TGF-[beta] coordinately activates TAK1/MEK/AKT/NFkB and SMAD pathways to promote osteoclast survival

To better understand the roles of TGF-[beta] in bone metabolism, we investigated osteoclast survival in response TGF-[beta] and found that TGF-[beta] inhibited apoptosis. We examined the receptors involved in promotion of osteoclast survival and found that the canonical TGF-[beta] receptor complex is involved in the survival response. The upstream MEK kinase TAK1 was rapidly activated following TGF-[beta] treatment. Since osteoclast survival involves MEK, AKT, and NF[kappa]B activation, we examined TGF-[beta] effects on activation of these pathways and observed rapid phosphorylation of MEK, AKT, IKK, I[kappa]B, and NF[kappa]B. The timing of activation coincided with SMAD activation and dominant negative SMAD expression did not inhibit NF[kappa]B activation, indicating that kinase pathway activation is independent of SMAD signaling. Inhibition of TAK1, MEK, AKT, NIK, IKK, or NF[kappa]B repressed TGF-[beta]-mediated osteoclast survival. Adenoviral-mediated TAK1 or MEK inhibition eliminated TGF-[beta]-mediated kinase pathway activation and constitutively active AKT expression overcame apoptosis induction following MEK inhibition. TAK1/MEK activation induces pro-survival BclXL expression and TAK1/MEK and SMAD pathway activation induces pro-survival Mcl-1 expression. These data show that TGF-[beta]-induced NFκB activation is through TAK1/MEK-mediated AKT activation, which is essential for TGF-[beta] to support of osteoclast survival. [PUBLICATION ABSTRACT]