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J Clin Endocrinol 83. McDonnell DP, Clemm DL, Hermann T, Goldman ME, Pike JW Metab 84:1966-1972. 1995 Analysis of estrogen receptor function in vitro reveals three 76. Kenny AM, Prestwood KM, Marcello KM, Raisz LG 2000 Deter- distinct classes of antiestrogens. Mol Endocrinol 9:659469. minants of bone density in healthy older men with low testoster- 84. Chen J, Kim J, Dalton JT 2005 Discovery and therapeutic promise one levels. J Gerontol A Biol Sci Med Sci 55A:M492-M497. of selective androgen receptor modulators. Mol Interv 5:173-188. Chapter 25. Parathyroid Hormone Robert A. Nissenson’ and Harald Juppner2 ‘Endocrine Research Unit, VA Medical Center, Departments of Medicine and Phjwiology, University of California, Sun Francisco, California; ‘Endocrine Unit and Pediatric Nephrology Unit, Departments o,f Medicine and Pediatrics, Harvard Medical School, Massachusetts General Hospitcil, Bostoii, Mrrssachusetts INTRODUCTION narrow limits over a wide range of dietary calcium intake. This chapter summarizes our current understanding of the biology The parathyroid glands first appear during evolution with the of PTH secretion and action. A nice historical perspective on movement of animals from an aquatic environment to a ter- this field has recently been published,(i) restrial environment deficient in calcium. Maintenance of ad- equate levels of plasma ionized calcium (1.0-1.3 mM) is re- quired for normal neuromuscular function, bone THE PTH POLYPEPTIDE FAMILY mineralization, and many other physiological processes. Chief Mammalian PTH is a single-chain 84 amino acid polypep- cells in the parathyroid gland secrete PTH in response to very tide hormone that is expressed almost exclusively in the para- small decrements in blood ionized calcium to maintain the thyroid gland, with lesser expression in the rodent hypothala- normocalcemic state. As discussed later, PTH accomplishes mus and thymus. The appearance of PTH precedes that of the this task by promoting bone resorption and releasing calcium parathyroid gland in evolution, because two forms of PTH from the skeletal reservoir; by inducing renal conservation of have been detected in teleosts that lack discrete parathyroid calcium and excretion of phosphate; and by indirectly enhanc- glands.(*.3) The physiological roles of PTH in fish have not yet ing intestinal calcium absorption by increasing the renal pro- been definitively established, although it has suggested based duction of the active vitamin D metabolite 1,25(OH), vitamin on sites of expression that PTH may play a role in the devel- D. Serum ionized calcium and 1,25(OH), vitamin D produce opment of the teleost neural system, cartilage, and bone.(4) feedback inhibition of the secretion of PTH, whereas serum Teleost PTHs display significant amino acid homology to phosphate increases PTH secretion. The interplay between se- mammalian PTHs in the 1-34 sequence of the mature peptides rum calcium, PTH, 1,25(OH), vitamin D, and phosphate per- (i.e., the region required for binding to and activating the G- mit serum ionized calcium levels to be maintained within very protein-coupled PTHl receptor; Fig. 1).Teleosts display wide- spread expression of a PTHl receptor that presumably medi- The authors state that they have no conflicts of interest. ates the physiological actions of PTH. 0 2008 American Society for Bone and Mineral Research 124 I CHAPTER25 PTH, PTHrP, and TIP39 is reflected in the organization of the genes encoding these polypeptides (Fig. 2). PTH SYNTHESIS AND SECRETION There is a single mammalian PTH gene that in humans is present on the short arm of chromosome 11. The primary translation product is the precursor molecule prepro-PTH that includes a 25 amino acid pre sequence, a 6 amino acid pro IChickPTH PTH - sequence, and an 84 amino acid mature PTH sequence.(13)The zPTHl pre sequence functions as a signal sequence that directs the nascent polypeptide to the machinery that transports it across fPTHl the membrane of the endoplasmic reticulum (ER), where the - pre sequence is cleaved. The function of the pro sequence is not as clearly defined, but it seems to be required for efficient ER transport of the polypeptide and may play a role in sub- sequent events such as protein folding.(I4)The pro sequence seems to be cleaved by the protease furin, producing the ma- rPTHrP1 ture 1-84 PTH polypeptide. Once produced and packaged into secretory vesicles with the parathyroid chief cell, PTH( 1-84) is mPTHrP PTHrP subject to alternative fates. The mature hormone can be se- creted through a classical exocytotic mechanism or it may be hPTHrPJ cleaved by calcium-sensitive proteases present within secretory vesicles, resulting in the production and secretion of fragments of PTH(1-84) that lack the amino-terminal domain and are thus inactive with respect to responses mediated by the PTHl receptor."') Cleavage of circulating PTH( 1-84) to carboxyl- fragments can also occur in peripheral tissues such as liver and GIP "l kidney.' '') Historically, cleavage of PTH( 1-84) has been viewed as a mechanism for biological inactivation of the hor- FIG. 1. Phylogenetic analysis of PTH and related polypeptides."' mone, but there is suggestive evidence that carboxyl-terminal Copyright 2004, The Endocrine Society. fragments of PTH may display unique biological properties.'") REGULATION OF PTH SECRETION BY PTH-related peptide (PTHrP) displays sequence homology EXTRACELLULAR CALCIUM with PTH that is limited to the amino-terminal 1-34 region of both peptides.'" PTHrP was originally identified as the hu- The major physiological function of the parathyroid glands moral mediator of hypercalcemia of malignan~y'~ and is is to act as a "calciostat," sensing the prevailing blood ionized now known to play a number of important physiological roles calcium level and adjusting the secretion of PTH accordingly (eg, control of endochondral bone development, smooth (Fig. 3). The relationship between ionized calcium and PTH muscle tone, and morphogenesis of the mammary gland).'x' secretion is a steep sigmoidal one, allowing significant changes The PTHrP gene has structural similarity to that of PTH, and in PTH secretion in response to very small changes in plasma the genes are presumed to be derived from a common ances- ionized calcium.