Pim-1 Regulates RANKL-Induced Osteoclastogenesis via NF-κB Activation and NFATc1 Induction

Pim kinases are emerging as important mediators of cytokine signaling pathways in hematopoietic cells. In this study, we demonstrate that Pim-1 positively regulates RANKL-induced osteoclastogenesis and that Pim-1 expression can be upregulated by RANKL signaling during osteoclast differentiation. The silencing of Pim-1 by RNA interference or overexpression of a dominant negative form of Pim-1 (Pim-1 DN) in bone marrow-derived macrophage cells attenuates RANKL-induced osteoclast formation. Overexpression of Pim-1 DN blocks RANKL-induced activation of TGF-beta-activated kinase 1 (TAK1) and NF-kappa B as well as expression of NFATc1 during osteoclastogenesis. However, we found that overexpression of TAK1 in the presence of Pim-1 DN rescues NF-kappa B activation. Additionally, Pim-1 interacts with RANK as well as TAK1, indicating that Pim-1 is involved in RANKL-induced NF-kappa B activation via TAK1. Furthermore, we demonstrate that Pim-1 also regulates NFATc1 transcription activity and subsequently induces osteoclast-associated receptor expression, an osteoclast-specific gene. Taken together, our results reveal that Pim-1 positively regulates RANKL-induced osteoclastogenesis. The Journal of Immunology, 2010, 185: 7460-7466.