TNF¦Á inhibits the development of osteoclasts through osteoblast-derived GM-CSF

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• 作者：Elvis  ; Atanga^a ;   ; ^{elvis.atanga@dkf.unibe.ch} ; Silvia  ; Dolder^a ;   ; ^{silvia.dolder@dkf.unibe.ch} ; Tina  ; Dauwalder^b ;   ; ^{tina.dauwalder@cslbehring.com} ; Antoinette  ; Wetterwald^a ;   ; ^{antoinette.wetterwald@dkf.unibe.ch} ; Willy  ; Hofstetter^a ;   ; ^{hofstetter@dkf.unibe.ch}
• 关键词：TNF¦Á ; Inflammation ; GM-CSF ; Osteoclastogenesis ; Differentiation
• 刊名：Bone
• 出版年：2011
• 出版时间：November 2011
• 年：2011
• 卷：49
• 期：5
• 页码：1090-1100
• 全文大小：1331 K

文摘

Inflammatory cytokines such as tumor necrosis factor-alpha (TNF¦Á) are potent stimulators of osteoclast formation and bone resorption and are frequently associated with pathologic bone metabolism. The cytokine exerts specific effects on its target cells and constitutes a part of the cellular microenvironment. Previously, TNF¦Á was demonstrated to inhibit the development of osteoclasts in vitro via an osteoblast-mediated pathway. In the present study, the molecular mechanisms of the inhibition of osteoclastogenesis were investigated in co-cultures of osteoblasts and bone marrow cells (BMC) and in cultures of macrophage-colony stimulating factor (M-CSF) dependent, non-adherent osteoclast progenitor cells (OPC) grown with M-CSF and receptor activator of NF-¦ÊB ligand (RANKL). Granulocyte-macrophage colony stimulating factor (GM-CSF), a known inhibitor of osteoclastogenesis was found to be induced in osteoblasts treated with TNF¦Á and the secreted protein accumulated in the supernatant. Dexamethasone (Dex), an anti-inflammatory steroid, caused a decrease in GM-CSF expression, leading to partial recovery of osteoclast formation. Flow cytometry analysis revealed that in cultures of OPC, supplemented with 10 % conditioned medium (CM) from osteoblasts treated with TNF¦Á/1,25(OH)₂D₃, expression of RANK and CD11c was suppressed. The decrease in RANK expression may be explained by the finding, that GM-CSF and the CM from wt osteoblasts were found to suppress the expression of c-Fos, Fra-1, and Nfatc-1. The failure of OPC to develop into CD11c⁺ dendritic cells suggests that cell development is not deviated to an alternative differentiation pathway, but rather, that the monocytes are maintained in an undifferentiated, F4/80⁺, state. The data further implies possible interactions among inflammatory cytokines. GM-CSF induced by TNF¦Á acts on early hematopoietic precursors, inhibiting osteoclastogenesis while acting as the growth factor for M-CSF independent inflammatory macrophages. These in turn may condition a microenvironment enhancing osteoclast differentiation and bone resorption upon migration of the OPC from circulation to the bone/bone marrow compartment.