Chapter category: Endocrine

Skeletal and Reproductive Abnormalities in Pth-Null Mice

This chapter appears in the following book:

Molecular Biology of the Parathyroid

Edited by: Tally Naveh-Many
ISBN: 0-306-47847-1
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Chapter authors:
Dengshun Miao, Bin He, Beate Lanske, Xiu-Ying Bai, Xin-Kang Tong, Geoffrey N. Hendy, David Goltzman and Andrew C. Karaplis

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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-hydroxylase (Cyp27b1) expression increased despite the absence of PTH, leading to a rise in circulating 1,25(OH)2D3 levels, marked osteoclastogenesis, 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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Additional chapters from this book:

Skeletal and Reproductive Abnormalities in Pth-Null Mice

Dengshun Miao, Bin He, Beate Lanske, Xiu-Ying Bai, Xin-Kang Tong, Geoffrey N. Hendy, David Goltzman and Andrew C. Karaplis

Genetic Causes of Hypoparathyroidism

Rachel I. Gafni and Michael A. Levine

Hypoparathyroidism is characterized clinically by the presence of hypocalcemia and hyperphosphatemia due to inadequate supply or effectiveness of circulating parathyroid hormone (PTH). It may be pre...

Molecular Genetic Abnormalities in Sporadic Hyperparathyroidism

Trisha M. Shattuck, Sanjay M. Mallya and Andrew Arnold

The biochemical state of primary hyperparathyroidism is generally caused by hypercellular parathyroid glands categorized as multigland hyperplasia, benign adenoma or malignant carcinoma. Most, and p...

Molecular Mechanisms in Parathyroid Tumorigenesis

Eitan Friedman

Primary hyperparathyroidism (1 HPT) is a relatively common disorder, with an estimated prevalence of 1:500-1:1000.1 In about 80%-85% of 1 HPT cases, a single enlarged parathyroid gland with a distin...

Parathyroid Gland Hyperplasia in Renal Failure

Adriana S. Dusso, Mario Cozzolino and Eduardo Slatopolsky

Secondary hyperparathyroidism, a frequent complication of chronic renal failure, is characterized by parathyroid hyperplasia and enhanced synthesis and secretion of parathyroid hormone (PTH).1-3 As ...

Vitamin D Analogs for the Treatment of Secondary Hyperparathyroidism in Chronic Renal Failure

Alex J. Brown

Secondary hyperparathyroidism (2oHPT) is a common complication in patients with chronic renal failure. The pathogenesis of 2oHPT is attributed primarily to phosphate retention and low serum 1,25(OH)...

Regulation of Parathyroid Hormone Gene Expression by 1,25-Dihydroxyvitamin D

Tally Naveh-Many and Justin Silver

Vitamin D’s active metabolite 1,25(OH)2D3 acts on the parathyroid to markedly decrease PTH gene transcription. It does this by binding to its specific receptor in the parathyroid which then binds ...

In Silico Analysis of Regulatory Sequences in the Human Parathyroid Hormone Gene

Alexander Kel, Maurice Scheer and Hubert Mayer

Parathyroid hormone (PTH) is intimately involved in the homeostasis of normal serum concentrations of calcium and phosphate, which, in turn, regulate the synthesis and secretion of PTH. The synthesi...

Regulation of Parathyroid Hormone mRNA Stability by Calcium and Phosphate

Rachel Kilav, Justin Silver and Tally Naveh-Many

Calcium and phosphate regulate parathyroid hormone (PTH) secretion, gene expression and if prolonged also parathyroid proliferation. The regulation of PTH gene expression by Ca2+ and Pi is post-tran...

The Calcium Sensing Receptor

Shozo Yano and Edward M. Brown

The acute secretory response of parathyroid hormone (PTH) is strictly regulated by the extracellular calcium concentration (Ca2+ o), and the G protein-coupled, calcium-sensing receptor (CaR) locate...

Toward an Understanding of Human Parathyroid Hormone Structure and Function

Lei Jin, Armen H. Tashjian, Jr., and Faming Zhang

Parathyroid hormone (PTH) is synthesized as a 115 amino acid precursor and secreted as an 84 amino acid polypeptide that regulates extracellular calcium homeostasis via actions directly on kidney an...

Parathyroid Hormone, from Gene to Protein

Osnat Bell, Justin Silver and Tally Naveh-Many

The biosynthetic pathway of parathyroid hormone (PTH) has been studied from gene expression to PTH intracellular processing.1 The processing of PTH has been described and involves the synthesis of a...

Development of Parathyroid Glands

Thomas Gunther and Gerard Karsenty

The parathyroid glands (PG) are the main source for circulating parathyroid hormone (PTH), a hormone that is essential for the regulation of calcium and phosphate metabolism. The PGs develop during ...

Chapter category: Endocrine

Skeletal and Reproductive Abnormalities in Pth-Null Mice

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