Regulation of tendon development by CCN1/Cyr61

项目摘要 肌腱发育的机制是迄今为止最不了解的任何组成部分， 肌肉骨骼系统这是一个值得关注的问题，因为肌腱损伤是常见的， 有限公司愈合通常导致瘢痕组织的形成，其在组成和机械上劣于 天然肌腱，导致柔韧性降低和复发性撕裂率高。CCN家族成员 基质细胞蛋白由于其在多种纤维化病症中的关键作用而被广泛研究，但是 它们在正常纤维组织如肌腱中的作用尚不清楚。我们发现CCN 1/Cyr 61高表达， 在肌腱和韧带中，以及在肌腱/韧带祖干细胞中切除Ccn 1小鼠 使用Scx-Cre（Ccn 1 SKO）的TPSC表现出马蹄内翻足样表型。组织学分析显示， 交叉韧带（ACL）、跟腱和髌腱比野生型明显更厚、更结实 (WT)出生时同窝出生的婴儿;这些缺陷在成年人中持续存在。受影响的肌腱表现出更强的机械 性能早期，但随着年龄的增长变得明显减弱。没有其他具有类似表型的突变体 被描述到目前为止。最初的RNA-Seq和表型分析显示，Ccn 1 SKO中受影响的肌腱 小鼠获得与活化的伤口成纤维细胞相似的基因表达谱。因此，我们有一个 独特的机会，以确定新的机制，调节肌腱的形成和重塑，有直接 治疗潜力我们计划：1）确定CCN 1/Cyr 61在肌腱形成和维持中的功能 通过Ccn 1 SKO小鼠的表型分析在体内进行，和2）测试CCN 1/Cyr 61在 TPSC/肌腱细胞促进肌腱生成表型并防止获得活化的伤口成纤维细胞 命运这些研究的成功将为未来的研究提供强有力的理由， CCN 1/Cyr 61在肌腱损伤/修复中的应用，并开发CCN 1/Cyr 61作为促进无瘢痕的治疗剂 肌腱愈合

PROJECT SUMMARY The mechanisms underlying tendon development are by far the least understood of any component of the musculoskeletal system. This is a concern because tendon injuries are common and treatment options are limited. Healing often results in formation of scar tissue, which is compositionally and mechanically inferior to native tendon, resulting in decreased flexibility and a high recurrent tear rate. Members of the CCN family of matricellular proteins have been extensively studied due to their key roles in multiple fibrotic conditions, but their roles in normal fibrous tissues like tendons are unknown. We found that CCN1/Cyr61 s highly expressed in tendon and ligament, and that mice in which Ccn1 is ablated in tendon/ligament progenitor stem cells (TPSCs) using Scx-Cre (Ccn1SKO) exhibit a clubfoot-like phenotype. Histological analysis revealed that anterior cruciate ligament (ACL), Achilles and patellar tendons are substantially thicker and more stout than in wild-type (WT) littermates at birth; these defects persist in adults. The affected tendon displays stronger mechanical properties early, but becomes significantly weaker with age. No other mutants with a similar phenotype have been described to date. Initial RNA-Seq and phenotypic analysis revealed that affected tendons in Ccn1SKO mice acquire a gene expression profile similar to that of activated wound fibroblasts. We therefore have a unique opportunity to identify new mechanisms regulating tendon formation and remodeling that have direct therapeutic potential. We plan to: 1) define the function of CCN1/Cyr61 in tendon formation and maintenance in vivo through phenotypic analysis of Ccn1SKO mice, and 2) test the hypothesis that CCN1/Cyr61 is required in TPSCs/tenocytes to promote the tenogenic phenotype and prevent acquisition of an activated wound fibroblast fate. Success with these studies would provide a strong rationale for future studies that evaluate the function of CCN1/Cyr61 in tendon injury/repair and develop CCN1/Cyr61 as a therapeutic agent to promote scarless tendon healing.