Kitaori Toshiyuki, Ito Hiromu, Schwarz Edward M, Tsutsumi Ryosuke, Yoshitomi Hiroyuki, Oishi Shinya, Nakano Masakazu, Fujii Nobutaka, Nagasawa Takashi, Nakamura Takashi
Kyoto University, Kyoto, Japan.
Arthritis Rheum. 2009 Mar;60(3):813-23. doi: 10.1002/art.24330.
Stromal cell-derived factor 1 (SDF-1; CXCL12/pre-B cell growth-stimulating factor) is a dominant chemokine in bone marrow and is known to be involved in inflammatory diseases, including rheumatoid arthritis. However, its role in bone repair remains unknown. The purpose of this study was to investigate the role of SDF-1 and its receptor, CXCR4, in bone healing.
The expression of SDF-1 during the repair of a murine structural femoral bone graft was examined by real-time polymerase chain reaction and immunohistochemical analysis. The bone graft model was treated with anti-SDF-1 neutralizing antibody or TF14016, an antagonist for CXCR4, and evaluated by histomorphometry. The functional effect of SDF-1 on primary mesenchymal stem cells was determined by in vitro and in vivo migration assays. New bone formation in an exchanging-graft model was compared with that in the autograft models, using mice partially lacking SDF-1 (SDF-1(+/-)) or CXCR4 (CXCR4(+/-)).
The expression of SDF1 messenger RNA was increased during the healing of live bone grafts but was not increased in dead grafts. High expression of SDF-1 protein was observed in the periosteum of the live graft. New bone formation was inhibited by the administration of anti-SDF-1 antibody or TF14016. SDF-1 increased mesenchymal stem cell chemotaxis in vitro in a dose-dependent manner. The in vivo migration study demonstrated that mesenchymal stem cells recruited by SDF-1 participate in endochondral bone repair. Bone formation was decreased in SDF-1(+/-) and CXCR4(+/-) mice and was restored by the graft bones from CXCR4(+/-) mice transplanted into the SDF-1(+/-) femur, but not vice versa.
SDF-1 is induced in the periosteum of injured bone and promotes endochondral bone repair by recruiting mesenchymal stem cells to the site of injury.
基质细胞衍生因子1（SDF-1；CXCL12/前B细胞生长刺激因子）是骨髓中一种主要的趋化因子，已知其参与包括类风湿性关节炎在内的炎症性疾病。然而，其在骨修复中的作用尚不清楚。本研究的目的是探讨SDF-1及其受体CXCR4在骨愈合中的作用。
通过实时聚合酶链反应和免疫组织化学分析检测小鼠结构性股骨移植修复过程中SDF-1的表达。骨移植模型用抗SDF-1中和抗体或CXCR4拮抗剂TF14016处理，并通过组织形态计量学进行评估。通过体外和体内迁移试验确定SDF-1对原代间充质干细胞的功能作用。使用部分缺乏SDF-1（SDF-1(+/-)）或CXCR4（CXCR4(+/-)）的小鼠，将交换移植模型中的新骨形成与自体移植模型中的新骨形成进行比较。
活骨移植愈合过程中SDF1信使核糖核酸的表达增加，但死骨移植中未增加。在活移植的骨膜中观察到SDF-1蛋白的高表达。给予抗SDF-1抗体或TF14016可抑制新骨形成。SDF-1在体外以剂量依赖的方式增加间充质干细胞的趋化性。体内迁移研究表明，由SDF-1招募的间充质干细胞参与软骨内骨修复。SDF-1(+/-)和CXCR4(+/-)小鼠的骨形成减少，将CXCR4(+/-)小鼠的移植骨移植到SDF-1(+/-)股骨中可恢复骨形成，但反之则不然。
SDF-1在受伤骨的骨膜中被诱导，并通过将间充质干细胞招募到损伤部位促进软骨内骨修复。
