Amylin and adrenomedullin: Novel regulators of bone growth

Bone growth is regulated by circulating hormones and locally generated factors. Understanding their mechanisms of action enables us to obtain a better appreciation of the cellular and molecular basis of bone remodelling, and could therefore be valuable in approaches to new therapies. In this review, we consider the actions on bone tissue of the peptide hormones amylin and adrenomedullin, known to circulate at picomolar concentrations. Adrenomedullin is also produced locally in bone. Amylin and U adrenomedullin are related peptides with some homology to both calcitonin and calcitonin gene-related peptide. These peptides have recently been found to stimulate the proliferation of osteoblasts in vitro, and to increase indices of bone formation when administered either locally or systemically in vivo. In addition, amylin inhibits bone resorption. Both amylin and adrenomedullin have also been found to act on chondrocytes, stimulating their proliferation in culture and increasing tibial growth plate thickness when administered systemically to adult mice. Like the peptides themselves, the receptors for the calcitonin family are also related to each other. Each peptide seems to act through its own distinct high affinity receptor, as well as through other receptors for the family, usually with lower affinity. Characterisation of the putative receptors expressed in osteoblasts, has provided some understanding of the physiological effects of amylin and adrenomedullin in these cells. Studies of structure-activity relationships have demonstrated that osteotropic effects of amylin and adrenomedullin can be retained in peptide fragments of the molecule whilst losing the parent molecule's effects on carbohydrate metabolism or vasodilatory properties respectively. Thus, these small peptides, or their analogues, are attractive candidates as anabolic therapies for osteoporosis.