TNFα inhibits the development of osteoclasts through osteoblast-derived GM-CSF
TNFα inhibits the development of osteoclasts through osteoblast-derived GM-CSF
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DOI：
10.1016/j.bone.2011.08.003
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发表时间：
2011-11-01
期刊：
影响因子：
4.1
通讯作者：
Hofstetter, Willy
中科院分区：
文献类型：
--
作者：
Atanga, Elvis;Dolder, Silvia;Hofstetter, Willy
炎性细胞因子如肿瘤坏死因子-α（TNF α）是破骨细胞形成和骨吸收的有效刺激物，并且经常与病理性骨代谢相关。细胞因子对其靶细胞发挥特异性作用，并构成细胞微环境的一部分。以前，TNF α被证明通过成骨细胞介导的途径抑制体外破骨细胞的发育。在本研究中，在成骨细胞和骨髓细胞（BMC）的共培养物中，以及在与巨噬细胞集落刺激因子（M-CSF）和NF-κ B配体受体激活剂（RANKL）一起生长的M-CSF依赖性非粘附破骨细胞祖细胞（OPC）的培养物中，研究了破骨细胞生成抑制的分子机制。粒细胞-巨噬细胞集落刺激因子（GMCSF），一种已知的破骨细胞生成抑制剂，被发现在用TNF α处理的成骨细胞中被诱导，并且分泌的蛋白质在上清液中积累。地塞米松（Dex），一种抗炎类固醇，引起GM-CSF表达的减少，导致破骨细胞形成的部分恢复。流式细胞术分析显示，在OPC培养物中，补充了10%的条件培养基（CM），条件培养基来自用TNF α/1，25（OH）（2）D（3）处理的成骨细胞，RANK和CD 11 c的表达受到抑制。RANK表达的降低可以通过发现GM-CSF和来自wt成骨细胞的CM抑制c-Fos的表达来解释。Fra-1和Nfatc-1。OPC未能发育成CD 11 c（+）树突状细胞表明细胞发育没有偏离替代分化途径，而是单核细胞维持在未分化的F4/80（+）状态。这些数据进一步暗示了炎性细胞因子之间可能的相互作用。由TNF α诱导的GM-CSF作用于早期造血前体，抑制破骨细胞生成，同时作为M-CSF非依赖性炎性巨噬细胞的生长因子。这些反过来可以调节微环境，增强破骨细胞分化和OPC从循环迁移到骨/骨髓室后的骨吸收。(C)2011年由Elsevier Inc.出版
Inflammatory cytokines such as tumor necrosis factor-alpha (TNF alpha) 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 alpha 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-kappa B ligand (RANKL). Granulocyte-macrophage colony stimulating factor (GMCSF), a known inhibitor of osteoclastogenesis was found to be induced in osteoblasts treated with TNF alpha 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 alpha/1,25(OH)(2)D(3), 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 alpha 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. (C) 2011 Published by Elsevier Inc.