Bone Abstracts

Osteoclasts are cells specialized for resorption of calcified tissue. Osteoclasts are formed from precursor cells of monocyte lineage under the control of receptor activator of nuclear factor kappaB ligand (RANKL). Mitogen- and stress-activated protein kinase 1 (MSK1) has been reported to be an important regulator of immune response and mitogenic signaling. In this study, we for the first time found that MSK1 was activated by RANKL in osteoclast precursor, bone marrow macrophages. The inhibition of upstream kinases, ERK1/2 and p38, but not JNK, could suppress the MSK activation upon RANKL stimulation. An MSK1 inhibitor efficiently repressed the induction of c-Fos and NFATc1 and the phosphorylation of CREB by RANKL. Besides, the inhibition of MSK1 successfully blocked RANKL-induced osteoclastogenesis. In addition, knockdown of MSK1 using siRNA significantly inhibited osteoclastic differentiation. The induction of c-Fos and NFATc1 and the phosphorylation of CREB and ATF2 were also inhibited by siRNA. Moreover, the knockdown of MSK1 could significantly block the recruitment of c-Fos to the NFATc1 promoter upon RANKL stimulation. NFATc1 retrovirus transduction almost completely rescued the defect in the differentiation of MSK1-silenced BMMs. Furthermore, in vivo knockdown of MSK1 could protect RANKL-induced osteoclastogenesis and bone erosion. Therefore, MSK1 is an important novel molecule involved in RANKL signaling and osteoclast differentiation.