Goodier Henry C J, Carr Andrew J, Snelling Sarah J B, Roche Lucy, Wheway Kim, Watkins Bridget, Dakin Stephanie G
Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Nuffield Orthopaedic Centre, Windmill Road, Headington, OX3 7LD, UK.
NIHR Oxford Biomedical Research Unit, Botnar Research Centre, University of Oxford, Windmill Road, Oxford, OX3 7LD, UK.
Arthritis Res Ther. 2016 Feb 17;18:48. doi: 10.1186/s13075-016-0947-8.
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)β and its associated superfamily are known to be key drivers of fibrosis and modulate extracellular matrix homeostasis. We hypothesised that differential expression of TGFβ superfamily members would exist between samples of human rotator cuff tendons with established disease compared to healthy control tendons.
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 TGFβ superfamily members in these healthy and diseased tendons.
TGFβ superfamily members were dysregulated in diseased compared to healthy tendons. Specifically, TGFβ-1, TGFβ receptor (R)1 and TGFβ R2 proteins were reduced (p < 0.01) in diseased compared to healthy tendons. At the mRNA level, TGFβ R1 was significantly reduced in samples of diseased tendons, whereas TGFβ R2 was increased (p < 0.01). BMP-2, BMP-7 and CTGF mRNA remained unchanged with tendon disease.
We propose that downregulation of TGFβ pathways in established tendon disease may be a protective response to limit disease-associated fibrosis. The disruption of the TGFβ 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 TGFβ 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.
病变肌腱的特征是纤维化瘢痕组织，这会对肌腱结构和功能产生不利影响，并增加再次受伤的可能性。与肺和肾组织相比，病变肌腱中纤维化的机制和表达谱研究较少，在肺和肾组织中，转化生长因子（TGF）β及其相关超家族是已知的纤维化关键驱动因素，并调节细胞外基质稳态。我们假设，与健康对照肌腱相比，患有已确诊疾病的人类肩袖肌腱样本中TGFβ超家族成员存在差异表达。
从前往骨科转诊中心就诊的患者中收集健康和病变的肩袖肌腱。通过超声引导活检收集病变的肌腱病（完整）和健康的肩袖肌腱，在常规手术清创期间收集撕裂的肌腱。采用免疫组织化学和定量实时聚合酶链反应来研究这些健康和病变肌腱中TGFβ超家族成员的蛋白质和基因表达谱。
与健康肌腱相比，病变肌腱中TGFβ超家族成员表达失调。具体而言，与健康肌腱相比，病变肌腱中TGFβ-1、TGFβ受体（R）1和TGFβ R2蛋白减少（p < 0.01）。在mRNA水平上，病变肌腱样本中TGFβ R1显著减少，而TGFβ R2增加（p < 0.01）。BMP-2、BMP-7和CTGF mRNA在肌腱疾病中保持不变。
我们提出，在已确诊的肌腱疾病中TGFβ通路的下调可能是一种保护性反应，以限制疾病相关的纤维化。疾病导致的TGFβ轴破坏表明相关的下游通路可能对维持健康的肌腱稳态很重要。我们研究的结果表明，患有已确诊肌腱疾病的患者不太可能从治疗性TGFβ阻断中获益，在几种动物模型中已将其作为一种治疗策略进行研究。未来的研究应调查肌腱疾病早期纤维化介质的表达谱，以更好地理解支撑肌腱纤维化的可靶向机制。
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