Abstract
Rotator cuff lesion with shoulder stiffness is a major cause of shoulder pain and motionlessness. Subacromial bursa fibrosis is a prominent pathological feature of the shoulder disorder. MicroRNA-29a (miR-29a) regulates fibrosis in various tissues; however, the miR-29a action to subacromial bursa fibrosis remains elusive. Here, we reveal that subacromial synovium in patients with rotator cuff tear with shoulder stiffness showed severe fibrosis, hypertrophy, and hyperangiogenesis histopathology along with significant increases in fibrotic matrices collagen (COL) 1A1, 3A1, and 4A1 and inflammatory cytokines, whereas miR-29a expression was downregulated. Supraspinatus and infraspinatus tenotomy-injured shoulders in transgenic mice overexpressing miR-29a showed mild swelling, vascularization, fibrosis, and regular gait profiles as compared to severe rotator cuff damage in wild-type mice. Treatment with miR-29a precursor compromised COL3A1 production and hypervascularization in injured shoulders. In vitro, gain of miR-29a function attenuated COL3A1 expression through binding to the 3’-untranslated region (3′-UTR) of COL3A1 in inflamed tenocytes, whereas silencing miR-29a increased the matrix expression. Taken together, miR-29a loss is correlated with subacromial bursa inflammation and fibrosis in rotator cuff tear with shoulder stiffness. miR-29a repressed subacromial bursa fibrosis through directly targeting COL3A1 mRNA, improving rotator cuff integrity and shoulder function. Collective analysis offers a new insight into the molecular mechanism underlying rotator cuff tear with shoulder stiffness. This study also highlights the remedial potential of miR-29a precursor for alleviating the shoulder disorder.
Highlights
Rotator cuff lesions with shoulder stiffness is a common cause of pain, limited motion, and poor biomechanical function of shoulder, terribly impacting patients’ daily life and activity [1,2]
We examined whether inflammation or fibrosis in subacromial bursa was correlated with rotator cuff tear with shoulder stiffness
Given that the miR-29 family members, like miR-29a, miR-29b, and miR-29c, are shown to regulate tissue fibrosis [15,16,17,19], we investigated whether the miR-29a family was relevant to rotor cuff tear with shoulder stiffness. miR-29a and miR-29b rather than miR-29c expression were significantly downregulated in subacromial bursa in the stiffness group (Figure 2A)
Summary
Rotator cuff lesions with shoulder stiffness is a common cause of pain, limited motion, and poor biomechanical function of shoulder, terribly impacting patients’ daily life and activity [1,2]. While the etiological factors remain uncertain [3], subacromial bursitis, like hypercellularity [3], degeneration [4], and hypervascularity [5], is a prominent feature of the shoulder disorder. We have previously revealed that chronic inflammation is correlated with rotator cuff lesions with shoulder stiffness in patients with diabetes [6]. Myofibroblasts overgrowth within subacromial bursa compartment is a notable pathohistological feature in the injured shoulders [7]. MiR-145, miR-223 and miR-494 regulate cystic fibrosis of airway epithelium [12]. With regard to microRNA actions to fibrotic responses, increasing reports show that many microRNAs, like miR-1, miR-133, miR-206 and miR-124, are involved in inflammatory myopathy [10] and fibrotic matrix deposition in pulmonary vascular fibroblasts [11]. miR-145, miR-223 and miR-494 regulate cystic fibrosis of airway epithelium [12]. miR-124 knockdown alters TGF-β1 signaling pathways, attenuating extracellular matrix production in renal tissue environments [13]
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