The deficiency of immunoregulatory receptor PD-1 causes mild osteopetrosis
The deficiency of immunoregulatory receptor PD-1 causes mild osteopetrosis
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DOI：
10.1016/j.bone.2004.06.018
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发表时间：
2004-11-01
期刊：
影响因子：
4.1
通讯作者：
Ohyama, K
中科院分区：
文献类型：
--
作者：
Nagahama, K;Aoki, K;Ohyama, K
近年来，免疫反应在代谢性骨病和/或局部骨破坏中的作用受到广泛关注。细胞毒性T淋巴细胞相关抗原4(CTLA-4)是免疫球蛋白(Ig)超家族的一员，对T细胞的激活具有负性调节作用。CTLA-4的缺失导致严重的骨量减少，破骨细胞生成增加，提示活化的T细胞在破骨细胞生成中起重要作用。程序性死亡-1(PD-1)是新近发现的免疫调节受体，也属于免疫球蛋白超家族。CTLA-4和PD-1均可在活化的T细胞上被诱导，但尚无PD-1与破骨细胞相关的报道。在本研究中，我们研究了PD-1缺陷小鼠PD-1(-/-)的骨表型，以及PD-1在破骨细胞生成和破骨细胞功能中的作用。在12周龄的PD-1(-/-)小鼠的外周定量计算机断层扫描(PQCT)中观察到，胫骨的骨小梁和皮质骨密度均显著增加。12周龄的PD-1(-/-)小鼠和年龄匹配的对照组的组织形态计量学分析显示，骨体积(BV/TV)增加了2倍，破骨细胞数量(N.Oc/BS)减少了55%。两组的骨形成指数相似。核因子kappaB配体(SRANKL)诱导的破骨细胞样细胞(OCL)从PD-1缺陷的脾细胞中获得的可溶性受体激活物(SRANKL)数量显著减少(减少25%)。另一方面，PD-1缺乏并不影响成熟破骨细胞的骨吸收活性。我们的结果表明，PD-1缺乏减少了破骨细胞的形成，导致了一种骨化表型。免疫球蛋白超家族的相同成员CTLA-4和PD-1负向调节免疫反应，可能对破骨细胞的形成和骨重建产生不同的影响。(C)2004 Elsevier Inc.保留所有权利。
Recently, the involvement of immune responses in metabolic bone disease and/or local bone destruction has received much attention. Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), a member of the immunoglobulin (Ig) superfamily, negatively regulates T cell activation. The deficiency of CTLA-4 induces profound osteopenia, with an increase in osteoclastogenesis, suggesting the important role of activated T cells in osteoclastogenesis. Programmed death-1 (PD-1) is the newly identified immunoregulatory receptor, which also belongs to the Ig superfamily. Both CTLA-4 and PD-1 are induced on activated T cells, however, there are no reports linking PD-1 with osteoclasts. In the present study, we have examined the bone phenotype in PD-1-deficient mice PD-1(-/-) and the role of PD-1 in osteoclastogenesis and osteoclast function. Both trabecular and cortical bone mineral densities of tibia were significantly increased, as observed in peripheral quantitative computed tomography (pQCT), at 12 weeks of age in PD-1(-/-) mice. Histomorphometric analysis of the PD-1(-/-) mice and the age-matched controls at 12 weeks of age showed a 2-fold increase in bone volume (BV/TV) with a 55% decrease in osteoclast number (N.Oc/BS). Bone formation indices were similar in both groups. The number of soluble receptor activator of nuclear factor kappaB ligand (sRANKL)-induced osteoclast-like cells (OCLs) derived from the PD-1-deficient splenocytes was significantly decreased (by 25%). On the other hand, PD-1 deficiency did not affect the bone-resorbing activity of mature osteoclasts. Our results suggest that PD-1 deficiency reduces osteoclastogenesis resulting in an osteopetrotic phenotype. Identical members of the Ig superfamily, CTLA-4 and PD-1, which negatively regulate immune responses, may differentially affect osteoclastogenesis and bone remodeling. (C) 2004 Elsevier Inc. All rights reserved.