Changes in the expression of matrix extracellular genes and TGFB family members in rotator cuff tears

Abstract

Lack of synthesis of extracellular matrix compounds may contribute to degeneration of the tendons. Thus, we aimed to evaluate the expression of extracellular matrix and TGFB family members in ruptured and non-ruptured tendons of the rotator cuff, as well as the effect of clinical factors on gene expression in tendon samples, and the relationship between histological findings and altered gene expression. Injured and non-injured supraspinatus tendon samples and subscapular non-injured tendon samples were collected from 38 patients with rotator cuff tears. Non-injured supraspinatus tendons were obtained from eight controls. Specimens were used for histological evaluation, quantification of collagen fibers, and mRNA and protein expression analyses. Increased COL1A1, COL1A2, COL3A1, COL5A1, FN1, TNC, and TGFBR1 mRNA expression was observed in the tear samples (p < 0.05). Duration of symptoms was correlated with the levels of collagen type I/III fibers (p = 0.032; ρ = 0.0447) and FN1 immunostaining (p = 0.031; ρ = 0.417). Smoking was associated with increased frequency of microcysts, myxoid degeneration, and COL5A1, FN1, TNC, and TGFB1 mRNA expression (p < 0.05). FN1 immunostaining was correlated with the number of years of smoking (p = 0.048; ρ = 0.384). Lower levels of collagen type I/III fibers were detected in samples with fissures (0 = 0.046). High frequency of microcysts was associated with increased COL5A1, FN1, and TNC expression (p < 0.05, for all comparisons). Neovascularization was associated with reduced FN1 (p = 0.035) and TGFBR1 expression (p = 0.034). Our findings show differential expression of matrix extracellular genes and TGFB family members in the degeneration process involved in rotator cuff tears. These molecular alterations are influenced by clinical factors. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:2542-2553, 2018.

Rotator Cuff Tear Susceptibility Is Associated With Variants in Genes Involved in Tendon Extracellular Matrix Homeostasis

“…Support for the last hypothesis is provided by the finding that the rare alleles of rs3196378 ( COL5A1 ) and of rs1590 ( TGFBR1 ) were only associated with the risk of RCT in males. Both SNPs are located in the 3′‐untranslated region (3′‐UTR), which is involved in the regulation of messenger RNA stability, and the expression of these genes seems to increase in an attempt to repair the degenerated tendon . Moreover, our findings in shoulder tendinopathy are also supported by previous investigations showing the role of the variant of COL5A1 in chronic Achilles tendinopathy as well as soft tissue injuries in rugby athletes .…”

“…With adjustment for clinical and genetic ancestry covariables, we demonstrated that the rare allele G of TGFB1 rs1800470 contributed to less susceptibility to tears and the G allele of MMP9 rs17576 was involved in the risk of RCT, which was confirmed in the haplotype analysis. An increased expression of TGFB1 and reduced expression of MMPs (such as MMP9 ) in tendons appear to be related to an attempt at new collagen fibers synthesis and assembly . Although evidence of the involvement of these genes in the pathobiology of RCT was already reported, this is the first study to show that SNPs of these genes may modulate the risk of this injury.…”

“…Several studies that investigated the role of molecular alterations in tendon tears and the failure of cuff healing have contributed the first insights into a direct role of genes and pathways in RCT. A case‐controlled gene and protein expression study confirms that the expression changes of extracellular matrix (ECM) genes (such as, collagen [e.g., COL1A1 and COL5A1 ], fibronectin 1 [ FN1 ], and tenascin C [ TNC ]) and transforming growth factor β (TGF‐β)‐family members (such as, TGFB1 and its receptor TGFBR1 ) are involved in the degeneration process related to RCT . Interestingly, some of the expression changes in COL5A1, FN1, TNC , and TGFB1 are associated with smoking habits; this observation helps in the elucidation of the mechanism by which the environment contributes to the modulation of key genes related to this injury .…”

“…A case‐controlled gene and protein expression study confirms that the expression changes of extracellular matrix (ECM) genes (such as, collagen [e.g., COL1A1 and COL5A1 ], fibronectin 1 [ FN1 ], and tenascin C [ TNC ]) and transforming growth factor β (TGF‐β)‐family members (such as, TGFB1 and its receptor TGFBR1 ) are involved in the degeneration process related to RCT . Interestingly, some of the expression changes in COL5A1, FN1, TNC , and TGFB1 are associated with smoking habits; this observation helps in the elucidation of the mechanism by which the environment contributes to the modulation of key genes related to this injury . Another case–control study shows systematic dysregulated expression and DNA methylation of some matrix metalloproteinases (MMPs; a large group of proteolytic enzymes responsible for the tissue remodeling and degradation of the ECM) and their inhibitors (tissue inhibitors of metalloproteinases [TIMPs]) in rotator cuff tendon samples of patients with supraspinatus tears .…”

Aspectos genéticos nas afecções do ombro

“…In 2018, our group described that the altered expression of the genes COL1A1, COL1A2, COL3A1, COL5A1, FN1, TNC, TGFB1, and TGFBR1 is involved in the process of degeneration in ruptures of the rotator cuff. 34 In a systematic review study, Dabija et al concluded that although previous studies provide preliminary evidence of genetic and family predisposition to RCIs, there is a lack of large genomic studies that can provide more definitive information and guide the early detection of individuals at risk, prophylactic rehabilitation and potential gene therapies and interventions in regenerative medicine. 10 A more recent study conducted an extensive analysis using Gene Expression Omnibus (GEO) gene expression profile gse93661 and bioinformatics analysis to investigate differentially expressed genes (DEGs) in satellite cells between samples of cases of supraspinal injury and subscapular tendon controls.…”