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

Pharmacological modulators of β-adrenoceptors can influence bone mineral density and fracture risk in humans. Studies reported that β-adrenoceptor ligands stimulate bone resorption by enhancing the expression of RANK-L, whereas the mechanisms by which β-adrenoreceptors regulate bone formation are poorly understood. Here we show that β2-adrenoceptor is predominantly expressed by bone cells, although low levels of β1- and β3-adrenoceptors were detectable. Noradrenaline and the selective β2-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 or 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 β2-adrenoceptors directly and indirectly stimulate osteoclast formation, but have no direct effect on osteoblast growth, differentiation or function.