Ly49Q, an MM-bearing NK receptor, positively regulates osteoclast differentiation
Ly49Q, an MM-bearing NK receptor, positively regulates osteoclast differentiation
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DOI：
10.1016/j.bbrc.2010.02.013
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发表时间：
2010-03-12
影响因子：
3.1
通讯作者：
Takayanagi, Hiroshi
中科院分区：
文献类型：
--
作者：
Hayashi, Mikihito;Nakashima, Tomoki;Takayanagi, Hiroshi
破骨细胞是吸收骨的多核细胞，在骨重建中起着关键作用。尽管免疫受体酪氨酸激活基序(ITAM)介导的信号转导对破骨细胞的分化至关重要，但免疫受体酪氨酸抑制基序(ITIM)的意义尚不清楚。在此，我们报道了具有ITIM基序的Ly49家族成员Ly49Q在破骨细胞形成中的作用。Ly49Q是NK受体Ly49家族中的一种，由核因子-kappa B受体激活剂配体(RANKL)在骨髓来源的单核/巨噬细胞前体细胞(BMMS)中选择性诱导。Ly49Q基因的敲除导致RANKL诱导的酒石酸抗性酸性磷酸酶(TRAP)阳性多核细胞的形成显著减少，并伴随着破骨细胞特异性基因如NFATc1、Tm7sf4、OSCAR、CTSK和Acp5的表达减少。在体外，Ly49Q缺陷细胞的破骨细胞生成也明显受损。Ly49Q缺乏的抑制作用可能是因为Ly49Q竞争Src同源结构域2磷酸酶-1(SHP-1)与成对免疫球蛋白样受体B(PIR-B)的结合，PIR-B是一种携带ITIM的受体，负向调节破骨细胞的分化。出乎意料的是，Ly49Q缺乏并未导致体内破骨细胞形成受损，提示存在代偿机制。这项研究提供了一个例子，其中携带ITIM的受体作为破骨细胞分化的积极调节因子发挥作用。(C)2010 Elsevier Inc.保留所有权利。
Osteoclasts, multinucleated cells that resorb bone, play a key role in bone remodeling. Although immunoreceptor tyrosine-based activation motif (ITAM)-mediated signaling is critical for osteoclast differentiation, the significance of immunoreceptor tyrosine-based inhibitory motif (ITIM) has not been well understood. Here we report the function of Ly49Q an Ly49 family member possessing an ITIM motif, in osteoclastogenesis. Ly49Q is selectively induced by receptor activator of nuclear factor-kappa B (NF-kappa B) ligand (RANKL) stimulation in bone marrow-derived monocyte/macrophage precursor cells (BMMs) among the Ly49 family of NK receptors. The knockdown of Ly49Q resulted in a significant reduction in the RANKL-induced formation of tartrate-resistance acid phosphatase (TRAP)-positive multinucleated cells, accompanied by a decreased expression of osteoclast-specific genes such as Nfatc1, Tm7sf4, Oscar, Ctsk, and Acp5. Osteoclastogenesis was also significantly impaired in Ly49Q-deficient cells in vitro. The inhibitory effect of Ly49Q-deficiency may be explained by the finding that Ly49Q competed for the association of Src-homology domain-2 phosphatase-1 (SHP-1) with paired immunoglobulin-like receptor-B (PIR-B), an ITIM-bearing receptor which negatively regulates osteoclast differentiation. Unexpectedly, Ly49Q deficiency did not lead to impaired osteoclast formation in vivo, suggesting the existence of a compensatory mechanism. This study provides an example in which an ITIM-bearing receptor functions as a positive regulator of osteoclast differentiation. (C) 2010 Elsevier Inc. All rights reserved.