The enthesis is a mineralized fibrocartilage transition that attaches tendon to bone and is vital for musculoskeletal function. Despite recent studies demonstrating the necessity of muscle loading for enthesis formation, the mechanisms that regulate enthesis formation and mechanoresponsiveness remain unclear. Therefore, the current study investigated the role of the gap junction protein connexin 43 in these processes by deleting Gja1 (the Cx43 gene) in the tendon and enthesis. Compared with their wild‐type (WT) counterparts, mice lacking Cx43 showed disrupted entheseal cell alignment, reduced mineralized fibrocartilage, and impaired biomechanical properties of the supraspinatus tendon entheses during postnatal development. Cx43‐deficient mice also exhibited reduced ability to complete a treadmill running protocol but no apparent deficits in daily activity, metabolic indexes, shoulder muscle size, grip strength, and major trabecular bone properties of the adjacent humeral head. To examine enthesis mechanoresponsiveness, young adult mice were subjected to modest treadmill exercise. Gja1 deficiency in the tendon and enthesis reduced entheseal anabolic responses to treadmill exercise: WT mice had increased expression of Sox9, Ihh, and Gli1 and increased Brdu incorporation, whereas Cx43‐deficient mice showed no changes or decreased levels with exercise. Collectively, the results demonstrated an essential role for Cx43 in postnatal tendon enthesis formation, function, and response to loading; results further provided evidence implicating a link between Cx43 function and the hedgehog signaling pathway. © 2020 American Society for Bone and Mineral Research.

中文翻译：

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连接蛋白 43 是小鼠肌腱附着点形成和对负荷的反应所必需的。

附着点是一种矿化的纤维软骨过渡，它将肌腱附着在骨骼上，对肌肉骨骼功能至关重要。尽管最近的研究表明肌肉负荷对于附着点形成的必要性，但调节附着点形成和机械反应的机制仍不清楚。因此，目前的研究通过删除Gja1来研究间隙连接蛋白连接蛋白 43 在这些过程中的作用（Cx43 基因）在肌腱和附着点中。与野生型 (WT) 小鼠相比，缺乏 Cx43 的小鼠在出生后发育过程中表现出附着点细胞排列紊乱、矿化纤维软骨减少以及冈上肌腱附着点的生物力学特性受损。Cx43 缺陷小鼠也表现出完成跑步机跑步方案的能力下降，但在日常活动、代谢指标、肩部肌肉大小、握力和相邻肱骨头的主要小梁骨特性方面没有明显缺陷。为了检查起止点机械反应，对年轻的成年小鼠进行适度的跑步机运动。肌腱和附着点中的Gja1缺陷降低了附着点对跑步机运动的合成代谢反应：WT 小鼠增加了Sox9的表达、Ihh和Gli1并增加了 Brdu 的掺入，而 Cx43 缺陷小鼠在运动时没有变化或水平下降。总的来说，这些结果证明了 Cx43 在出生后肌腱附着点形成、功能和对负荷的反应中的重要作用；结果进一步提供了证据表明 Cx43 功能与刺猬信号通路之间存在联系。© 2020 美国骨骼和矿物研究协会。