TGF-beta-induced SOCS3 expression augments TNF-alpha-induced osteoclast formation.
Osteoclast differentiation is dependent on TGF-beta to prime precursors to the osteoclast lineage. The mechanism by which TGF-beta enables osteoclast formation is unknown. One possibility is that TGF-beta opposes pro-inflammatory JAK/STAT signalling. Recently, we showed that TGF-beta-induces SOCS3, an inhibitor of the JAK/STAT pathway, in precursors and enhances SOCS3 in RANKL-induced osteoclasts. We therefore elected to test the role of SOCS3 in the effect of other regulators of osteoclastic differentiation. We found that TNF-alpha-induced osteoclasts also express SOCS3 and TGF-beta strongly up-regulates this. Moreover, TNF-alpha-induced osteoclast differentiation and total resorbed bone area were enhanced in SOCS3-retrovirally infected precursors, whereas antisense knockdown of SOCS3 suppressed formation and the augmentative effect of TGF-beta. Furthermore, SOCS3 overexpression blunted the anti-osteoclastic effect of IFN-beta but not IL-10. This suggests that TGF-beta-induced expression of SOCS3 may represent a crucial mechanism by which TGF-beta antagonizes specific anti-osteoclastic JAK/STAT signals, priming precursors for resorption rather than inflammatory functions.
D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D005786:Gene Expression Regulation / Q000502:physiology*; D016899:Interferon-beta / Q000037:antagonists & inhibitors; D016753:Interleukin-10 / Q000037:antagonists & inhibitors; D008297:Male; D051379:Mice; D010010:Osteoclasts / Q000166:cytology*; D011506:Proteins / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D012097:Repressor Proteins; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014157:Transcription Factors; D016212:Transforming Growth Factor beta / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D017931:DNA Primers; D011506:Proteins; D012333:RNA, Messenger; D012097:Repressor Proteins; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D016899:Interferon-beta