Mechanisms of Integrin α2β1 driven cell-matrix interaction in the course of bone regeneration and fracture healing

骨再生和骨折愈合过程中整合素α2β1驱动细胞-基质相互作用的机制

• 批准号: 437825722
• 负责人: Professor Dr. Richard Stange
• 金额: --
• 依托单位: Institut für Muskuloskelettale Medizin
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/437825722?language=en
• 关键词: Mechanisms; Integrin; driven; cell; matrix

Integrins, a well characterized family of heterodimeric cell adhesion and signal transduction proteins, serve as receptors, focal adhesion components and transducers of mechanical signals. Integrin α2β1 is the major receptor for fibrillary collagens in bone. Recently we could show that in the absence of this protein bone forming cells are primed to produce more matrix i.e. collagen type I which alleviates the effects of age related bone degradation. To transfer this to a clinical problem, we want to investigate the role of integrin α2β1 in fracture repair. In preliminary studies we could demonstrate that 7 days after fracture healing in the integrin α2β1 deficient bone appears to be more advanced. The fracture callus is further developed, and we could detect more overall collagen in the fracture callus. The aim of this project is to determine whether the accelerated fracture repair continues to the overall clinical outcome. Further investigations will elucidate the molecular mechanisms which are involved in the integrin α2β1 dependent over-expression of collagen type I. Therefore we will investigate a well-known pathway involved in expression of collagen and bone matrix, the TGFβ and accordingly the BMP-pathway. This will be done by in-vitro analyzation of the expression of collagen and bone target genes under inhibition of either TGF-β or BMP. Finally we will translate these findings into clinical application by exogenous inhibition of integrin α2β1 in vitro as well as in vitro. As effector we have chosen rhodocetin, a potent and stable compound of snake venom with highly specific integrin α2β1 inhibition as well as an alternative approach with integrin α2β1 blocking antibody. Improving the outcome of fracture repair by these investigations could be a novel therapeutic approach to treat osteoporotic and non-healing fractures.

整合素是一类重要的异源二聚体细胞黏附和信号转导蛋白家族，是机械信号的受体、粘着斑组分和信号转导分子。整合素α-2-β-1是骨组织中纤维状胶原的主要受体。最近，我们可以证明，在缺乏这种蛋白的情况下，骨形成细胞可以产生更多的基质，即I型胶原，从而减轻与年龄相关的骨降解的影响。为了将其转化为临床问题，我们想要研究整合素α2β1在骨折修复中的作用。在初步研究中，我们可以证明，整合素α-2-β-1缺失的骨在骨折愈合后7天似乎更先进。骨折痂进一步发育，在骨折痂中可以检测到更多的全胶原蛋白。本项目的目的是确定加速骨折修复是否继续对整体临床结果产生影响。进一步的研究将阐明整合素α-2-β-1依赖的I型胶原过度表达的分子机制。因此，我们将研究一个众所周知的涉及胶原和骨基质表达的途径，即转化生长因子β和相应的骨形态发生蛋白途径。这将通过体外分析转化生长因子-β或骨形态发生蛋白抑制下的胶原和骨靶基因的表达来完成。最后，我们将通过在体外和体外对整合素α-2和β-1的外源性抑制将这些发现转化为临床应用。我们选择了具有高度特异性整合素α2β1抑制作用的蛇毒化合物柔红素作为效应剂，以及使用整合素α2β1封闭抗体的替代方法。通过这些研究改善骨折修复的结果可能是治疗骨质疏松性和不可愈合骨折的一种新的治疗方法。