Activin A stimulates IκB-α/NFκB and rank expression for osteoclast differentiation, but not AKT survival pathway in osteoclast precursors

Recent studies have reported that activin A enhances osteoclastogenesis in cultures of mouse bone marrow cells stimulated with receptor activator of nuclear factor‐κB ligand (RANKL) and macrophage colony‐stimulating factor (M‐CSF). However, the exact mechanisms by which activin A functions during osteoclastogenesis are not clear. RANKL stimulation of RANK/TRAF6 signaling increases nuclear factor‐κB (NFκB) nuclear translocation and activates the Akt/PKB cell survival pathway. Here we report that activin A alone activates IκB‐α, and stimulates nuclear translocation of NFκB and receptor activator of nuclear factor‐κB (RANK) expression for osteoclastogenesis, but not Akt/PKB survival signal transduction including BAD and mammalian target of rapamycin (mTOR) for survival in osteoclast precursors in vitro. Activin A alone failed to activate Akt, BAD, and mTOR by immunoblotting, and it also failed to prevent apoptosis in osteoclast precursors. While activin A activated IκB‐α and induced nuclear translocation of phosphorylated‐NFκB, and it also enhanced RANK expression in osteoclast precursors. Moreover, activin A enhanced RANKL‐ and M‐CSF‐stimulated nuclear translocation of NFκB. Our data suggest that activin A enhances osteoclastogenesis treated with RANKL and M‐CSF via stimulation of RANK, thereby increasing the RANKL stimulation. Activin A alone activated the NFκB pathway, but not survival in osteoclast precursors in vitro, but it is, thus, insufficient as a sole stimulus to osteoclastogenesis. J. Cell. Biochem. 90: 59–67, 2003. © 2003 Wiley‐Liss, Inc.