RESUMO
Transforming growth factor-beta (TGF-beta) elicits a variety of effects on cellular proliferation and differentiation. The major repository for TGF-beta is bone, where it possesses separate facilitative and suppressive actions on osteoclast differentiation and bone resorption. Without a direct enabling stimulus from TGF-beta monocytes cannot form osteoclasts but instead follow macrophage differentiation pathways. This facilitative action depends on an ability to promote a state in which precursors are resistant to anti-osteoclastic inflammatory signals. Following the initiation of resorption TGF-beta is released from bone matrix. This acts on osteoblasts to reduce the availability of the osteoclast differentiation factor, RANKL (receptor activator of NFkappaB ligand) and thereby indirectly limits further osteoclast formation. Thus TGF-beta has a fundamental role in the control of bone resorption having actions that first allow monocytes to develop into osteoclasts then subsequently limiting the extent and duration of resorption after its release from the bone matrix.
Assuntos
Reabsorção Óssea/metabolismo , Fator de Crescimento Transformador beta/fisiologia , Animais , Proteínas de Transporte/metabolismo , Diferenciação Celular , Humanos , Glicoproteínas de Membrana/metabolismo , Monócitos/metabolismo , Monócitos/patologia , Osteoblastos/metabolismo , Osteoclastos/metabolismo , Osteoclastos/patologia , Ligante RANK , Receptor Ativador de Fator Nuclear kappa-B , Transdução de SinaisRESUMO
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.
Assuntos
Regulação da Expressão Gênica/fisiologia , Osteoclastos/citologia , Proteínas/genética , Proteínas Repressoras , Fatores de Transcrição , Fator de Crescimento Transformador beta/fisiologia , Fator de Necrose Tumoral alfa/fisiologia , Animais , Sequência de Bases , Primers do DNA , Interferon beta/antagonistas & inibidores , Interleucina-10/antagonistas & inibidores , Masculino , Camundongos , RNA Mensageiro/genética , Proteína 3 Supressora da Sinalização de Citocinas , Proteínas Supressoras da Sinalização de CitocinaRESUMO
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.