A potential role for adrenomedullin as a local regulator of bone growth

Bone remodeling is a complex process of coordinated resorption and formatio n of bone, which is regulated by systemic hormones and by local factors. We have previously shown that the peptide hormone adrenomedullin is mitogenic to osteoblastic cells in vitro and that it promotes bone growth in vivo. T he aim of the present study was to characterize the expression of molecules that may mediate adrenomedullin signaling in osteoblasts and to investigat e the expression of adrenomedullin itself in these cells. The first adrenom edullin receptor that was cloned is the seven-transmembrane G protein-coupl ed receptor, L1. Two additional receptors for adrenomedullin, which arise f rom interactions between calcitonin receptor-like receptor and receptor act ivity modifying proteins 2 or 3, have now been described. In the current st udy, we used RT-PCR and Northern blot analysis to demonstrate that messenge r RNA for the three adrenomedullin receptors, as well as for adrenomedullin itself, is expressed in primary rat osteoblasts. Treating primary osteobla sts with transforming growth factor-p and insulin-like growth factor-beta m oderately reduced adrenomedullin RNA levels, whereas PTH had no effect. We have shown by immunocytochemistry that adrenomedullin peptide is present in osteoblasts, and by competitive binding assays that I-125-adrenomedullin b inds with high affinity to intact osteoblasts and to osteoblast cell membra nes. Coexpression of adrenomedullin and adrenomedullin receptors in osteobl asts, taken together with our previous finding that adrenomedullin is mitog enic to these cells, raises the possibility that this peptide is a local re gulator of bone growth.