β2-Adrenoreceptor ligands regulate osteoclast differentiation in vitro by direct and indirect mechanisms

Pharmacological modulators of beta-adrenoceptors can influence bone mineral density and fracture risk in humans. Studies reported that P-adrenoceptor ligands stimulate bone resorption by enhancing the expression of RANK-L, whereas the mechanisms by which beta-adrenoreceptors regulate bone formation are poorly understood. Here we show that beta 2-adrenoceptor is predominantly expressed by bone cells, although low levels of beta 1- and beta 3-adrenoceptors were detectable. Noradrenaline and the selective beta 2-adrenoceptor agonists isoprenaline and salmeterol Stimulated osteoclast formation and bone resorption in BM osteoblast co-cultures and increased expression of RANK-L by osteoblasts. All three ligands enhanced RANK-L induced osteoclast formation and increased osteoclast multinuclearity. There was no significant effect of noradrenaline OF isoprenaline on osteoblast growth, differentiation or function. These findings confirm the importance of the sympathetic nervous system in the regulation of bone mass, and demonstrate that pharmacological agonists of beta 2-adrenoceptors directly and indirectly stimulate osteoclast formation, but have no direct effect on osteoblast growth, differentiation or function. (c) 2008 Elsevier Inc. All rights reserved.