CD38/ADP-ribosyl cyclase: A new role in the regulation of osteoclastic bone resorption

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 a nd sequenced full-length CD38 cDNA from a rabbit osteoclast cDNA library. T he predicted amino acid sequence displayed 59, 59, and 50% similarity, resp ectively, to the mouse, rat, and human CD38. In situ RT-PCR revealed intens e cytoplasmic staining of osteoclasts. confirming CD38 mRNA expression. Bot h confocal microscopy and Western blotting confirmed the plasma membrane lo calization of the CB38 protein. The ADP-ribosyl cyclase activity of osteocl astic CD38 was next demonstrated by its ability to cyclize the NAD(+) surro gate, NGD(+), to its fluorescent derivative cGDP-ribose. We then examined t he effects of CD38 on osteoclast function. CD38 activation by an agonist an tibody (A10) in the presence of substrate (NAD(+)) triggered a cytosolic Ca 2+ signal. Both ryanodine receptor modulators, ryanodine, and caffeine, mar kedly attenuated this cytosolic Ca2+ change. Furthermore, the anti-CD38 ago nist antibody expectedly inhibited bone resorption in the pit assay and ele vated interleukin-6 (IL-6) secretion. IL-6, in turn, enhanced CD38 mRNA exp ression. Taken together, the results provide compelling evidence for a new role for CD38/ADP-ribosyl cyclase in the control of bone resorption, most l ikely exerted via cADPr.