Institute of Infection, Immunity and Inflammation, College of Medicine, Veterinary and Life Sciences, University of Glasgow, UK.
Ann Rheum Dis. 2012 Feb;71(2):302-10. doi: 10.1136/ard.2011.154229. Epub 2011 Oct 4.
To seek evidence for the role of hypoxia in early human tendinopathy, and thereafter to explore mechanisms whereby tissue hypoxia may regulate apoptosis, inflammatory mediator expression and matrix regulation in human tenocytes.
Fifteen torn supraspinatus tendon (established pathology) and matched intact subscapularis tendon (representing 'early pathology') biopsies were collected from patients undergoing arthroscopic shoulder surgery. Control samples of the subscapularis tendon were collected from 10 patients undergoing arthroscopic stabilisation surgery. Markers of hypoxia were quantified by immunohistochemical methods. Human tendon-derived primary cells were derived from hamstring tendon tissue obtained during hamstring tendon anterior cruciate ligament reconstruction. The impact of hypoxia upon tenocyte biology ex vivo was measured using quantitative real-time PCR, multiplex cytokine assays, apoptotic proteomic profiling, immunohistochemistry and annexin V fluorescence-activated cell sorter staining.
Increased expression of hypoxia-inducible factor 1α, Bcl-2 and clusterin was detected in subscapularis tendon samples compared with both matched torn samples and non-matched control samples (p<0.01). Hypoxic tenocytes exhibited increased production of proinflammatory cytokines (p<0.001), altered matrix regulation (p<0.01) with increased production of collagen type III operating through a mitogen-activated protein kinase-dependent pathway. Finally, hypoxia increased the expression of several mediators of apoptosis and thereby promoted tenocyte apoptosis.
Hypoxia promotes the expression of proinflammatory cytokines, key apoptotic mediators and drives matrix component synthesis towards a collagen type III profile by human tenocytes. The authors propose hypoxic cell injury as a critical pathophysiological mechanism in early tendinopathy offering novel therapeutic opportunities in the management of tendon disorders.
探寻缺氧在早期人类腱病中的作用，进而探索组织缺氧可能通过何种机制调节人腱细胞中的细胞凋亡、炎症介质表达和基质调节。
从接受关节镜肩关节手术的患者中采集 15 例撕裂的冈上肌腱（已确立的病理学）和匹配的完整肩胛下肌腱（代表“早期病理学”）活检样本。从 10 例接受关节镜稳定手术的患者中采集肩胛下肌腱的对照样本。通过免疫组织化学方法定量缺氧标志物。从跟腱前交叉韧带重建术中获得的腘绳肌腱组织中获得人腱源性原代细胞。使用定量实时 PCR、多重细胞因子测定、凋亡蛋白质组学分析、免疫组织化学和膜联蛋白 V 荧光激活细胞分选染色，测量缺氧对腱细胞生物学的体外影响。
与匹配的撕裂样本和非匹配对照样本相比，肩胛下肌腱样本中缺氧诱导因子 1α、Bcl-2 和聚集素的表达增加（p<0.01）。缺氧的腱细胞表现出促炎细胞因子的产生增加（p<0.001），基质调节改变（p<0.01），III 型胶原的产生增加，通过丝裂原激活蛋白激酶依赖性途径发挥作用。最后，缺氧增加了几种凋亡介质的表达，从而促进了腱细胞凋亡。
缺氧促进人腱细胞中促炎细胞因子、关键凋亡介质的表达，并通过人腱细胞驱动基质成分合成向 III 型胶原谱发展。作者提出缺氧细胞损伤是早期腱病中的一个关键病理生理机制，为肌腱疾病的治疗提供了新的治疗机会。
