{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:47:03Z","timestamp":1787028423734,"version":"build-2736575974"},"reference-count":48,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2019,11,15]],"date-time":"2019-11-15T00:00:00Z","timestamp":1573776000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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\u2019-untranslated region (3\u2032-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.<\/jats:p>","DOI":"10.3390\/ijms20225742","type":"journal-article","created":{"date-parts":[[2019,11,15]],"date-time":"2019-11-15T11:24:32Z","timestamp":1573817072000},"page":"5742","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["MicroRNA-29a Mitigates Subacromial Bursa Fibrosis in Rotator Cuff Lesion with Shoulder Stiffness"],"prefix":"10.3390","volume":"20","author":[{"given":"Jih-Yang","family":"Ko","sequence":"first","affiliation":[{"name":"Departments of Orthopedic Surgery, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan"},{"name":"Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei-Shiung","family":"Lian","sequence":"additional","affiliation":[{"name":"Department of Medical Research, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan"},{"name":"Core Lab for Phenomics&amp; Diagnostics, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsai-Chen","family":"Tsai","sequence":"additional","affiliation":[{"name":"Departments of Orthopedic Surgery, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Shan","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Medical Research, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan"},{"name":"Core Lab for Phenomics&amp; Diagnostics, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chin-Kuei","family":"Hsieh","sequence":"additional","affiliation":[{"name":"Department of Medical Research, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan"},{"name":"Core Lab for Phenomics&amp; Diagnostics, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chung-Wen","family":"Kuo","sequence":"additional","affiliation":[{"name":"Department of Medical Research, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan"},{"name":"Core Lab for Phenomics&amp; Diagnostics, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng-Sheng","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Medical Research, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan"},{"name":"Core Lab for Phenomics&amp; Diagnostics, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan"},{"name":"Graduate Institute of Clinical Medical Sciences, Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,11,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"832","DOI":"10.1002\/jor.22806","article-title":"Mechanisms of tendon injury and repair","volume":"33","author":"Thomopoulos","year":"2015","journal-title":"J. Orthop. Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1016\/j.arthro.2018.10.126","article-title":"Management of Concomitant Preoperative Rotator Cuff Pathology and Adhesive Capsulitis: A Systematic Review of Indications, Treatment Approaches, and Outcomes","volume":"35","author":"Zhang","year":"2019","journal-title":"Arthroscopy"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1695","DOI":"10.1002\/jor.21416","article-title":"Interleukin-1beta stimulates stromal-derived factor-1alpha expression in human subacromial bursa","volume":"29","author":"Blaine","year":"2011","journal-title":"J. Orthop. Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"701","DOI":"10.5435\/00124635-201111000-00006","article-title":"Subacromial impingement syndrome","volume":"19","author":"Harrison","year":"2011","journal-title":"J. Am. Acad. Orthop. Surg."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2891","DOI":"10.1177\/0363546515608485","article-title":"Platelet-Rich Plasma Injection with Arthroscopic Acromioplasty for Chronic Rotator Cuff Tendinopathy: A Randomized Controlled Trial","volume":"43","author":"Carr","year":"2015","journal-title":"Am. J. Sports Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1547","DOI":"10.1016\/j.jse.2013.01.011","article-title":"Increased interleukin 1beta levels in the subacromial fluid in diabetic patients with rotator cuff lesions compared with nondiabetic patients","volume":"22","author":"Siu","year":"2013","journal-title":"J. Shoulder Elb. Surg."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1090","DOI":"10.1002\/jor.20631","article-title":"Increased IL-1beta expression and myofibroblast recruitment in subacromial bursa is associated with rotator cuff lesions with shoulder stiffness","volume":"26","author":"Ko","year":"2008","journal-title":"J. Orthop. Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1887","DOI":"10.1242\/dev.050526","article-title":"The miR-143-adducin3 pathway is essential for cardiac chamber morphogenesis","volume":"137","author":"Deacon","year":"2010","journal-title":"Development"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/j.cell.2009.01.002","article-title":"MicroRNAs: Target recognition and regulatory functions","volume":"136","author":"Bartel","year":"2009","journal-title":"Cell"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1022","DOI":"10.1002\/art.38292","article-title":"Inhibition of myogenic microRNAs 1133, and 206 by inflammatory cytokines links inflammation and muscle degeneration in adult inflammatory myopathies","volume":"66","author":"Georgantas","year":"2014","journal-title":"Arthritis Rheumatol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1161\/CIRCRESAHA.114.301633","article-title":"MicroRNA-124 controls the proliferative, migratory, and inflammatory phenotype of pulmonary vascular fibroblasts","volume":"114","author":"Wang","year":"2014","journal-title":"Circ. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"3354","DOI":"10.4049\/jimmunol.1202960","article-title":"Regulation of cystic fibrosis transmembrane conductance regulator by microRNA-145, -223, and -494 is altered in DeltaF508 cystic fibrosis airway epithelium","volume":"190","author":"Oglesby","year":"2013","journal-title":"J. Immunol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1681\/ASN.2013010072","article-title":"MicroRNA-214 antagonism protects against renal fibrosis","volume":"25","author":"Denby","year":"2014","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1355","DOI":"10.1016\/j.biochi.2013.03.010","article-title":"MicroRNA-29 family, a crucial therapeutic target for fibrosis diseases","volume":"95","author":"He","year":"2013","journal-title":"Biochimie"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1885","DOI":"10.1016\/j.ajpath.2013.08.027","article-title":"Canonical transforming growth factor-beta signaling regulates disintegrin metalloprotease expression in experimental renal fibrosis via miR-29","volume":"183","author":"Ramdas","year":"2013","journal-title":"Am. J. Pathol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"978","DOI":"10.1038\/labinvest.2012.70","article-title":"Expression of platelet-derived growth factor-C and insulin-like growth factor I in hepatic stellate cells is inhibited by miR-29","volume":"92","author":"Kwiecinski","year":"2012","journal-title":"Lab. Invest."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1251","DOI":"10.1038\/mt.2012.36","article-title":"miR-29 inhibits bleomycin-induced pulmonary fibrosis in mice","volume":"20","author":"Xiao","year":"2012","journal-title":"Mol. Ther."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"14851","DOI":"10.1074\/jbc.M111.314922","article-title":"Protective role of estrogen-induced miRNA-29 expression in carbon tetrachloride-induced mouse liver injury","volume":"287","author":"Zhang","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3584","DOI":"10.1038\/s41598-017-03616-w","article-title":"MicroRNA-29a counteracts synovitis in knee osteoarthritis pathogenesis by targeting VEGF","volume":"7","author":"Ko","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1007\/s10495-013-0909-4","article-title":"MicroRNA-29a protects against acute liver injury in a mouse model of obstructive jaundice via inhibition of the extrinsic apoptosis pathway","volume":"19","author":"Tiao","year":"2014","journal-title":"Apoptosis"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1698","DOI":"10.1681\/ASN.2013050527","article-title":"MicroRNA-29a promotion of nephrin acetylation ameliorates hyperglycemia-induced podocyte dysfunction","volume":"25","author":"Lin","year":"2014","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"6774","DOI":"10.1038\/ncomms7774","article-title":"MicroRNA29a regulates IL-33-mediated tissue remodelling in tendon disease","volume":"6","author":"Millar","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1111","DOI":"10.1002\/jor.22646","article-title":"Skeletal muscle fibrosis and stiffness increase after rotator cuff tendon injury and neuromuscular compromise in a rat model","volume":"32","author":"Sato","year":"2014","journal-title":"J. Orthop. Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1007\/s11886-018-0953-3","article-title":"PET molecular targets and near-infrared fluorescence imaging of artherosclerosis","volume":"20","author":"Celeng","year":"2018","journal-title":"Curr. Cardiol. Rep."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1007\/s00109-016-1422-3","article-title":"Chaperonin 60 regulation of SOX9 ubiquitination mitigates the development of knee osteoarthritis","volume":"94","author":"Ko","year":"2016","journal-title":"J. Mol. Med."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"de Oliveria, C., Patel, K., Mishra, V., Trivedi, R.N., Noel, P., Singh, A., Yaron, J.R., and Singh, V.P. (2016). Characterization and predictive value of near infrared 2-deoxyglucose optical imaging in sever acute pancreatitis. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0149073"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1007\/s11926-014-0476-x","article-title":"Rotator cuff biology and biomechanics: A review of normal and pathological conditions","volume":"17","author":"Huegel","year":"2015","journal-title":"Curr. Rheumatol. Rep."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e0018","DOI":"10.2106\/JBJS.OA.18.00018","article-title":"The effect of lipid disorders on the risk of rotator cuff disease: A systematic review and meta-analysis","volume":"3","author":"Lai","year":"2018","journal-title":"JBJS Open Access"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1598","DOI":"10.1016\/j.arthro.2015.01.026","article-title":"Smoking predisposes to rotator cuff pathology and shoulder dysfunction: A systematic review","volume":"31","author":"Bishop","year":"2015","journal-title":"Arthroscopy"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e252","DOI":"10.1016\/j.jse.2017.03.005","article-title":"One-stage surgical treatment for concomitant rotator cuff tears with shoulder stiffness has comparable results with isolated rotator cuff tears: A systematic review","volume":"26","author":"Sabzevari","year":"2017","journal-title":"J. Shoulder Elbow. Surg."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"948","DOI":"10.1177\/0363546515623031","article-title":"Double-row repair lowers the retear risk after accelerated rehabilitation","volume":"44","author":"Franceschi","year":"2016","journal-title":"Am. J. Sports Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1007\/s40122-017-0065-6","article-title":"Frequency of shoulder corticosteroid injections for pain and stiffness after shoulder surgery and their potential to enhance outcomes with physiotherapy: A retrospective study","volume":"6","author":"Skedros","year":"2017","journal-title":"Pain Ther."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3322","DOI":"10.1177\/0363546517720199","article-title":"Hyaluronic acid accelerates tendon-to-bone healing after rotator cuff Repair","volume":"45","author":"Honda","year":"2017","journal-title":"Am. J. Sports Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"792","DOI":"10.1177\/0885328218811386","article-title":"Freeze-dried chitosan-platelet-rich plasma implants improve supraspinatus tendon attachment in a transosseous rotator cuff repair model in the rabbit","volume":"33","author":"Chevrier","year":"2019","journal-title":"J. Biomater. Appl."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2336","DOI":"10.1177\/0363546517707202","article-title":"A Long preoperative duration of symptoms is associated with worse functional outcomes after 1-stage arthroscopic treatment of rotator cuff tears with shoulder stiffness","volume":"45","author":"Chen","year":"2017","journal-title":"Am. J. Sports Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1186\/s13018-019-1075-3","article-title":"Comparison of one-stage versus two-stage procedure for the management of patients with rotator cuff tear and concomitant shoulder stiffness","volume":"14","author":"Zhuo","year":"2019","journal-title":"J. Orthop. Surg. Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1016\/j.arthro.2014.09.002","article-title":"Clinical outcomes of rotator cuff repair with arthroscopic capsular release and manipulation for rotator cuff tear with stiffness: A matched-pair comparative study between patients with and without stiffness","volume":"31","author":"Cho","year":"2015","journal-title":"Arthroscopy"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1183","DOI":"10.7863\/ultra.34.7.1183","article-title":"Assessment of the postoperative appearance of the rotator cuff tendon using serial sonography after arthroscopic repair of a rotator cuff tear","volume":"34","author":"Yoo","year":"2015","journal-title":"J. Ultrasound Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1097\/00004728-200603000-00030","article-title":"Range of normal and abnormal subacromial\/subdeltoid bursa fluid","volume":"30","author":"White","year":"2006","journal-title":"J. Comput. Assist. Tomogr."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1002\/jor.23662","article-title":"The role of mechanobiology in progression of rotator cuff muscle atrophy and degeneration","volume":"36","author":"Gibbons","year":"2018","journal-title":"J. Orthop. Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1186\/s13075-016-1165-0","article-title":"Profibrotic mediators in tendon disease: A systematic review","volume":"18","author":"Morita","year":"2016","journal-title":"Arthritis Res. Ther."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2823","DOI":"10.1002\/jor.24064","article-title":"Effect of micro-RNA on tenocytes and tendon-related gene expression: A systematic review","volume":"36","author":"Dubin","year":"2018","journal-title":"J. Orthop. Res."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Kim, S.K., Roos, T.R., Roos, A.K., Kleimeyer, J.P., Ahmed, M.A., Goodlin, G.T., Fredericson, M., Ioannidis, J.P., Avins, A.L., and Dragoo, J.L. (2017). Genome-wide association screens for Achilles tendon and ACL tears and tendinopathy. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0170422"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2415","DOI":"10.1016\/j.ymthe.2017.07.015","article-title":"MicroRNA29a treatment improves early tendon injury","volume":"25","author":"Watts","year":"2017","journal-title":"Mol. Ther."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Sharma, A.K., Levian, B., Shah, P., Mosich, G.M., Husman, R., Arinello, A., Gatto, J.D., Hu, V.J., McClintick, D.J., and Jensen, A.R. (2019). Aged mice demonstrate greater muscle degeneration of chronically injured rotator cuff. J. Orthop. Res.","DOI":"10.1002\/jor.24468"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1302\/2046-3758.61.BJR-2016-0232.R1","article-title":"Inhibition of proly 4-hydroxylase decreases muscle fibrosis following chronic rotator cuff tear","volume":"6","author":"Gumucio","year":"2017","journal-title":"Bone Jt. Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1080\/03008207.2016.1189910","article-title":"Murine supraspinatus tendon injury model to identify the cellular origins of rotator cuff healing","volume":"57","author":"Yoishida","year":"2016","journal-title":"Connect. Tissue Res."},{"key":"ref_48","first-page":"331","article-title":"Perivascular stem cells diminish muscle atrophy following massive rotator cuff tears in a small animal model","volume":"99","author":"Eliasberg","year":"2017","journal-title":"J. Bone Joint. Am."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/22\/5742\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:34:49Z","timestamp":1760189689000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/22\/5742"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,11,15]]},"references-count":48,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2019,11]]}},"alternative-id":["ijms20225742"],"URL":"https:\/\/doi.org\/10.3390\/ijms20225742","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,11,15]]}}}