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CD38/ADP-Ribosyl Cyclase: A New Role in the Regulation of Osteoclastic Bone Resorption

Li Sun, Olugbenga A. Adebanjo, Baljit S. Moonga, Susanne Corisdeo, Hindupur K. Anandatheerthavarada, Gopa Biswas, Toshiya Arakawa, Yoshiyuki Hakeda, Antoliy Koval, Bali Sodam, Peter J. R. Bevis, A. James Moser, F. Anthony Lai, Solomon Epstein, Bruce R. Troen, Masayoshi Kumegawa and Mone Zaidi
The Journal of Cell Biology
Vol. 146, No. 5 (Sep. 6, 1999), pp. 1161-1171
Stable URL: http://www.jstor.org/stable/1619390
Page Count: 11
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CD38/ADP-Ribosyl Cyclase: A New Role in the Regulation of Osteoclastic Bone Resorption
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Abstract

The multifunctional ADP-ribosyl cyclase, CD38, catalyzes the cyclization of NAD+ to cyclic ADP-ribose (cADPr). The latter gates Ca2+ release through microsomal membrane-resident ryanodine receptors (RyRs). We first cloned and sequenced full-length CD38 cDNA from a rabbit osteoclast cDNA library. The predicted amino acid sequence displayed 59, 59, and 50% similarity, respectively, to the mouse, rat, and human CD38. In situ RT-PCR revealed intense cytoplasmic staining of osteoclasts, confirming CD38 mRNA expression. Both confocal microscopy and Western blotting confirmed the plasma membrane localization of the CD38 protein. The ADP-ribosyl cyclase activity of osteoclastic CD38 was next demonstrated by its ability to cyclize the NAD+ surrogate, NGD+, to its fluorescent derivative cGDP-ribose. We then examined the effects of CD38 on osteoclast function. CD38 activation by an agonist antibody (A10) in the presence of substrate ( NAD+) triggered a cytosolic Ca2+ signal. Both ryanodine receptor modulators, ryanodine, and caffeine, markedly attenuated this cytosolic Ca2+ change. Furthermore, the anti-CD38 agonist antibody expectedly inhibited bone resorption in the pit assay and elevated interleukin-6 (IL-6) secretion. IL-6, in turn, enhanced CD38 mRNA expression. Taken together, the results provide compelling evidence for a new role for CD38/ADP-ribosyl cyclase in the control of bone resorption, most likely exerted via cADPr.

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