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

doi:10.1083/jcb.146.5.1161

A correction to this article has been published: J. Cell Biol. 146 (6) 1391-1392

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© The Rockefeller University Press, 0021-9525/1999/9/1161/ $5.00
The Journal of Cell Biology, Volume 146, Number 5, September 6, 1999 1161-1172

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

Li Sun^a, Olugbenga A. Adebanjo^a, Baljit S. Moonga^a, Susanne Corisdeo^b, Hindupur K. Anandatheerthavarada^c, Gopa Biswas^c, Toshiya Arakawa^e, Yoshiyuki Hakeda^e, Antoliy Koval^a, Bali Sodam^a, Peter J.R. Bevis^a, A. James Moser^a, F. Anthony Lai^d, Solomon Epstein^a, Bruce R. Troen^b, Masayoshi Kumegawa^e, and Mone Zaidi^a
^a Center for Osteoporosis and Skeletal Aging, Department of Medicine, Medical College of Pennsylvania and Veterans Affairs Medical Center, Philadelphia, Pennsylvania 19104
^b Lankanau Medical Research Center, Merion, Pennsylvania 19066
^c School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104
^d Department of Medicine, University of Cardiff, Cardiff, United Kingdom
^e Mekai University, Saitama, Japan

Correspondence to: Mone Zaidi, Division of Endocrinology, Box 1055, Mount Sinai School of Medicine, 1 Gustave Levy Place, New York, NY 10029. Tel:(212) 241-8797 E-mail:mone.zaidi{at}smtplink.mssm.edu.

The multifunctional ADP-ribosyl cyclase, CD38, catalyzes thecyclization of NAD⁺ to cyclic ADP-ribose (cADPr). The lattergates Ca²⁺ release through microsomal membrane-resident ryanodinereceptors (RyRs). We first cloned and sequenced full-lengthCD38 cDNA from a rabbit osteoclast cDNA library. The predictedamino acid sequence displayed 59, 59, and 50% similarity, respectively,to the mouse, rat, and human CD38. In situ RT-PCR revealed intensecytoplasmic staining of osteoclasts, confirming CD38 mRNA expression.Both confocal microscopy and Western blotting confirmed theplasma membrane localization of the CD38 protein. The ADP-ribosylcyclase activity of osteoclastic CD38 was next demonstratedby its ability to cyclize the NAD⁺ surrogate, NGD⁺, to its fluorescentderivative cGDP-ribose. We then examined the effects of CD38on osteoclast function. CD38 activation by an agonist antibody(A10) in the presence of substrate (NAD⁺) triggered a cytosolicCa²⁺ signal. Both ryanodine receptor modulators, ryanodine,and caffeine, markedly attenuated this cytosolic Ca²⁺ change.Furthermore, the anti-CD38 agonist antibody expectedly inhibitedbone 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 fora new role for CD38/ADP-ribosyl cyclase in the control of boneresorption, most likely exerted via cADPr.

Key Words: Ca²⁺ channel, ryanodine receptor, bone resorption, cADPr, osteoporosis

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