Comparison of transforming growth factor beta expression in healthy and diseased human tendon
Comparison of transforming growth factor beta expression in healthy and diseased human tendon
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DOI：
10.1186/s13075-016-0947-8
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发表时间：
2016-02-17
影响因子：
4.9
通讯作者：
Dakin, Stephanie G.
中科院分区：
文献类型：
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作者：
Goodier, Henry C. J.;Carr, Andrew J.;Dakin, Stephanie G.
背景：病变肌腱的特征是纤维化瘢痕组织，它对肌腱的结构和功能产生不利影响，并增加了再次损伤的可能性。与肺和肾组织相比，病变肌腱纤维化的机制和表达谱尚未得到充分研究，在肺和肾组织中，转化生长因子(TGF) β及其相关超家族已知是纤维化和调节细胞外基质稳态的关键驱动因素。我们假设，与健康对照肌腱相比，已患病的人类肌腱样本中TGF β超家族成员的表达存在差异。方法：从就诊于骨科转诊中心的患者中收集健康和患病的肩袖肌腱。病变肌腱（完整）和健康肌腱通过超声引导活检收集，撕裂肌腱在常规手术清创中收集。采用免疫组织化学和实时定量聚合酶链反应研究TGF β超家族成员在健康和病变肌腱中的蛋白和基因表达谱。结果：与健康肌腱相比，病变肌腱中TGF β超家族成员表达异常。其中，病变肌腱中TGF β -1、TGF β受体(R) 1和TGF β R2蛋白含量较健康肌腱降低（p < 0.01）。在mRNA水平上，病变肌腱中TGF β R1显著降低，TGF β R2显著升高（p < 0.01）。BMP-2、BMP-7和CTGF mRNA在肌腱疾病中保持不变。结论：我们认为TGF β通路的下调可能是一种限制疾病相关纤维化的保护性反应。TGF β轴与疾病的破坏表明，相关的下游途径可能对维持健康的肌腱稳态很重要。我们的研究结果表明，已有肌腱疾病的患者不太可能从TGF β阻断治疗中获益，TGF β阻断治疗已在几种动物模型中作为治疗策略进行了研究。未来的研究应该研究纤维化介质在肌腱疾病早期的表达谱，以提高对肌腱纤维化的靶向机制的理解。
Background: Diseased tendons are characterised by fibrotic scar tissue, which adversely affects tendon structure and function and increases the likelihood of re-injury. The mechanisms and expression profiles of fibrosis in diseased tendon is understudied compared to pulmonary and renal tissues, where transforming growth factor (TGF)beta and its associated superfamily are known to be key drivers of fibrosis and modulate extracellular matrix homeostasis. We hypothesised that differential expression of TGF beta superfamily members would exist between samples of human rotator cuff tendons with established disease compared to healthy control tendons.Methods: Healthy and diseased rotator cuff tendons were collected from patients presenting to an orthopaedic referral centre. Diseased tendinopathic (intact) and healthy rotator cuff tendons were collected via ultrasound-guided biopsy and torn tendons were collected during routine surgical debridement. Immunohistochemistry and quantitative real-time polymerase chain reaction were used to investigate the protein and gene expression profiles of TGF beta superfamily members in these healthy and diseased tendons.Results: TGF beta superfamily members were dysregulated in diseased compared to healthy tendons. Specifically, TGF beta-1, TGF beta receptor (R) 1 and TGF beta R2 proteins were reduced (p < 0.01) in diseased compared to healthy tendons. At the mRNA level, TGF beta R1 was significantly reduced in samples of diseased tendons, whereas TGF beta R2 was increased (p < 0.01). BMP-2, BMP-7 and CTGF mRNA remained unchanged with tendon disease.Conclusions: We propose that downregulation of TGF beta pathways in established tendon disease may be a protective response to limit disease-associated fibrosis. The disruption of the TGF beta axis with disease suggests associated downstream pathways may be important for maintaining healthy tendon homeostasis. The findings from our study suggest that patients with established tendon disease would be unlikely to benefit from therapeutic TGF beta blockade, which has been investigated as a treatment strategy in several animal models. Future studies should investigate the expression profile of fibrotic mediators in earlier stages of tendon disease to improve understanding of the targetable mechanisms underpinning tendon fibrosis.