The role of peptides and receptors of the calcitonin family in the regulation of bone metabolism.

The 'calcitonin family' is a group of peptide hormones that share structural similarities with calcitonin, and includes calcitonin gene-related peptide (CGRP), amylin, adrenomedullin and adrenomedullin 2 (intermedin). These hormones are produced by different tissues, with calcitonin being produced in thyroid C cells, alphaCGRP predominantly in neural tissue, amylin in beta-islet cells of the pancreas and adrenomedullin in many tissues and cell types. Bone appears to be a common target for all the peptides of the calcitonin family, although the specific bone effects of the peptides vary. Administration of calcitonin produces rapid lowering of serum calcium levels, mainly through inhibition of bone resorption by osteoclasts. In vitro and in a number of animal experimental models, amylin and CGRP are also effective in inhibiting osteoclast activity and bone resorption. Amylin, adrenomedullin and CGRP can also affect cells of the osteoblast lineage, inducing osteoblast proliferation and promoting bone formation. Receptors for the peptides of the calcitonin family are formed by heterodimerization of the calcitonin receptor (CTR) or calcitonin receptor-like receptor (CLR) with receptor activity modifying proteins (RAMPs). Although the different combinations of these proteins create receptors with distinct ligand specificities, there is a degree of cross-reactivity and the receptors are able to bind other ligands from the family, usually with lower affinity. Analysis of the expression of the receptors for the calcitonin family in 16 samples of human osteoblasts showed high levels of CLR and RAMP1, low levels of RAMP2 and no expression of RAMP3 or CTR. Recent studies of the bone phenotype of knockout animals lacking the calcitonin, alphaCGRP or amylin gene indicated that in this experimental system the main physiological role of amylin in bone is the inhibition of bone resorption, that of CGRP is the activation of bone formation, while calcitonin, unexpectedly appears to be inhibiting bone formation without affecting bone resorption. Further investigations will be required to determine the mechanisms of action of calcitonin peptides in bone and their significance to human bone physiology.