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Curcumin (Diferuloylmethane) Inhibits Receptor Activator of NF-B Ligand-Induced NF-B Activation in Osteoclast Precursors and Suppresses Osteoclastogenesis¹

Cytokine Research Section, Department of Bioimmunotherapy, Unit 143, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030

Numerous studies have indicated that inflammatory cytokines play a major role in osteoclastogenesis, leading to the bone resorption that is frequently associated with cancers and other diseases. Gene deletion studies have shown that receptor activator of NF-B ligand (RANKL) is one of the critical mediators of osteoclastogenesis. How RANKL mediates osteoclastogenesis is not fully understood, but an agent that suppresses RANKL signaling has potential to inhibit osteoclastogenesis. In this report, we examine the ability of curcumin (diferuloylmethane), a pigment derived from turmeric, to suppress RANKL signaling and osteoclastogenesis in RAW 264.7 cells, a murine monocytic cell line. Treatment of these cells with RANKL activated NF-B, and preexposure of the cells to curcumin completely suppressed RANKL-induced NF-B activation. Curcumin inhibited the pathway leading from activation of IB kinase and IB phosphorylation to IB degradation. RANKL induced osteoclastogenesis in these monocytic cells, and curcumin inhibited both RANKL- and TNF-induced osteoclastogenesis and pit formation. Curcumin suppressed osteoclastogenesis maximally when added together with RANKL and minimally when it was added 2 days after RANKL. Whether curcumin inhibits RANKL-induced osteoclastogenesis through suppression of NF-B was also confirmed independently, as RANKL failed to activate NF-B in cells stably transfected with a dominant-negative form of IB and concurrently failed to induce osteoclastogenesis. Thus overall these results indicate that RANKL induces osteoclastogenesis through the activation of NF-B, and treatment with curcumin inhibits both the NF-B activation and osteoclastogenesis induced by RANKL.

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