and Reproductive Abnormalities in Pth-Null Mice. In: Molecular Biology of the Parathyroid. Molecular Biology Intelligence Unit. Springer, Boston, MA. https://doi.org/10.1007/0-387-27530-4_13
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DOI: https://doi.org/10.1007/0-387-27530-4_13
Publisher Name: Springer, Boston, MA
Print ISBN: 978-0-306-47847-5
Online ISBN: 978-0-387-27530-7
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