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

Original Article

Cd38/Adp-Ribosyl Cyclase

: A New Role in the Regulation of Osteoclastic Bone Resorption



Li Suna, Olugbenga A. Adebanjoa, Baljit S. Moongaa, Susanne Corisdeob, Hindupur K. Anandatheerthavaradac, Gopa Biswasc, Toshiya Arakawae, Yoshiyuki Hakedae, Antoliy Kovala, Bali Sodama, Peter J.R. Bevisa, A. James Mosera, F. Anthony Laid, Solomon Epsteina, Bruce R. Troenb, Masayoshi Kumegawae, and Mone Zaidia

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
Division of Endocrinology, Box 1055, Mount Sinai School of Medicine, 1 Gustave Levy Place, New York, NY 10029.(212) 241-8797

mone.zaidi{at}smtplink.mssm.edu

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.

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

© 1999 The Rockefeller University Press

1.used in this paper: BCIP, 5-bromo-4-chloro-3-indoyl-phosphate; cADPr, cyclic ADP-ribose; IL-6, interleukin 6; NBT, 4-nitroblue tetrazolium chloride; RyRs, ryanodine receptors; TRAP, tartrate-resistant acid phosphatase

L. Sun and O.A. Adebanjo contributed equally to this paper.


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