Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Bone Resorption / genetics
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Bone Resorption / metabolism
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Calcium / metabolism
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Calcium Signaling / drug effects
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Calcium Signaling / physiology*
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Cell Differentiation / drug effects
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Cell Differentiation / physiology*
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Cell Line
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Down-Regulation / drug effects
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Down-Regulation / physiology
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Humans
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Mice
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NFATC Transcription Factors / genetics
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NFATC Transcription Factors / metabolism
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Osteoclasts / cytology
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Osteoclasts / enzymology*
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Phospholipase C gamma / genetics
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Phospholipase C gamma / metabolism*
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Proteomics
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RANK Ligand / genetics
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RANK Ligand / metabolism*
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RNA, Small Interfering / genetics
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RNA, Small Interfering / pharmacology
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Skull / cytology
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Skull / metabolism
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src-Family Kinases / antagonists & inhibitors
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src-Family Kinases / biosynthesis*
Substances
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NFATC Transcription Factors
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Nfatc1 protein, mouse
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RANK Ligand
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RNA, Small Interfering
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Tnfsf11 protein, mouse
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lyn protein-tyrosine kinase
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src-Family Kinases
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Phospholipase C gamma
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Plcg1 protein, mouse
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Calcium