Lyn inhibits osteoclast differentiation by interfering with PLCgamma1-mediated Ca2+ signaling.
Osteoclasts differentiate from macrophage-lineage cells to become specialized for bone resorption function. By a proteomics approach, we found that Lyn was down-regulated by the osteoclast differentiation factor, receptor activator of NF-kappaB ligand (RANKL). The forced reduction of Lyn caused a striking increase in the RANKL-induced PLCgamma1, Ca(2+), and NFATc1 responses during differentiation. These data suggest that Lyn plays a negative role in osteoclastogenesis by interfering with the PLCgamma1-mediated Ca(2+) signaling that leads to NFATc1 activation. Consistent with the in vitro results, in vivo injection of Lyn specific siRNA into mice calvariae provoked a fulminant bone resorption. Our study provides the first evidence of the involvement of Lyn in the negative regulation of osteoclastogenesis by RANKL.
Yoon
Soo-Hyun
SH
Department of Cell and Developmental Biology, Seoul National University, Seoul, Republic of Korea.
Lee
Youngkyun
Y
Kim
Hyung-Joon
HJ
Lee
Zang Hee
ZH
Hyung
Seok-Won
SW
Lee
Sang-Won
SW
Kim
Hong-Hee
HH
D000818:Animals; D001862:Bone Resorption / Q000235:genetics / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D051379:Mice; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology / Q000201:enzymology*; D051966:Phospholipase C gamma / Q000235:genetics / Q000378:metabolism*; D040901:Proteomics; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology; D012886:Skull / Q000166:cytology / Q000378:metabolism; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis*
D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; D053245:RANK Ligand; D034741:RNA, Small Interfering; C505689:Tnfsf11 protein, mouse; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D051966:Phospholipase C gamma; C117399:Plcg1 protein, mouse; D002118:Calcium