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Mount Sinai Bone Program and Department of Medicine and Geriatrics, Mount Sinai School of Medicine, and Division of Endocrinology and Geriatric Research Education and Clinical Center (GRECC), Veterans Affairs Medical Center, New York, New York, USA;
* Trudeau Institute, Lake Placid, New York, USA;
The Laboratory of Physiology, University of Cambridge, CB2 3EG, UK; and
Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
1Correspondence: Division of Endocrinology, Box 1055, Mount Sinai School of Medicine, One Gustave Levy Place, New York, NY 10029, USA. E-mail: mone.zaidi{at}mssm.edu
We have evaluated the role of the ADP-ribosyl cyclase, CD38, in bone remodeling, a process by which the skeleton is being renewed constantly through the coordinated activity of osteoclasts and osteoblasts. CD38 catalyzes the cyclization of its substrate, NAD+, to the Ca2+-releasing second messenger, cyclic ADP-ribose (cADPr). We have shown previously that CD38 is expressed both in osteoblasts and osteoclasts. Its activation in the osteoclast triggers Ca2+ release through ryanodine receptors (RyRs), stimulation of interleukin-6 (IL-6), and an inhibition of bone resorption. Here, we have examined the consequences of deleting the CD38 gene in mice on skeletal remodeling. We report that CD38-/- mice displayed a markedly reduced bone mineral density (BMD) at the femur, tibia, and lumbar spine at 3 months and at the lumbar spine at 4 months, with full normalization of the BMD at all sites at 5 months. The osteoporosis at 3 months was accompanied by a reduction in primary spongiosa and increased osteoclast surfaces on histomorphometric analysis. Hematopoetic stem cells isolated ex vivo from CD38-/- mice showed a dramatic 
fourfold increase in osteoclast formation in response to incubation for 6 days with RANK-L and M-CSF. The osteoclasts so formed in these cultures showed a 2.5-fold increase in resorptive activity compared with wild-type cells. However, when adherent bone marrow stromal cells were allowed to mature into alkaline phosphatase-positive colony-forming units (CFU-Fs), those derived from CD38-/- mice showed a significant reduction in differentiation compared with wild-type cells. Real-time RT-PCR on mRNA isolated from osteoclasts at day 6 showed a significant reduction in IL-6 and IL-6 receptor mRNA, together with significant decreases in the expression of all calcineurin A isoforms, 
, ß, and 
. These findings establish a critical role for CD38 in osteoclast formation and bone resorption. We speculate that CD38 functions as a cellular NAD+ "sensor," particularly during periods of active motility and secretion.—Sun, L., Iqbal, J., Dolgilevich, S., Yuen, T., Wu, X.-B., Moonga, B. S., Adebanjo, O. A., Bevis, P. J. R., Lund, F., Huang, C. L. H., Blair, H. C., Abe, E., Zaidi, M. Disordered osteoclast formation and function in a CD38 (ADP-ribosyl cyclase) -deficient mouse establishes an essential role for CD38 in bone resorption.
Key Words: Ca2+ channel • osteoclast • ryanodine receptor • bone resorption • osteoporosis
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