Tashjian Robert Z, Lock Ian, Granger Erin K, Wang Yangliang, Lee Younghee, Chalmers Peter N, Jones Kevin B
Department of Orthopaedics, University of Utah School of Medicine, Salt Lake City, Utah, USA.
Department of Biomedical Informatics, University of Utah School of Medicine, Salt Lake City, Utah, USA.
Orthop J Sports Med. 2020 Jun 29;8(6):2325967120927480. doi: 10.1177/2325967120927480. eCollection 2020 Jun.
Although the cause of rotator cuff tearing is likely multifactorial and a genetic predisposition has been proposed, the biochemical basis remains unknown.
To determine gene expression profiles in torn rotator cuff tendon tissue through use of RNA sequencing.
Controlled laboratory study.
The supraspinatus tendon edge was biopsied in 24 patients undergoing arthroscopic rotator cuff repair for full-thickness supraspinatus rotator cuff tears. The supraspinatus tendon was also biopsied in 9 patients undergoing open reduction and internal fixation for a proximal humeral fracture (controls). Total RNA was extracted and sequenced. Differential gene expression was analyzed between the tear and control groups, and a secondary analysis was conducted between groups defined by an unbiased clustering.
Tear and control transcriptomes demonstrated significant differential expression in more than 3000 genes. The identified differential genes were highlighted in pathways involved in inflammation in control patients and extracellular matrix generation in patients with tears. Secondary analysis using unsupervised and thus unbiased hierarchical clustering revealed 2 clusters (c2 and c3). Cluster c3 contained smaller ( < .001) and less retracted ( = .018) tears (ie, tears earlier in the progression of rotator cuff disease) with increased expression of hypoxia target genes. Cluster c2 contained larger, more retracted tears (ie, tears further in the progression of rotator cuff disease) with increased expression of endothelial cell markers and chronic inflammation target genes. Tears in c2 had significantly worse healing rates compared with tears in c3 (0% vs 89%; = .007).
Smaller, less retracted tears had increased expression of hypoxia target genes and improved healing, whereas larger, more retracted tears were associated with endothelial cell markers and worse healing. Thus, hypoxia may be the inciting event for tear development, whereas with tear enlargement, a chronic, inflammatory, angiogenic process may predominate.
Identification of differential gene expression in rotator cuff tears may be a reliable tool to predict repair healing in the future.
尽管肩袖撕裂的病因可能是多因素的，并且有人提出存在遗传易感性，但其生化基础仍不清楚。
通过RNA测序确定撕裂的肩袖肌腱组织中的基因表达谱。
对照实验室研究。
对24例因全层冈上肌肩袖撕裂而接受关节镜下肩袖修复的患者的冈上肌腱边缘进行活检。还对9例因肱骨近端骨折接受切开复位内固定的患者的冈上肌腱进行活检（对照组）。提取总RNA并进行测序。分析撕裂组和对照组之间的差异基因表达，并对通过无偏聚类定义的组之间进行二次分析。
撕裂组和对照组的转录组在3000多个基因中表现出显著差异表达。所鉴定的差异基因在对照组患者的炎症相关通路和撕裂患者的细胞外基质生成相关通路中得到突出显示。使用无监督且因此无偏的层次聚类进行的二次分析揭示了2个聚类（c2和c3）。聚类c3包含较小（<0.001）且回缩较少（=0.018）的撕裂（即肩袖疾病进展早期的撕裂），缺氧靶基因表达增加。聚类c2包含较大、回缩更多的撕裂（即肩袖疾病进展更后期的撕裂），内皮细胞标志物和慢性炎症靶基因表达增加。与c3中的撕裂相比，c2中的撕裂愈合率明显更差（0%对89%；=0.007）。
较小、回缩较少的撕裂缺氧靶基因表达增加且愈合改善，而较大、回缩更多的撕裂与内皮细胞标志物相关且愈合较差。因此，缺氧可能是撕裂发展的起始事件，而随着撕裂扩大，慢性、炎症性、血管生成过程可能占主导。
鉴定肩袖撕裂中的差异基因表达可能是未来预测修复愈合的可靠工具。
