A mutation of cysteine 46 in IKK-β promotes mPGES-1 and caveolin-1 expression to exacerbate osteoclast differentiation and osteolysis.

IKK-β is indispensable for inflammatory osteolysis, the functional residues of IKK-β are therapeutic drug targets for developing inhibitors to treat multiple diseases now. Thus it remains appealing to find the new residues of IKK-β to influence osteoclasts for alleviating bone loss diseases such as rheumatoid arthritis (RA). By employing IKK-β cysteine 46-A transgenic (IKK-βC46A) mice, we found that mutation of cysteine 46 to alanine in IKK-β exacerbated inflammatory bone destruction in vivo, and increased osteoclast differentiation and bone resorption ex vivo and in vitro. Consistent with these, IKK-β kinase activity as well as c-Fos, NFATc1 were up-regulated in bone marrow macrophages (BMMs) from IKK-βC46A mice during RANKL-induced osteoclastogenesis. Of interesting, we further identified and demonstrated that the expressions of mPGES-1 and caveolin-1 were heightened in BMMs of IKK-βC46A mice compared to those in WT mice in RANKL-induced osteoclastogenesis. Together, it revealed that mutating cysteine 46 in IKK-β could increase caveolin-1 and mPGES-1 expression to facilitate osteoclast differentiation and osteolysis. Cysteine 46 can serve as a novel target in IKK-β for designing inhibitors to treat osteolysis.