{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T16:36:23Z","timestamp":1788280583869,"version":"build-2803163510"},"reference-count":45,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2018,3,12]],"date-time":"2018-03-12T00:00:00Z","timestamp":1520812800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the Bio &amp; Medical Technology Development Program of the NRF funded by the Korean government, MSIP","award":["NRF-2017M3A9B3063640"],"award-info":[{"award-number":["NRF-2017M3A9B3063640"]}]},{"name":"the Bio &amp; Medical Technology Development Program of the NRF funded by the Korean government, MSIP","award":["NRF-2017M3A9F5030273"],"award-info":[{"award-number":["NRF-2017M3A9F5030273"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Tendon rupture induces an inflammatory response characterized by release of pro-inflammatory cytokines and impaired tendon performance. This study sought to investigate the therapeutic effects of simvastatin-loaded porous microspheres (SIM\/PMSs) on inflamed tenocytes in vitro and collagenase-induced Achilles tendinitis in vivo. The treatment of SIM\/PMSs in lipopolysaccharide (LPS)-treated tenocytes reduced the mRNA expressions of pro-inflammatory cytokines (Matrix metalloproteinase-3 (MMP-3), cyclooxygenase-2 (COX-2), interleukin-6 (IL-6), and tumor necrosis factor-\u03b1 (TNF-\u03b1)). In addition, the local injection of SIM\/PMSs into the tendons of collagenase-induced Achilles tendinitis rat models suppressed pro-inflammatory cytokines (MMP-3, COX-2, IL-6, TNF-\u03b1, and MMP-13). This local treatment also upregulated anti-inflammatory cytokines (IL-4, IL-10, and IL-13). Furthermore, treatment with SIM\/PMSs also improved the alignment of collagen fibrils and effectively prevented collagen disruption in a dose-dependent manner. Therefore, SIM\/PMSs treatment resulted in an incremental increase in the collagen content, stiffness, and tensile strength in tendons. This study suggests that SIM\/PMSs have great potential for tendon healing and restoration in Achilles tendinitis.<\/jats:p>","DOI":"10.3390\/ijms19030820","type":"journal-article","created":{"date-parts":[[2018,3,12]],"date-time":"2018-03-12T13:13:48Z","timestamp":1520860428000},"page":"820","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["Exploring the In Vivo Anti-Inflammatory Actions of Simvastatin-Loaded Porous Microspheres on Inflamed Tenocytes in a Collagenase-Induced Animal Model of Achilles Tendinitis"],"prefix":"10.3390","volume":"19","author":[{"given":"Chandong","family":"Jeong","sequence":"first","affiliation":[{"name":"Department of Orthopedic Surgery and Rare Diseases Institute, Korea University College of Medicine, Guro Hospital, Guro-dong, Guro-gu, Seoul 08308, Korea"},{"name":"Department of Biomedical Science, Korea University College of Medicine, Anam-dong, Seongbuk-gu, Seoul 02841, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sung","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery and Rare Diseases Institute, Korea University College of Medicine, Guro Hospital, Guro-dong, Guro-gu, Seoul 08308, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyu-Sik","family":"Shim","sequence":"additional","affiliation":[{"name":"Department of Biomedical Science, Korea University College of Medicine, Anam-dong, Seongbuk-gu, Seoul 02841, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hak-Jun","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery and Rare Diseases Institute, Korea University College of Medicine, Guro Hospital, Guro-dong, Guro-gu, Seoul 08308, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mi","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery and Rare Diseases Institute, Korea University College of Medicine, Guro Hospital, Guro-dong, Guro-gu, Seoul 08308, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3625-4128","authenticated-orcid":false,"given":"Kyeongsoon","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Systems Biotechnology, Chung-Ang University, Anseong, Gyeonggi-do 17546, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hae-Ryong","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery and Rare Diseases Institute, Korea University College of Medicine, Guro Hospital, Guro-dong, Guro-gu, Seoul 08308, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2018,3,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.4055\/cios.2015.7.1.1","article-title":"Achilles tendinosis: Treatment options","volume":"7","author":"Lopez","year":"2015","journal-title":"Clin. Orthop. Surg."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"840","DOI":"10.1016\/S0749-8063(98)70021-0","article-title":"Overuse tendon conditions: Time to change a confusing terminology","volume":"14","author":"Maffulli","year":"1998","journal-title":"Arthroscopy"},{"key":"ref_3","first-page":"187","article-title":"Tendon injury and tendinopathy: Healing and repair","volume":"87","author":"Sharma","year":"2005","journal-title":"J. Bone Jt.  Surg. Am."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1016\/j.cardiores.2005.12.002","article-title":"Structure and function of matrix metalloproteinases and timps","volume":"69","author":"Nagase","year":"2006","journal-title":"Cardiovasc. Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1113\/jphysiol.2003.046094","article-title":"Cyclo-oxygenase-2 mediated prostaglandin release regulates blood flow in connective tissue during mechanical loading in humans","volume":"551","author":"Langberg","year":"2003","journal-title":"J. Physiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1111\/j.1600-0838.2010.01265.x","article-title":"The role of pro-inflammatory and immunoregulatory cytokines in tendon healing and rupture: New insights","volume":"21","author":"Wiegand","year":"2011","journal-title":"Scand. J. Med. Sci. Sports"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1136\/bmj.316.7128.333","article-title":"Quantitative systematic review of topically applied non-steroidal anti-inflammatory drugs","volume":"316","author":"Moore","year":"1998","journal-title":"BMJ"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1111\/j.1600-0838.2007.00746.x","article-title":"Chronic tendinopathy tissue pathology, pain mechanisms, and etiology with a special focus on inflammation","volume":"18","author":"Fredberg","year":"2008","journal-title":"Scand. J. Med. Sci. Sports"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1016\/S0140-6736(02)07811-X","article-title":"Corticosteroid injections, physiotherapy, or a wait-and-see policy for lateral epicondylitis: A randomised controlled trial","volume":"359","author":"Smidt","year":"2002","journal-title":"Lancet"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1093\/toxsci\/kfv239","article-title":"Prevention of simvastatin-induced inhibition of tendon cell proliferation and cell cycle progression by geranylgeranyl pyrophosphate","volume":"149","author":"Tsai","year":"2016","journal-title":"Toxicol. Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2582745","DOI":"10.1155\/2017\/2582745","article-title":"Statins reduce lipopolysaccharide-induced cytokine and inflammatory mediator release in an in vitro model of microglial-like cells","volume":"2017","author":"McFarland","year":"2017","journal-title":"Med. Inflamm."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"983","DOI":"10.1016\/S0140-6736(98)05917-0","article-title":"Inhibition of proinflammatory cytokine production by pravastatin","volume":"353","author":"Rosenson","year":"1999","journal-title":"Lancet"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"994","DOI":"10.1111\/j.1582-4934.2010.01036.x","article-title":"Statins potently reduce the cytokine-mediated IL-6 release in SMC\/MNC cocultures","volume":"15","author":"Loppnow","year":"2011","journal-title":"J. Cell. Mol. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/S0735-1097(01)01360-2","article-title":"Long-term risk stratification for survivors of acute coronary syndromes. Results from the long-term intervention with pravastatin in ischemic disease (lipid) study. Lipid study investigators","volume":"38","author":"Marschner","year":"2001","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1016\/S1297-319X(02)00389-5","article-title":"Statins and muscles: What price glory?","volume":"69","author":"Hayem","year":"2002","journal-title":"Jt. Bone Spine"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1606","DOI":"10.1016\/j.amjcard.2008.01.041","article-title":"Review of side-effect profile of combination ezetimibe and statin therapy in randomized clinical trials","volume":"101","author":"Kashani","year":"2008","journal-title":"Am. J. Cardiol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Eliasson, P., Svensson, R.B., Giannopoulos, A., Eismark, C., Kjaer, M., Schjerling, P., and Heinemeier, K.M. (2017). Simvastatin and atorvastatin reduce the mechanical properties of tendon constructs in vitro and introduce catabolic changes in the gene expression pattern. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0172797"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1016\/j.colsurfb.2015.05.003","article-title":"Fabrication of a BMP-2-immobilized porous microsphere modified by heparin for bone tissue engineering","volume":"134","author":"Kim","year":"2015","journal-title":"Coll. Surf. B Biointerfaces"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/j.colsurfb.2016.07.050","article-title":"Ibuprofen-loaded porous microspheres suppressed the progression of monosodium iodoacetate-induced osteoarthritis in a rat model","volume":"147","author":"Park","year":"2016","journal-title":"Coll. Surf. B Biointerfaces"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1016\/j.jiec.2017.03.057","article-title":"Osteogenesis and new bone formation of alendronate-immobilized porous plga microspheres in a rat calvarial defect model","volume":"52","author":"Lee","year":"2017","journal-title":"J. Ind. Eng. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.jiec.2017.09.016","article-title":"In vitro and in vivo anti-inflammatory and tendon-healing effects in achilles tendinopathy of long-term curcumin delivery using porous microspheres","volume":"58","author":"Kim","year":"2018","journal-title":"J. Ind. Eng. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Hollinger, J.O., and Battistone, G.C. (1986). Biodegradable bone repair materials. Synthetic polymers and ceramics. Clin. Orthop. Relat. Res., 290\u2013305.","DOI":"10.1097\/00003086-198606000-00046"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1016\/S0278-5919(03)00004-8","article-title":"Types and epidemiology of tendinopathy","volume":"22","author":"Maffulli","year":"2003","journal-title":"Clin. Sports Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1212","DOI":"10.1016\/S0735-1097(97)00324-0","article-title":"HMG-CoA reductase inhibitors decrease CD11b expression and CD11b-dependent adhesion of monocytes to endothelium and reduce increased adhesiveness of monocytes isolated from patients with hypercholesterolemia","volume":"30","author":"Weber","year":"1997","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1016\/0735-1097(95)80006-3","article-title":"Disease-free intervals after partial ileal bypass in patients with coronary heart disease and hypercholesterolemia: Report from the program on the surgical control of the hyperlipidemias (posch)","volume":"26","author":"Buchwald","year":"1995","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1097\/MJT.0000000000000039","article-title":"Is statin use associated with tendon rupture? A population-based retrospective cohort analysis","volume":"22","author":"Contractor","year":"2015","journal-title":"Am. J. Ther."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1097\/FJC.0b013e3181a0ce8b","article-title":"Association between statin therapy and tendon rupture: A case-control study","volume":"53","author":"Beri","year":"2009","journal-title":"J. Cardiovasc. Pharmacol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2126","DOI":"10.1177\/0363546515588173","article-title":"The effect of diabetes, hyperlipidemia, and statins on the development of rotator cuff disease: A nationwide, 11-year, longitudinal, population-based follow-up study","volume":"43","author":"Lin","year":"2015","journal-title":"Am. J. Sports Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2869","DOI":"10.1177\/0363546514545856","article-title":"Statins enhance rotator cuff healing by stimulating the COX2\/PGE2\/EP4 pathway: An in vivo and in vitro study","volume":"42","author":"Dolkart","year":"2014","journal-title":"Am. J. Sports Med."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Hoffman, K.B., Kraus, C., Dimbil, M., and Golomb, B.A. (2012). A survey of the FDA\u2019s AERS database regarding muscle and tendon adverse events linked to the statin drug class. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0042866"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.fct.2014.12.014","article-title":"Structural and biomechanical changes in the achilles tendon after chronic treatment with statins","volume":"77","author":"Vieira","year":"2015","journal-title":"Food Chem. Toxicol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1002\/art.23309","article-title":"Network of the French Pharmacovigilance Centers. Tendinous disorders attributed to statins: A study on ninety-six spontaneous reports in the period 1990\u20132005 and review of the literature","volume":"59","author":"Marie","year":"2008","journal-title":"Arthritis Rheum."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1016\/S0736-0266(02)00141-9","article-title":"IL-1 beta induces COX2, MMP-1, -3 and -13, ADAMTS-4, IL-1 beta and IL-6 in human tendon cells","volume":"21","author":"Tsuzaki","year":"2003","journal-title":"J. Orthop. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1071","DOI":"10.1002\/jor.21079","article-title":"Effect of pro-inflammatory and immunoregulatory cytokines on human tenocytes","volume":"28","author":"John","year":"2010","journal-title":"J. Orthop. Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1016\/S0192-0561(96)00068-9","article-title":"Inhibitory effect of fluvastatin, an hmg-coa reductase inhibitor, on the expression of adhesion molecules on human monocyte cell line","volume":"18","author":"Niwa","year":"1996","journal-title":"Int. J. Immunopharmacol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1760","DOI":"10.1161\/01.CIR.101.15.1760","article-title":"Hydroxymethylglutaryl coenzyme a reductase inhibitors modify the inflammatory response of human macrophages and endothelial cells infected with chlamydia pneumoniae","volume":"101","author":"Kothe","year":"2000","journal-title":"Circulation"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1161\/01.ATV.0000068646.76823.AE","article-title":"Statins inhibit secretion of metalloproteinases-1, -2, -3, and -9 from vascular smooth muscle cells and macrophages","volume":"23","author":"Luan","year":"2003","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1302\/2046-3758.36.2000281","article-title":"The role of animal models in tendon research","volume":"3","author":"Hast","year":"2014","journal-title":"Bone Jt. Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"64","DOI":"10.2460\/ajvr.1998.59.01.64","article-title":"Effects of training on collagen fibril populations in the suspensory ligament and deep digital flexor tendon of young thoroughbreds","volume":"59","author":"Firth","year":"1998","journal-title":"Am. J. Vet. Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"211","DOI":"10.3389\/fnagi.2015.00211","article-title":"Mechanical stimulation (pulsed electromagnetic fields \u201cpemf\u201d and extracorporeal shock wave therapy \u201ceswt\u201d) and tendon regeneration: A possible alternative","volume":"7","author":"Rosso","year":"2015","journal-title":"Front. Aging Neurosci."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1007\/s00264-007-0398-6","article-title":"Stimulation of tendon repair: Mechanical loading, gdfs and platelets. A mini-review","volume":"31","author":"Aspenberg","year":"2007","journal-title":"Int. Orthop."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1843","DOI":"10.1016\/j.jhsa.2008.07.020","article-title":"Effect of interleukin-10 overexpression on the properties of healing tendon in a murine patellar tendon model","volume":"33","author":"Ricchetti","year":"2008","journal-title":"J. Hand Surg. Am."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1016\/j.coph.2013.05.013","article-title":"Changes in macrophage phenotype as the immune response evolves","volume":"13","author":"Lichtnekert","year":"2013","journal-title":"Curr. Opin. Pharmacol."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Jeong, Y.J., Kim, I., Cho, J.H., Park, D.W., Kwon, J.E., Jung, M.W., Meng, X., Jo, S.M., Song, H.S., and Cho, Y.M. (2015). Anti-osteoarthritic effects of the litsea japonica fruit in a rat model of osteoarthritis induced by monosodium iodoacetate. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0134856"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1089\/rej.2013.1439","article-title":"Treatment with simiaofang, an anti-arthritis chinese herbal formula, inhibits cartilage matrix degradation in osteoarthritis rat model","volume":"16","author":"Xu","year":"2013","journal-title":"Rejuvenation Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/3\/820\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T14:56:41Z","timestamp":1760194601000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/3\/820"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,3,12]]},"references-count":45,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2018,3]]}},"alternative-id":["ijms19030820"],"URL":"https:\/\/doi.org\/10.3390\/ijms19030820","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,3,12]]}}}