RGS10-null mutation impairs osteoclast differentiation resulting from the loss of [Ca2+]i oscillation regulation.
Increased osteoclastic resorption leads to many bone diseases, including osteoporosis and rheumatoid arthritis. While rapid progress has been made in characterizing osteoclast differentiation signaling pathways, how receptor activator of nuclear factor kappaB (NF-kappaB) ligand (RANKL) evokes essential [Ca2+]i oscillation signaling remains unknown. Here, we characterized RANKL-induced signaling proteins and found regulator of G-protein signaling 10 (RGS10) is predominantly expressed in osteoclasts. We generated RGS10-deficient (RGS10-/-) mice that exhibited severe osteopetrosis and impaired osteoclast differentiation. Our data demonstrated that ectopic expression of RGS10 dramatically increased the sensitivity of osteoclast differentiation to RANKL signaling; the deficiency of RGS10 resulted in the absence of [Ca2+]i oscillations and loss of NFATc1; ectopic NFATc1 expression rescues impaired osteoclast differentiation from deletion of RGS10; phosphatidylinositol 3,4,5-trisphosphate (PIP3) is essential to PLCgamma activation; and RGS10 competitively interacts with Ca2+/calmodulin and PIP3 in a [Ca2+]i-dependent manner to mediate PLCgamma activation and [Ca2+]i oscillations. Our results revealed a mechanism through which RGS10 specifically regulates the RANKL-evoked RGS10/calmodulin-[Ca2+]i oscillation-calcineurin-NFATc1 signaling pathway in osteoclast differentiation using an in vivo model. RGS10 provides a potential therapeutic target for the treatment of bone diseases.
Yang
Shuying
S
Department of Cytokine Biology, The Forsyth Institute, Boston, Massachusetts 02115, USA.
Li
Yi-Ping
YP
D000818:Animals; D020013:Calcium Signaling; D002147:Calmodulin / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D047108:Embryonic Development; D005260:Female; D006130:Growth Disorders / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology* / Q000378:metabolism*; D010022:Osteopetrosis / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D051966:Phospholipase C gamma / Q000378:metabolism; D011247:Pregnancy; D053245:RANK Ligand / Q000378:metabolism; D020710:RGS Proteins / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D015398:Signal Transduction
D002147:Calmodulin; D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; D053245:RANK Ligand; D020710:RGS Proteins; C491068:Rgs10 protein, mouse; C505689:Tnfsf11 protein, mouse; D051966:Phospholipase C gamma