Tendons have a uniaxially aligned structure with a hierarchical organization of collagen fibrils crucial for tendon function. Collagen XII is expressed in tendons and has been implicated in the regulation of fibrillogenesis. It is a non-fibrillar collagen belonging to the Fibril-Associated Collagens with Interrupted Triple Helices (FACIT) family. Mutations in COL12A1 cause myopathic Ehlers Danlos Syndrome with a clinical phenotype involving both joints and tendons supporting critical role(s) for collagen XII in tendon development and function. Here we demonstrate the molecular function of collagen XII during tendon development using a Col12a1 null mouse model. Col12a1 deficiency altered tenocyte shape, formation of interacting cell processes, and organization resulting in impaired cell–cell communication and disruption of hierarchal structure as well as decreased tissue stiffness. Immuno-localization revealed that collagen XII accumulated on the tenocyte surface and connected adjacent tenocytes by building matrix bridges between the cells, suggesting that collagen XII regulates intercellular communication. In addition, there was a decrease in fibrillar collagen I in collagen XII deficient tenocyte cultures compared with controls suggesting collagen XII signaling specifically alters tenocyte biosynthesis. This suggests that collagen XII provides feedback to tenocytes regulating extracellular collagen I. Together, the data indicate dual roles for collagen XII in determination of tendon structure and function. Through association with fibrils it functions in fibril packing, fiber assembly and stability. In addition, collagen XII influences tenocyte organization required for assembly of higher order structure; intercellular communication necessary to coordinate long range order and feedback on tenocytes influencing collagen synthesis. Integration of both regulatory roles is required for the acquisition of hierarchal structure and mechanical properties.

肌腱具有单轴排列的结构，具有对肌腱功能至关重要的胶原原纤维的分层组织。 XII 胶原蛋白在肌腱中表达，并参与原纤维形成的调节。它是一种非纤维状胶原蛋白，属于间断三螺旋纤维相关胶原蛋白 (FACIT) 家族。 COL12A1突变会导致肌病性埃勒斯丹洛斯综合征，其临床表型涉及关节和肌腱，支持 XII 型胶原蛋白在肌腱发育和功能中的关键作用。在这里，我们使用Col12a1无效小鼠模型展示了 XII 胶原蛋白在肌腱发育过程中的分子功能。 Col12a1缺乏会改变肌腱细胞的形状、相互作用的细胞过程的形成和组织，导致细胞间通讯受损、层次结构破坏以及组织硬度降低。免疫定位显示，胶原蛋白 XII 积聚在肌腱细胞表面，并通过在细胞之间建立基质桥连接相邻的肌腱细胞，这表明胶原蛋白 XII 调节细胞间通讯。此外，与对照组相比，缺乏胶原蛋白 XII 的肌腱细胞培养物中纤维状胶原蛋白 I 有所减少，这表明胶原蛋白 XII 信号传导特异性地改变了肌腱细胞的生物合成。这表明胶原蛋白 XII 向调节细胞外胶原蛋白 I 的肌腱细胞提供反馈。总而言之，这些数据表明胶原蛋白 XII 在确定肌腱结构和功能中的双重作用。通过与原纤维结合，它在原纤维堆积、纤维组装和稳定性方面发挥作用。 此外，XII 胶原蛋白影响组装高级结构所需的肌腱细胞组织；细胞间通讯对于协调影响胶原蛋白合成的肌腱细胞的长程秩序和反馈是必需的。为了获得层次结构和机械性能，需要整合两种调节作用。