Parathyroid Hormone Secretion and Action: Evidence for Discrete Receptors for the Carboxyl-Terminal Region and Related Biological Actions of Carboxyl- Terminal Ligands
Timothy M. Murray,
Leticia G. Rao,
Paola Divieti and
F. Richard Bringhurst
Department of Medicine, University of Toronto, and the Division of Endocrinology and Metabolism, St. Michael’s Hospital (T.M.M., L.G.R.), Toronto, Ontario, Canada M5B 1A6; and the Endocrine Unit (P.D., F.R.B.), Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114
Correspondence: Address all correspondence and requests for reprints to: Timothy M. Murray, M.D., F.R.C.P.(C), St. Michael’s Hospital, 38 Shuter Street, Suite 213, Toronto, Ontario M5B 1A6, Canada. E-mail: drtimothy.murray{at}utoronto.ca
PTH is a major systemic regulator of the concentrations of calcium,phosphate, and active vitamin D metabolites in blood and ofcellular activity in bone. Intermittently administered PTH andamino-terminal PTH peptide fragments or analogs also augmentbone mass and currently are being introduced into clinical practiceas therapies for osteoporosis. The amino-terminal region ofPTH is known to be both necessary and sufficient for full activityat PTH/PTHrP receptors (PTH1Rs), which mediate the classicalbiological actions of the hormone. It is well known that multiplecarboxyl-terminal fragments of PTH are present in blood, wherethey comprise the major form(s) of circulating hormone, butthese fragments have long been regarded as inert by-productsof PTH metabolism because they neither bind to nor activatePTH1Rs. New in vitro and in vivo evidence, together with olderobservations extending over the past 20 yr, now points stronglyto the existence of novel large carboxyl-terminal PTH fragmentsin blood and to receptors for these fragments that appear tomediate unique biological actions in bone. This review tracesthe development of this field in the context of the evolutionof our understanding of the "classical" receptor for amino-terminalPTH and the now convincing evidence for these receptors forcarboxyl-terminal PTH. The review summarizes current knowledgeof the structure, secretion, and metabolism of PTH and its circulatingfragments, details available information concerning the pharmacologyand actions of carboxyl-terminal PTH receptors, and frames theirlikely biological and clinical significance. It seems likelythat physiological parathyroid regulation of calcium and bonemetabolism may involve receptors for circulating carboxy-terminalPTH ligands as well as the action of amino-terminal determinantswithin the PTH molecule on the classical PTH1R.
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