Inhibition of IKK-β blocks osteoclast formation and activity

NF-κB is a key determinant in orchestration of osteoclast formation and function and is an attractive drug target since deregulation of NF-κB plays an important role in various pathological processes. Two major signaling pathways activate NF-κB, the canonical-pathway via the kinases of IKK-α, ß and γ and the alternative-pathway through IKK-α and NIK. Objectives: In this study we used a novel selective and specific IKK-ß inhibitor of the classical NF-κB pathway named the AVE1627 to clarity the role of IKK-ß in osteoclasts (OC) formation and bone resorbing activity. Methods: OC were generated using bone marrow macrophages in the presence of M-CSF and RANKL and using co-culture system with primary osteoblasts. To check the effect on LPS-induced bone resorption in vivo mice were injected with LPS on calvariae and AVE1627 was given twice a day for five days. Results: AVE1627 dose-dependently inhibited the osteoclatogenesis in vitro. In addition bone resorbing activity of mature OC were inhibited by AVE1627 at the concentrations of 3-4 μM. Micro-computed tomography revealed resorption pits on calvariae of LPS-injected mice compared to the PBS vehicle-injected mice. AVE1627 dose dependently prevented the resorption lacunae brought by LPS. In addition LPS significantly reduced the bone mineral density (BMD) compared to the control group. IKK-ß inhibitor AVE1627 significantly inhibited this reduction of BMD brought by LPS at 50mg/kg/5days. AVE1627 also significantly reduced the in vivo osteoclastogenesis by LPS at 25 mg/kg and 50 mg/kg for 5 days. Conclusion: Therefore these data suggest that the inhibition of IKK-β of classical NF-κB pathway is adequate to block the OC formation and bone-resorbing activity in vitro and in vivo.