Specificity of RGS10A as a key component in the RANKL signaling mechanism for osteoclast differentiation.
Significant progress has been made in studies of the mechanisms by which RANKL induces terminal osteoclast differentiation. However, many crucial details in the RANKL-evoked signaling pathway for osteoclast differentiation remain to be defined. We characterized genes specifically expressed in osteoclasts by differential screening of a human osteoclastoma cDNA library, and found that the regulator of G-protein signaling 10A (RGS10A), but not the RGS10B isoform, was specifically expressed in human osteoclasts. The expression of RGS10A is also induced by RANKL in osteoclast precursors and is prominently expressed in mouse osteoclast-like cells. RGS10A silencing by RNA interference blocked intracellular [Ca2+]i oscillations, the expression of NFAT2, and osteoclast terminal differentiation in both bone marrow cells and osteoclast precursor cell lines. Reintroduction of RGS10A rescued the impaired osteoclast differentiation. RGS10A silencing also resulted in premature osteoclast apoptosis. RGS10A silencing affected the RANKL-[Ca2+]i oscillation-NFAT2 signaling pathway but not other RANKL-induced responses. Our data demonstrate that target components of RGS10A are distinct from those of RGS12 in the RANKL signaling mechanism. Our results thus show the specificity of RGS10A as a key component in the RANKL-evoked signaling pathway for osteoclast differentiation, which may present a promising target for therapeutic intervention.
Yang
Shuying
S
Department of Cytokine Biology, The Forsyth Institute, Boston, MA 02115, USA.
Chen
Wei
W
Stashenko
Philip
P
Li
Yi-Ping
YP
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D015723:Gene Library; D006801:Humans; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism; D051379:Mice; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology / Q000502:physiology*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism*; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism*; D020710:RGS Proteins / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction / Q000502:physiology*; D014018:Tissue Distribution
D050778:NFATC Transcription Factors; D020033:Protein Isoforms; D053245:RANK Ligand; D020710:RGS Proteins; C101113:RGS10 protein, human; C106375:RGS12 protein, human; C491068:Rgs10 protein, mouse; C505688:TNFSF11 protein, human; C505689:Tnfsf11 protein, mouse; D016173:Macrophage Colony-Stimulating Factor