Effects of amylin and adrenomedullin on the skeleton

Amylin and adrenomedullin are related peptides with some homology to both calcitonin and calcitonin gene-related peptide (CGRP). All these peptides have in common a 6-amino acid ring structure at the amino-terminus created by a disulfide bond. In addition, the carboxy-termini are amidated. Both amylin and adrenomedullin have recently been found to stimulate the proliferation of osteoblasts in vitro, and to increase indices of bone formation in vivo when administered either locally or systemically. Both amylin and adrenomedullin have also been found to act on chondrocytes (Cornish et al., submitted for publication), stimulating their proliferation in culture and increasing tibial growth plate thickness when administered systemically to adult mice. Studies of structure-activity relationships have demonstrated that osteotropic effects of amylin and adrenomedullin can be retained in peptide fragments of the molecules. The full-length peptide of amylin has known effects on fuel metabolism, and systemic administration of amylin is also associated with increased fat mass. However, the octapeptide fragment of the molecule, amylin-(1-8), is osteotropic and yet has no activity on fuel metabolism. Similar fragments of adrenomedullin have also been defined, which retain activity on bone but lack the parent peptide's vasodilator properties. Both amylin-(1-8) and adrenomedullin-(27-52) act as anabolic agents on bone, increasing bone strength when administered systemically. Thus, these small peptides, or analogues of it, are potential candidates as anabolic therapies for osteoporosis. Both amylin and adrenomedullin may have effects on bone metabolism. Amylin is secreted following eating and may direct calcium and protein absorbed from the meal into new bone synthesis. Amylin circulates in high concentrations in obese individuals, and might contribute to the association between bone mass and fat mass. Our recent findings demonstrating the co-expression of adrenomedullin and adrenomedullin receptors in osteoblasts, along with the findings that the peptide and its receptor are easily detectable during rodent embryogenesis, suggest that this peptide is a local regulator of bone growth. Thus, the findings reviewed in this paper illustrate that amylin and adrenomedullin may be relevant to the normal regulation of bone mass and to the design of agents for the treatment of osteoporosis.