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Am J Physiol Cell Physiol 291: C529-C537, 2006. First published April 12, 2006; doi:10.1152/ajpcell.00354.2005
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GROWTH, DIFFERENTIATION, AND APOPTOSIS

CGRP inhibits osteoprotegerin production in human osteoblast-like cells via cAMP/PKA-dependent pathway

I. Villa,1 E. Mrak,1,2 A. Rubinacci,1 F. Ravasi,1 and F. Guidobono2

1Bone Metabolic Unit, Scientific Institute H San Raffaele, Milan; and 2Department of Pharmacology, Chemotherapy, and Medical Toxicology, University of Milan, Milan, Italy

Submitted 14 July 2005 ; accepted in final form 4 April 2006

The osteoprotegerin (OPG)/receptor activator of nuclear factor-{kappa}B ligand (RANKL)/receptor activator of nuclear factor-{kappa}B (RANK) system was evaluated as a potential target of CGRP anabolic activity on bone. Primary cultures of human osteoblast-like cells (hOB) express calcitonin receptor-like receptor (CLR) and receptor activity modifying protein 1, and, because CGRP stimulates cAMP (one of the modulators of OPG production in osteoblasts), it was investigated whether it affects OPG secretion and expression in hOB. CGRP treatment of hOB (10–11 M–10–7 M) dose-dependently inhibited OPG secretion with an EC50 of 1.08 x 10–10 M, and also decreased its expression. This action was blocked by the antagonist CGRP8–37. Forskolin, a stimulator of cAMP production, and dibutyryl cAMP also reduced the production of OPG. CGRP (10–8 M) enhanced protein kinase A (PKA) activity in hOB, and hOB exposure to the PKA inhibitor, H89 (2 x 10–6 M), abolished the inhibitory effect of CGRP on OPG secretion. Conditioned media from CGRP-treated hOB increased the number of multinucleated tartrate-resistant acid phosphatase-positive cells and the secretion of cathepsin K in human peripheral blood mononuclear cells compared with the conditioned media of untreated hOB. These results show that the cAMP/PKA pathway is involved in the CGRP inhibition of OPG mRNA and protein secretion in hOB and that this effect favors osteoclastogenesis. CGRP could thus modulate the balance between osteoblast and osteoclast activity, participating in the fine tuning of all of the bone remodeling phases necessary for the subsequent anabolic effect.

receptor-activity-modifying proteins; protein kinase A; osteoclast; cathepsin K


Address for reprint requests and other correspondence: F. Guidobono, Dept. of Pharmacology, Chemotherapy and Medical Toxicology, Univ. of Milan, Via Vanvitelli 32, 20129 Milan, Italy (e-mail: francesca.guidobono{at}unimi.it)






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