Activin A inhibits RANKL-mediated osteoclast formation, movement and function in murine bone marrow macrophage cultures

Abstract

The process of osteoclastic bone resorption is complex and regulated at multiple levels. The role of osteoclast (OCL) fusion and motility in bone resorption are unclear, with the movement of OCL on bone largely unexplored. RANKL is a potent stimulator of murine osteoclastogenesis, and Activin A (ActA) enhances that stimulation in whole bone marrow. ActA treatment does not induce osteoclastogenesis in stroma-free murine bone marrow macrophage cultures (BMM), but rather inhibits RANKL-induced osteoclastogenesis. We hypothesized that ActA and RANKL differentially regulate osteoclastogenesis via OCL precursor and mature OCL migration. Time-lapse video microscopy measured ActA and RANKL effects on BMM and OCL motility and function. ActA completely inhibited RANKL-stimulated OCL motility, differentiation and bone resorption, via a mechanism mediated by ActA-dependent changes in SMAD2, AKT and IκB signaling. The potent and dominant inhibitory effect of ActA was associated with decreased OCL lifespan, as ActA significantly increased activated caspase-3 in mature OCL and OCL precursors. Collectively, these data demonstrate a dual action for ActA on murine OCLs.