aintaining extracellular calcium concentrations within a narrow range is critical for the survival of most vertebrates. PTH, together with vitamin D, responds to hypocalcemia to increase extracellu M lar calcium levels, by acting on bone, kidney and intestine. The recent intro duction of PTH as a major therapeutic agent in osteoporosis has directed renewed interest in this important hormone and in the physiology of the parathyroid gland. The parathyroid is unique in that low serum calcium stimulates PTH secretion. As hypocalcemia persists, there is also an increase in PTH synthesis. Chronic hypocalcemia leads to hypertrophy and hyper plasia of the parathyroid gland together with increased production of the hormone. Phosphate is also a key modulator of PTH secretion, gene expres sion and parathyroid cell proliferation. Understanding the biology of the parathyroid as well as the mecha nisms of associated diseases has taken great strides in recent years. This book summarizes the molecular mechanisms involved in the function of the para thyroid gland. The first chapter reviews the development of the parathyroid gland and the genes involved in this process as identified using genetically manipulated mice. Then the biosynthetic pathway of PTH from gene ex pression to its intracellular processing and the sequences in the gene control ling its transcription as well as those regulating mRNA processing, stability and translation are described.
Table of ContentsPreface 1. Development of Parathyroid Glands - Thomas Günther and Gerard Karsenty Physiology of the Parathyroid Glands Development of Parathyroid Glands in Vertebrates Genetic Control of Parathyroid Gland Development 2. Parathyroid Hormone, from Gene to Protein - Osnat Bell, Justin Silver and Tally Naveh-Many The Prepro PTH Peptide Homology of the Mature PTH The PTH mRNA Cloning of the PTH cDNAs Homology of the cDNA Sequences Structure of the PTH mRNA The PTH Gene The 5’ Flanking Region The 3' Flanking Region Chromosomal Location of the Human PTH Gene 3. Toward an Understanding of Human Parathyroid Hormone Structure and Function - Lei Jin, Armen H. Tashjian, Jr., and Faming Zhang PTH and Its Receptor Family PTH Structural Determination Structural Based Design of PTH Analogs 4. The Calcium Sensing Receptor - Shozo Yano and Edward M. Brown Biochemical Characteristics of the CaR Disorders Presenting with Abnormalities in Calcium Metabolism and in the CaR Signaling Pathways of the CaR Drugs Acting on the CaR 5. Regulation of Parathyroid Hormone mRNA Stability by Calcium and Phosphate - Rachel Kilav, Justin Silver and Tally Naveh-Many Regulation of the Parathyroid Gland by Calcium and Phosphate Protein Binding and PTH mRNA Stability Identification of the PTH mRNA 3’-UTR Binding Proteins and Their Function Identification of the Minimal cis Acting Protein Binding Element in the PTH mRNA 3’-UTR The Structure of the PTH cisActing Element 6. In Silico Analysis of Regulatory Sequences in the Human Parathyroid Hormone Gene - Alexander Kel, Maurice Scheer and Hubert Mayer Global Homology of PTH Gene between Human and Mouse Computer Assisted Search for Potential Cis-Regulatory Elements in PTH Gene Phylogenetic Footprint: Identification of TF Binding Sites by Comparison of Regulatory Regions of PTH Gene of Different Organisms Discussion 7. Regulation of Parathyroid Hormone Gene Expression by 1,25-Dihydroxyvitamin D - Tally Naveh-Many and Justin Silver Transcriptional Regulation of the PTH Gene by 1,25(OH)2D3 Calreticulin and the Action of 1,25(OH)2D3 on the PTH Gene PTH Degradation Secondary Hyperparathyroidism and Parathyroid Cell Proliferation 8. Vitamin D Analogs for the Treatment of Secondary Hyperparathyroism in Chronic Renal Failure - Alex J. Brown Pathogenesis of Secondary Hyperparathyroidism in Chronic Renal Failure Treatment of Secondary Hyperparathyroidism Mechanisms for the Selectivity of Vitamin D Analogs Future Perspectives 9. Parathyroid Gland Hyperplasia in Renal Failure - Adriana S. Dusso, Mario Cozzolino and Eduardo Slatopolsky Parathyroid Tissue Growth in Normal Conditions and in Renal Failure Dietary Phosphate Regulation of Parathyroid Cell Growth in Uremia Vitamin D Regulation of Uremia- and High Phosphate-Induced Parathyroid Cell Growth Calcium Regulation of Uremia-Induced Parathyroid Growth 10. Molecular Mechanisms in Parathyroid Tumorigenesis - Eitan Friedman Oncogenes Involved in Parathyroid Tumor Development