The possible role of TGF-beta-induced suppressors of cytokine signaling expression in osteoclast/macrophage lineage commitment in vitro.
Osteoclast formation is dependent on the ability of TGF-beta to enable receptor activator of NF-kappaB ligand (RANKL)-induced commitment of hemopoietic precursors to the osteoclastic lineage. The mechanism by which TGF-beta enables formation is unknown. One possibility is that TGF-beta opposes Janus kinase (JAK)/STAT signals generated by inhibitory cytokines such as IFN-beta. The JAK/STAT pathway is activated by cytokines that induce resistance to osteoclast formation, such as IFN-gamma and M-CSF, and the effect of these is opposed by TGF-beta. Recently, a group of STAT-induced factors, termed suppressors of cytokine signaling (SOCS), has been identified that inhibit JAK/STAT signals. Therefore, we tested the ability of TGF-beta to induce SOCS expression in osteoclast precursors and examined the effect of SOCS expression on osteoclast/macrophage lineage commitment. We found that while SOCS mRNA is undetectable in macrophages, osteoclasts express SOCS-3, and TGF-beta up-regulates this expression. Furthermore, TGF-beta rapidly induces sustained SOCS-3 expression in macrophage/osteoclast precursors. To determine whether SOCS-3 plays a role in osteoclast differentiation we expressed SOCS-3 in precursors using a retroviral system. We found that osteoclast differentiation was significantly enhanced in SOCS-3-infected precursors, and SOCS-3 expression enables formation in the presence of anti-TGF-beta Ab. On the other hand, antisense knockdown of SOCS-3 strongly suppressed osteoclast formation and significantly blunted the response to TGF-beta. Moreover, like TGF-beta, SOCS-3 expression opposed the inhibitory effect of IFN-beta. These data suggest that TGF-beta-induced expression of SOCS-3 may represent a mechanism by which TGF-beta suppresses inhibitory cytokine signaling, priming precursors for a role in bone resorption.
Fox
Simon W
SW
Department of Cellular Pathology, St. George's Hospital Medical School, London, United Kingdom. swfox@sghms.ac.uk
Haque
S Jaharul
SJ
Lovibond
Alison C
AC
Chambers
Timothy J
TJ
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D002454:Cell Differentiation / Q000235:genetics; D019070:Cell Lineage / Q000502:physiology; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000502:physiology; D005822:Genetic Vectors; D006023:Glycoproteins / Q000378:metabolism; D016899:Interferon-beta / Q000037:antagonists & inhibitors / Q000502:physiology; D008264:Macrophages / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000502:physiology; D051379:Mice; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D010010:Osteoclasts / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism*; D053244:Osteoprotegerin; D014176:Protein Biosynthesis; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D011506:Proteins / Q000235:genetics / Q000502:physiology; D053245:RANK Ligand; D012333:RNA, Messenger / Q000096:biosynthesis; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor; D012097:Repressor Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D012190:Retroviridae / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014157:Transcription Factors; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000502:physiology*
D002352:Carrier Proteins; D016207:Cytokines; D006023:Glycoproteins; D008562:Membrane Glycoproteins; D020319:Oligodeoxyribonucleotides, Antisense; D053244:Osteoprotegerin; D011506:Proteins; D053245:RANK Ligand; D012333:RNA, Messenger; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; D012097:Repressor Proteins; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; C505687:Tnfrsf11a protein, mouse; C506031:Tnfrsf11b protein, mouse; C505689:Tnfsf11 protein, mouse; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D016899:Interferon-beta; D011505:Protein-Tyrosine Kinases