RANKL maintains bone homeostasis through c-Fos-dependent induction of interferon-β
RANKL maintains bone homeostasis through c-Fos-dependent induction of interferon-β
复制标题
DOI：
10.1038/416744a
复制
发表时间：
2002-04-18
期刊：
影响因子：
64.8
通讯作者：
Taniguchi, T
中科院分区：
文献类型：
--
作者：
Takayanagi, H;Kim, S;Taniguchi, T
破骨细胞是单核/巨噬细胞来源的细胞，可以侵蚀骨基质：调节它们的分化对于理解骨质疏松等骨骼疾病的发病机制和治疗至关重要(1，2)。RANKL(核因子-kappaB受体激活剂配体)，也被称为Tnfsf11，是诱导破骨细胞分化的关键信号(3-5)，必须受到严格的调控才能维持骨骼的动态平衡。但目前尚不清楚RANKL向细胞内部发出的信号是否与任何调控机制有关。在这里，我们发现RANKL诱导破骨细胞前体细胞中的干扰素-β基因，并且干扰素-β通过干扰RANKL诱导的c-Fos的表达来抑制分化，c-Fos是破骨细胞形成所必需的转录因子。这种干扰素-β基因的诱导机制不同于病毒诱导的机制，它依赖于c-Fos本身。因此，一种自我调节机制运作--RANKL诱导的c-Fos诱导自己的抑制物。通过观察到缺乏干扰素-β信号的小鼠表现出严重的骨量减少(骨量丢失)并伴有增强的破骨细胞生成，强调了这种调节机制对骨稳态的重要性。我们的研究将干扰素-β系统置于一个新的背景下，并可能为骨疾病的治疗提供分子基础。
Osteoclasts are cells of monocyte/macrophage origin that erode bone matrix: regulation of their differentiation is central to the understanding of the pathogenesis and treatment of bone diseases such as osteoporosis(1,2). Signalling by RANKL (receptor activator of NF-kappaB ligand), also known as Tnfsf11, is essential for the induction of osteoclast differentiation(3-5), and it must be strictly regulated to maintain bone homeostasis. But it is not known whether RANKL signalling to the cell interior is linked to any regulatory mechanisms. Here we show that RANKL induces the interferon-beta (IFN-beta) gene in osteoclast precursor cells, and that IFN-beta inhibits the differentiation by interfering with the RANKL-induced expression of c-Fos, an essential transcription factor for the formation of osteoclasts. This IFN-beta gene induction mechanism is distinct from that induced by virus, and is dependent on c-Fos itself. Thus an autoregulatory mechanism operates-the RANKL-induced c-Fos induces its own inhibitor. The importance of this regulatory mechanism for bone homeostasis is emphasized by the observation that mice deficient in IFN-beta signalling exhibit severe osteopenia (loss of bone mass) accompanied by enhanced osteoclastogenesis. Our study places the IFN-beta system in a new context, and may offer a molecular basis for the treatment of bone diseases.