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Guggulsterone Inhibits Osteoclastogenesis Induced by Receptor Activator of Nuclear Factor-B Ligand and by Tumor Cells by Suppressing Nuclear Factor-B Activation

Authors' Affiliation: Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, Texas

Requests for reprints: Bharat B. Aggarwal, Cytokine Research Laboratory, Department of Experimental Therapeutics, Box 143, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-792-3503. ext. 6459; Fax: 713-794-1613; E-mail: aggarwal{at}mdanderson.org.

Bone resorption is commonly associated with aging and with certain types of cancer, including multiple myeloma and breast cancer. What induces bone resorption is not fully understood, but the role of osteoclasts is well established. Recently, receptor activator of nuclear factor-B (NF-B) ligand (RANKL), a member of the tumor necrosis factor superfamily, was implicated as a major mediator of bone resorption, suggesting that agents that can suppress RANKL signaling have the potential to inhibit bone resorption or osteoclastogenesis. Guggulsterone [4,17(20)-pregnadiene-3,16-dione], isolated from the guggul tree Commiphora mukul and used to treat osteoarthritis and bone fractures, was recently shown to antagonize the farnesoid X receptor, decrease the expression of bile acid–activated genes, and suppress the NF-B activation induced by various carcinogens. We investigated whether guggulsterone could modulate RANKL signaling and osteoclastogenesis induced by RANKL or tumor cells. We found that treatment of monocytes with guggulsterone suppressed RANKL-activated NF-B activation (as indicated by gel-shift assay) and that this suppression correlated with inhibition of IB kinase and phosphorylation and degradation of IB, an inhibitor of NF-B. Guggulsterone also suppressed the differentiation of monocytes to osteoclasts in a dose-dependent and time-dependent manner. Suppression of osteoclastogenesis by the NF-B-specific inhibitory peptide implies a link between NF-B and osteoclastogenesis. Finally, differentiation to osteoclasts induced by coincubating human breast tumor cells (MDA-MB-468) or human multiple myeloma (U266) cells with monocytes was also completely suppressed by guggulsterone. Collectively, our results indicate that guggulsterone suppresses RANKL and tumor cell–induced osteoclastogenesis by suppressing the activation of NF-B.

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