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 Ca(2+) 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 Ca(2+) signal. Both ryanodine receptor modulators, ryanodine, and caffeine, markedly attenuated this cytosolic Ca(2+) 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.
Sun
L
L
Center for Osteoporosis and Skeletal Aging, Department of Medicine, Medical College of Pennsylvania and Veterans Affairs Medical Center, Philadelphia, Pennsylvania 19104, USA.
Adebanjo
O A
OA
Moonga
B S
BS
Corisdeo
S
S
Anandatheerthavarada
H K
HK
Biswas
G
G
Arakawa
T
T
Hakeda
Y
Y
Koval
A
A
Sodam
B
B
Bevis
P J
PJ
Moser
A J
AJ
Lai
F A
FA
Epstein
S
S
Troen
B R
BR
Kumegawa
M
M
Zaidi
M
M
D036541:ADP-ribosyl Cyclase; D051997:ADP-ribosyl Cyclase 1; D000246:Adenosine Diphosphate Ribose / Q000031:analogs & derivatives / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D000831:Animals, Newborn; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D001483:Base Sequence; D001862:Bone Resorption; D020013:Calcium Signaling; D002462:Cell Membrane / Q000201:enzymology; D002478:Cells, Cultured; D003001:Cloning, Molecular; D036563:Cyclic ADP-Ribose; D004789:Enzyme Activation; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism / Q000494:pharmacology; D008562:Membrane Glycoproteins; D008969:Molecular Sequence Data; D009243:NAD / Q000031:analogs & derivatives / Q000378:metabolism; D009244:NAD+ Nucleosidase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D010010:Osteoclasts / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D017386:Sequence Homology, Amino Acid
D015703:Antigens, CD; D000943:Antigens, Differentiation; D015850:Interleukin-6; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D019837:Ryanodine Receptor Calcium Release Channel; D009243:NAD; D036563:Cyclic ADP-Ribose; D000246:Adenosine Diphosphate Ribose; D036541:ADP-ribosyl Cyclase; C498154:CD38 protein, human; C498156:Cd38 protein, rat; D009244:NAD+ Nucleosidase; D051997:ADP-ribosyl Cyclase 1