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A Common Downstream Signaling Activity of Osteoclast Survival Factors That Prevent Nitric Oxide-Promoted Osteoclast Apoptosis¹

Department of Orthodontics (K.Ka., Y.Ko., F.H., K.Ko.), Department of Pharmacology (T.N., M.S., Y.Ka., H.S.), Nagasaki University School of Dentistry, Nagasaki 852-8588, Japan

Address all correspondence and requests for reprints to: Hideaki Sakai, DDS., Ph.D., Department of Pharmacology, Nagasaki University School of Dentistry, 1–7-1, Sakamoto, Nagasaki 852-8588, Japan. E-mail: h-sakai{at}net.nagasaki-u.ac.jp

Treatment with NO-releaser NOC18 significantly promoted apoptosis in murine osteoclast-like cells, with a transient increase in caspase-3-like protease activity. In contrast, the apoptosis was protected against by caspase inhibitors, most efficiently with the broadly acting caspase specific inhibitor z-Asp-CH₂-DCB, indicating involvement of multiple caspases in progression of the apoptosis. Among osteoclast survival factors examined, calcitonin completely protected against morphologically defined-apoptosis and the increase of caspase-3-like protease activity. The effect of calcitonin was mimicked by treatment of cells with (Bu)₂cAMP and forskolin, and abolished by protein kinase-A inhibitor H-89. Independently from the PKA activation, colony stimulating factor-1, interleukin-1ß and the receptor activator of NF-B ligand also protected against the apoptosis but were less effective than calcitonin. All survival factors investigated inhibited conversion of procaspases-3 and -9 to their mature forms in the cells. Thus, downstream antiapoptotic signaling activity from each factor overlapped in inhibition of caspases. However, how this was attained seemed to be different from each other. Typically, only colony stimulating factor-1 up-regulated expression of endogenous caspase inhibitor protein, X-linked inhibitor of apoptosis (XIAP), in the osteoclast-like cells.

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