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Department of Medicine, University of Toronto, and the Division of Endocrinology and Metabolism, St. Michael's Hospital, Toronto, Ontario, Canada (T.M.M., L.G.R.); and the Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts (P.D., F.R.B.)
* To whom correspondence should be addressed. E-mail: drtimothy.murray{at}utoronto.ca.
Parathyroid hormone (PTH) is a major systemic regulator of the concentrations of calcium, phosphate and active vitamin D metabolites in blood, and of cellular activity in bone. Intermittently administered PTH and amino-terminal PTH peptide fragments or analogs also augment bone mass, and currently are being introduced into clinical practice as therapies for osteoporosis. The amino-terminal region of PTH is known to be both necessary and sufficient for full activity at PTH/PTHrP receptors, which mediate the classical biological actions of the hormone. It is well known that multiple carboxyl-terminal fragments of PTH are present in blood, where they comprise the major form(s) of circulating hormone, but these fragments have long been regarded as inert by-products of PTH metabolism because they neither bind to nor activate PTH/PTHrP receptors. New in vitro and in vivo evidence, together with older observations extending over the past twenty years, now points strongly to the existence of novel large carboxyl-terminal PTH fragments in blood and to receptors for these fragments that appear to mediate unique biological actions in bone. This review traces the development of this field in the context of the evolution of our understanding of the "classical" receptor for amino-terminal PTH and the now convincing evidence for these receptors for carboxyl-terminal PTH. The review summarizes current knowledge of the structure, secretion and metabolism of PTH and its circulating fragments, details available information concerning the pharmacology and actions of carboxyl-terminal PTH receptors, and frames their likely biological and clinical significance. It seems likely that physiological parathyroid regulation of calcium and bone metabolism may involve receptors for circulating carboxy-terminal PTH ligands as well as the action of amino-terminal determinants within the PTH molecule on the classical PTH/PTHrP receptor.
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