Transforming Growth Factor-ß Coordinately Induces Suppressor of Cytokine Signaling 3 and Leukemia Inhibitory Factor to Suppress Osteoclast Apoptosis

Local release of TGF-ß during times of high bone turnover leads to elevated levels within the bone microenvironment, and we have shown that TGF-ß suppresses osteoclast apoptosis. Therefore, understanding the influences of TGF-ß on bone resorbing osteoclasts is critical to the design of therapies to reduce excess bone loss. Here we investigated the mechanisms by which TGF-ß sustains suppression of osteoclast apoptosis. We found TGF-ß rapidly increased leukemia inhibitory factor (LIF) expression and secretion by phosphorylated mothers against decapentaplegic-dependent and -independent signaling pathways. TGF-ß also induced suppressor of cytokine signaling 3 (SOCS3) expression, which was required for TGF-ß or LIF to promote osteoclast survival by. Blocking LIF or SOCS3 blocked TGF-ß promotion of osteoclast survival, confirming that LIF and SOCS3 expression are necessary for TGF-ß-mediated suppression of osteoclast apoptosis. Investigation of the mechanisms by which LIF promotes osteoclast survival revealed that LIF-induced expression of Bcl-XL and repressed Bcl-2 interacting domain expression by activating MAPK kinase, AKT, and nuclear factor-¿B pathways. Suppression of Janus kinase/signal transducer and activator of transcription signaling further increased Bcl-XL expression and enhanced osteoclast survival, supporting that this pathway is not involved in prosurvival effects of TGF-ß and LIF. These data show that TGF-ß coordinately induces LIF and SOCS3 to promote prosurvival signaling. This alters the ratio of prosurvival Bcl2 family member Bcl-XL to proapoptotic family member Bcl-2 interacting domain, leading to prolonged osteoclast survival.