Calcitonin and bone formation: a knockout full of surprises.

Historical perspectives In this issue of the JCI, the elegant publication by Hoff and colleagues (1), by serendipity or on purpose, falls on the 40th anniversary of the discovery of calcitonin (CT) as a hypocalcemic principle from the parathyroid gland (2). The parathyroid origin of calcitonin was revisited shortly thereafter, and a thyroid C cell origin was firmly established (3, 4). Calcitonins from several species — mammals, birds, and fishes — were subsequently purified (5), and the first of many calcitonin receptors was cloned in 1991 (6). Tissue-specific alternative splicing of the calcitonin gene at exon 4 was shown to result in production of a novel 37–amino acid peptide: calcitonin gene–related peptide-α (CGRP-α) (7). Both CGRP and calcitonin date back to their neural origins in protochordates and primitive chordates (8). Nonetheless, while CGRP is an established vasodilator and neuromodulator (8, 9), calcitonin has had a checkered history, to say the least, both as a hormone and as a drug. A novel effect on bone formation (1), direct or indirect, is thus intriguing and, if proven, will surely add another historical dimension to calcitonin’s role in skeletal biology. Molecular mechanism of calcitonin action Calcitonin is a 32–amino acid peptide with an N-terminal disulphide bridge and a C-terminal prolineamide residue. Both ends of the molecule contain species-invariant residues that are required for its binding to highaffinity G protein–coupled receptors on the osteoclast (5). Attempts to map the entire bimolecular surface of the hormone receptor complex through photolabeling studies have yielded important new information on contact sites (10). It has also become clear that conformational flexibility of a given calcitonin molecule is the primary determinant of its biological potency (5). Thus, the more flexible fish calcitonins (eel and salmon), containing amino acids such as Gly with less bulky side chains, are about 40fold more potent than mammalian (porcine, ovine, and human) homologs (11, 12). The ligand specificity of a particular calcitonin receptor isoform is defined by receptor activity–modifying proteins (RAMPs) that form heterodimers with a pair of receptors (13). Femtomolar calcitonin concentrations inhibit the resorptive function of mature osteoclasts, with quiescence (Q effect) being followed by margin retraction (R effect) (14). These kinetically separable morphological changes, Q and R, are exerted through separate cAMPand Ca2+-dependent signaling pathways involving distinct G proteins (14–17).