GARP-TGFβ1蛋白复合体在骨髓间充质干细胞抑制炎性牙槽骨吸收中的作用研究

牙周炎骨缺损修复手段尚有局限性，修饰后的骨髓间充质干细胞（BMMSCs）具有应用前景。我们前期研究发现：高表达转化生长因子β1（TGF-β1）的BMMSCs细胞凋亡减少并可诱导调节性T细胞的分化、抑制炎症因子的分泌；局部注射TGF-β1可减缓牙周炎牙槽骨吸收，提示了高表达TGF-β1的BMMSCs在牙周炎骨缺损修复中的作用。BMMSCs胞膜上的富含亮氨酸重复序列蛋白（GARP）是TGF-β1的受体，其从胞内转运至胞膜并与TGF-β1结合后使其活化。据此我们提出假说：BMMSCs细胞膜上的GARP-TGFβ1蛋白复合体是其发挥免疫调节作用的关键；上调GARP在胞膜上的表达将增加GARP-TGFβ1蛋白复合体形成进而增强BMMSCs的功能。我们拟从分子、细胞、组织和动物水平来验证我们的假说，并探讨GARP细胞内跨膜转运的调控机制，为炎性骨吸收的治疗提供新的思路。

Alveolar bone absorption is a common result of chronic inflammatory cell infiltration in periodontitis. The alveolar bone regeneration after periodontitis treatment remains unsatisfactory in current clinical practice. Bone marrow mesenchymal stem cells (BMMSCs), which possess immune-regulatory properties, might have a promising therapeutic effect on the inflammatory bone absorption of periodontitis. Our previous studies showed that (1) When co-cultured with CD4+T lymphocyte, BMMSCs with highly expressed Transforming Growth Factor beta 1 (TGF-β1) can induce the differentiation of regulatory T cells (Tregs) and inhibit the expression of inflammatory cytokines released by other pro-inflammatory T cell subtypes, thus prevent themselves from apoptosis. (2) In the rat periodontitis model, the inflammatory alveolar bone absorption can be suppressed by application of rats’ recombined TGF-β1 protein gel in their gingival sulcus. Therefore, TGF-β1 could be the critical factor in modulating alveolar bone regeneration. TGF-β1 is produced as a latent form, which could prompt to be activated when binding with a transmembrane protein glycoprotein A repetitions predominant (GARP) on BMMSCs. The relocalization of intracellular GARP to the surface of BMMSCs can be conferred to its polypeptide-folding reaction when it binds to its molecular chaperone, which might play very important role in controlling the activation of TGF- β1. Based on these findings, we suggest that (1) The BMMSCs possibly exert their immune-regulatory effect through the GARP-TGFβ1 complex. (2)The up-regulation of membrane locating GARP might amplify their immunosuppressive capability. We would utilize various kinds of techniques such as bioinformatics analysis, protein co-immunoprecipitation and RNA interferences to test our hypothesis. By decoding the detailed mechanism of how active TGF-β1 is provide by BMMSCs to suppress the inflammation, we would like to provide a new perspective on treating inflammatory bone absorption in the clinical context.