Inductive Mechanisms and Roles of MMPs in Tendon Healing

描述（由申请人提供）：我们发现内部肌腱细胞生活在细胞和承重纤维型胶原之间的细胞周ECM中。此外，我们已经证明MMPs 2和9在损伤后在体内表达。同样，我们已经证实，在体外，肌腱细胞在附着于I型胶原后增加了MMP-2、MMP-9和MMP-14的产生。我们的总体假设是：损伤后，肌腱细胞增殖和迁移，从而破坏了它们之前的稳态ECM接触，形成新的ECM相互作用，其中包括I型胶原蛋白。ECM配体的这种变化，我们的初步工作表明I型胶原结扎可能是关键，是导致诱导伤口愈合蛋白的一系列线索的一部分。随着肌腱愈合的进展，MMPs在分解代谢重塑、生长因子调节和新基质沉积中发挥着不可或缺的作用。为了评估这种肌腱愈合的一般模型，我们提出了以下体内和体外方法：扩大我们在体外对肌腱细胞的实验操作，以研究ECM影响这些基因表达的机制。2. 通过对小鼠肌腱愈合的评估，在体内检测MMP-9和MMP-14在肌腱修复中的功能作用。3. 对基因表达进行调查，作为了解胶原蛋白引发的MMP反应发生的更大背景的第一步。

DESCRIPTION (provided by applicant): We have found that internal tendon cells live within a pericellular ECM that is between the cells and the load-bearing fibrillar type I collagen. Further, we have demonstrated that MMPs 2 and 9 are expressed in vivo after injury. Similarly, We have established that in vitro, tendon cells increase the production of MMP-2, MMP-9 and MMP-14 after attachment to type I collagen. Our overall hypothesis is: after injury, tendon cells proliferate and migrate and in so doing disrupt their previous steady-state ECM contacts and form new ECM interactions which include type I collagen. This change in ECM ligands, and our preliminary work suggests type I collagen ligation may be key, is part of the constellation of cues that result in the induction of wound healing proteins. As tendon healing then progresses, MMPs play an integral role in catabolic remodeling, growth factor modulation and new matrix deposition. To evaluate this general model of tendon healing, we propose the following in vivo and in vitro approaches: 1. expand our experimental manipulation of tendon cells in vitro to study the mechanisms by which ECM influences the expression of these genes. 2. examine in vivo the functional role of MMP-9 and MMP-14 in tendon repair by the evaluation of tendon healing in null mice. 3. carry out a survey of gene expression as a first step to understanding the greater context within which the collagen-elicited MMP response occurs.