Enthesopathy is a disorder of bone, tendon, or ligament insertion. It represents one-fourth of all tendon-ligament diseases and is one of the most difficult tendon-ligament disorders to treat. Despite its high prevalence, the exact pathogenesis of this condition remains unknown. Here, we show that TGF-β was activated in both a semi-Achilles tendon transection (SMTS) mouse model and in a dorsiflexion immobilization (DI) mouse model of enthesopathy. High concentrations of active TGF-β recruited mesenchymal stromal stem cells (MSCs) and led to excessive vessel formation, bone deterioration, and fibrocartilage calcification. Transgenic expression of active TGF-β1 in bone also induced enthesopathy with a phenotype similar to that observed in SMTS and DI mice. Systemic inhibition of TGF-β activity by injection of 1D11, a TGF-β–neutralizing antibody, but not a vehicle antibody, attenuated the excessive vessel formation and restored uncoupled bone remodeling in SMTS mice. 1D11-treated SMTS fibrocartilage had increased proteoglycan and decreased collagen X and matrix metalloproteinase 13 expression relative to control antibody treatment. Notably, inducible knockout of the TGF-β type II receptor in mouse MSCs preserved the bone microarchitecture and fibrocartilage composition after SMTS relative to the WT littermate controls. Thus, elevated levels of active TGF-β in the enthesis bone marrow induce the initial pathological changes of enthesopathy, indicating that TGF-β inhibition could be a potential therapeutic strategy.

中文翻译：

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骨腱插入过程中异常的 TGF-β 激活会诱发类似附着点病的疾病


附着点病是一种骨、肌腱或韧带附着障碍。它占所有肌腱韧带疾病的四分之一，是最难治疗的肌腱韧带疾病之一。尽管患病率很高，但这种情况的确切发病机制仍不清楚。在这里，我们发现 TGF-β 在半跟腱横断 (SMTS) 小鼠模型和背屈固定 (DI) 小鼠附着点病模型中均被激活。高浓度的活性 TGF-β 会招募间充质基质干细胞 (MSC)，导致过度的血管形成、骨质恶化和纤维软骨钙化。骨中活性 TGF-β1 的转基因表达也会诱导附着点病变，其表型与在 SMTS 和 DI 小鼠中观察到的相似。通过注射 1D11（一种 TGF-β 中和抗体，而不是载体抗体）对 TGF-β 活性进行系统性抑制，可减弱 SMTS 小鼠的过度血管形成并恢复非偶联骨重塑。相对于对照抗体处理，1D11处理的SMTS纤维软骨蛋白聚糖增加，X胶原蛋白和基质金属蛋白酶13表达减少。值得注意的是，相对于 WT 同窝对照，小鼠 MSC 中 TGF-β II 型受体的诱导敲除在 SMTS 后保留了骨微结构和纤维软骨组成。因此，附着点骨髓中活性 TGF-β 水平升高会诱发附着点病变的初始病理变化，表明抑制 TGF-β 可能是一种潜在的治疗策略。