Inhibitory immunoglobulin-like receptors LILRB and PIR-B negatively regulate osteoclast development
Inhibitory immunoglobulin-like receptors LILRB and PIR-B negatively regulate osteoclast development
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DOI：
10.4049/jimmunol.181.7.4742
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发表时间：
2008-10-01
影响因子：
4.4
通讯作者：
Takai, Toshiyuki
中科院分区：
文献类型：
--
作者：
Mori, Yu;Tsuji, Sukenao;Takai, Toshiyuki
破骨细胞是源自骨髓单核细胞的多核细胞，它负责骨吸收，与源自非造血间充质的成骨细胞一起，对维持骨稳态至关重要。nf - κ B配体受体激活因子（Receptor activator of nf - κ B ligand， RANKL）和M-CSF分别表达于成骨细胞表面，由成骨细胞分泌，是促进破骨细胞形成的重要因子。与破骨细胞形成的激活过程相反，破骨细胞形成的抑制机制知之甚少。本研究表明，募集含有Src同源2结构域的酪氨酸磷酸酶1 （SHP-1）的抑制性igg样受体与其他髓系细胞一样在破骨细胞前细胞上表达，并在破骨细胞的发育中发挥调节作用。我们分别检测了配对的igg样受体(PIR)-B和白细胞igg样受体（LILR）B的四种亚型在培养的小鼠和人源破骨细胞前体细胞上的细胞表面表达，结果表明，在RANKL和M-CSF存在的情况下，所有这些含有itim的抑制受体都组成性地募集SHP-1，其中一些可以在体外抑制破骨细胞的发育。荧光能量转移分析表明，小鼠PIR-B或其人类同源物LILRB1与同一细胞表面的MHC I类分子的组成性结合是发育调节的机制之一。这些结果构成了细胞表面含有itim的igg样受体调控破骨细胞形成的第一个证据。调节这些调节受体可能是控制各种骨骼系统疾病和炎症性关节炎的新途径。
Osteoclasts, multinucleated cells of myeloid-monocytic origin, are responsible for bone resorption, which is crucial for maintenance of bone homeostasis in concert with bone-forming osteoblasts of nonhematopoietic, mesenchymal origin. Receptor activator of NF-kappa B ligand (RANKL) and M-CSF, expressed on the surface of and secreted by osteoblasts, respectively, are essential factors that facilitate osteoclast formation. In contrast to the activation processes for osteoclast formation, inhibitory mechanisms for it are poorly understood. Herein we demonstrate that inhibitory Ig-like receptors recruiting Src homology 2 domain-containing tyrosine phosphatase 1 (SHP-1) are expressed on osteoclast precursor cells like other myeloid cells, and that they play a regulatory role in the development of osteoclasts. We detected cell-surface expression of paired Ig-like receptor (PIR)-B and four isoforms of leukocyte Ig-like receptor (LILR)B on cultured osteoclast precursor cells of mouse and human origin, respectively, and showed that all of these ITIM-harboring inhibitory receptors constitutively recruit SHP-1 in the presence of RANKL and M-CSF, and that some of them can suppress osteoclast development in vitro. Fluorescence energy transfer analyses have suggested that the constitutive binding of either murine PIR-B or its human ortholog LILRB1 to MHC class I molecules on the same cell surface comprises one of the mechanisms for developmental regulation. These results constitute the first evidence of the regulation of osteoclast formation by cell-surface, ITIM-harboring Ig-like receptors. Modulation of these regulatory receptors may be a novel way to control various skeletal system disorders and inflammatory arthritis.