Compressive mechanical force augments osteoclastogenesis by bone marrow macrophages through activation of c-Fms-mediated signaling

Little is known about the effects of mechanical forces on osteoclastogenesis by bone marrow macrophages (BMMs) in the absence of mechanosensitive cells, including osteoblasts and fibroblasts. In this study, we examined the effects of mechanical force on osteoclastogenesis by applying centrifugal force to BMMs using a horizontal microplate rotor. Our findings, as measured by an in vitro model system, show that tumor necrosis factor (TNF)-α is capable of inducing osteoclast differentiation from BMMs and bone resorption in the presence of macrophage-colony stimulating factor (M-CSF) and is further facilitated by receptor activator of nuclear factor-kappaB (NF-κB) ligand (RANKL). Application of force to BMMs accelerated TNF-α-induced osteoclastogenesis; this was inhibited either by anti-TNF-α or anti-TNF-α receptor but not by OPG. TNF-α also increased c-Fms expression at both mRNA and protein levels in BMMs. An anti-c-Fms antibody completely inhibited osteoclast differentiation and bone resorption induced by TNF-α but partially blocked osteoclastogenesis stimulated in combination with RANKL. These results suggest that TNF-α (in the presence of M-CSF) is capable of inducing osteoclastogenesis from BMMs, and that osteoclastogenesis is significantly stimulated by force application through the activation of c-Fms-mediated signaling. Overall, the present study reveals the facilitating effect of mechanical force on osteoclastic differentiation from BMMs without the addition of mechanosensitive cells.