FHL2 inhibits the activated osteoclast in a TRAF6-dependent manner
FHL2 inhibits the activated osteoclast in a TRAF6-dependent manner
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DOI：
10.1172/jci24921
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发表时间：
2005-10-01
影响因子：
15.9
通讯作者：
Teitelbaum, SL
中科院分区：
文献类型：
--
作者：
Bai, ST;Kitaura, H;Teitelbaum, SL
TNF受体相关因子6（TRAF 6）与NF-κ B受体激活因子（RANK）的胞质结构域相关。该事件是正常破骨细胞生成的核心。我们发现TRAF 6还与FHL 2（四个半LIM结构域2）相互作用，FHL 2是一种仅LIM结构域的蛋白质，以细胞类型特异性方式作为转录辅激活因子或辅阻遏因子发挥作用。FHL 2 mRNA和蛋白在骨髓巨噬细胞中检测不到，并在体外与破骨细胞分化同步增加。FHL 2抑制野生型破骨细胞前体中TRAF 6诱导的NF-κ B活性，并且与其作为TRAF 6介导的RANK信号传导抑制剂的作用一致，TRAF 6/RANK结合在FHL 2（-/-）破骨细胞中增强。FHL 2过表达延迟RANK配体诱导的（RANKL诱导的）破骨细胞形成和细胞骨架组织。有趣的是，破骨细胞驻留的FHL 2在体内未处理的野生型小鼠中检测不到，但在RANKL治疗和诱导炎性关节炎后的小鼠中大量存在。反映RANKL敏感性增加，FHL 2（-/-）小鼠产生的破骨细胞比野生型小鼠更早达到成熟并最佳组织其细胞骨架。因此，FHL 2（-/-）破骨细胞是高吸收的，缺乏该蛋白的小鼠经历增强的RANKL和炎性关节炎刺激的骨丢失。因此，FHL 2是一种抗破骨细胞生成分子，通过减弱TRAF 6介导的RANK信号传导发挥其作用。
TNF receptor-associated factor 6 (TRAF6) associates with the cytoplasmic domain of receptor activator of NF-KB (RANK). This event is central to normal osteoclastogenesis. We discovered that TRAF6 also interacts with FHL2 (four and a half LIM domain 2), a LIM domain-only protein that functions as a transcriptional coactivator or corepressor in a cell-type-specific manner. FHL2 mRNA and protein are undetectable in marrow macrophages and increase pari passu with osteoclast differentiation in vitro. FHL2 inhibits TRAF6-induced NF-KB activity in wild-type osteoclast precursors and, in keeping with its role as a suppressor of TRAF6-mediated RANK signaling, TRAF6/RANK association is enhanced in FHL2(-/-) osteoclasts. FHL2 overexpression delays RANK ligand-induced (RANKL-induced) osteoclast formation and cytoskeletal organization. Interestingly, osteoclast-residing FHL2 is not detectable in naive wild-type mice, in vivo, but is abundant in those treated with RANKL and following induction of inflammatory arthritis. Reflecting increased RANKL sensitivity, osteoclasts generated from FHL2(-/-) mice reach maturation and optimally organize their cytoskeleton earlier than their wild-type counterparts. As a consequence, FHL2(-/-) osteoclasts are hyperresorptive, and mice lacking the protein undergo enhanced RANKL and inflammatory arthritis-stimulated bone loss. FHL2 is, therefore, an antiosteoclastogenic molecule exerting its effect by attenuating TRAF6-mediated RANK signaling.