{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T03:53:15Z","timestamp":1793332395996,"version":"4.5.0"},"reference-count":39,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,4,9]],"date-time":"2021-04-09T00:00:00Z","timestamp":1617926400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100017053","name":"NSFC-Xinjiang Joint Fund","doi-asserted-by":"publisher","award":["81860746 81760398 82060411 2018D01C187 U1503221"],"award-info":[{"award-number":["81860746 81760398 82060411 2018D01C187 U1503221"]}],"id":[{"id":"10.13039\/100017053","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>Osteoarthritis (OA) is a degenerative joint disease with multiple etiologies that affects individuals worldwide. No effective interventions are currently available to reverse the pathological process of OA. Sodium butyrate (NaB), a component of short-chain fatty acids (SCFAs), has multiple biological activities, including the attenuation of inflammation and anti-tumor activities in various diseases. However, whether the protective effects of NaB in OA are associated with the promotion of autophagy had not been investigated. Here, we explored the chondroprotective properties of NaB in an interleukin (IL)-1\u03b2-induced inflammatory chondrocyte model and an anterior cruciate ligament transection (ACLT) mouse model. Hematoxylin and eosin (HE), Safranin O, and immunohistochemical staining were performed to evaluate the effects of NaB treatment on articular cartilage. An optimal NaB dose for chondrocyte treatment was determined <jats:italic>via<\/jats:italic> cell counting kit-8 assays. Immunofluorescence and transmission electron microscopy were used to detect autophagy in chondrocytes. Flow cytometry was utilized to detect reactive oxygen species (ROS), cell cycle activity, and apoptosis in chondrocytes. Western blot and immunostaining were performed to evaluate the protein expression levels of relevant indicators. We found that the administration of NaB by oral gavage could attenuate cartilage degradation. In parallel, NaB treatment could enhance the activation of autophagy, increase autophagic flux, decrease extracellular matrix degradation, and reduce apoptosis by restraining inflammation, ROS production, and cell cycle arrest in IL-1\u03b2-treated chondrocytes. The protective effects of NaB could be partially abolished by the autophagy inhibitor 3-methyladenine (3-MA), which indicated that the protective effects of NaB against OA were partially governed by the enhancement of autophagy to restrain the formation of inflammatory mediators and ROS and regulate cell cycle progression and apoptosis in chondrocytes. In conclusion, NaB could attenuate OA progression by restoring impaired autophagy and autophagic flux <jats:italic>via<\/jats:italic> the phosphoinositide 3-kinase (PI3K)\/protein kinase B (Akt)\/mammalian target of rapamycin (mTOR) pathway, both <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic>, implying that NaB could represent a novel therapeutic approach for OA.<\/jats:p>","DOI":"10.3389\/fphar.2021.659597","type":"journal-article","created":{"date-parts":[[2021,4,9]],"date-time":"2021-04-09T05:44:20Z","timestamp":1617947060000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":33,"title":["Microbial Metabolite Sodium Butyrate Attenuates Cartilage Degradation by Restoring Impaired Autophagy and Autophagic Flux in Osteoarthritis Development"],"prefix":"10.3389","volume":"12","author":[{"given":"Haikang","family":"Zhou","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guoqing","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rendong","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yicheng","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huhu","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hairong","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Cao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,4,9]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"631","DOI":"10.1007\/s10495-010-0458-z","article-title":"Cell death of chondrocytes is a combination between apoptosis and autophagy during the pathogenesis of osteoarthritis within an experimental model","volume":"15","author":"Almonte-Becerril","year":"2010","journal-title":"Apoptosis"},{"key":"B2","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1038\/nrrheum.2015.12","article-title":"Activate autophagy to prevent cartilage degeneration?","volume":"11","author":"Barranco","year":"2015","journal-title":"Nat. Rev. Rheumatol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"e001037","DOI":"10.1136\/rmdopen-2019-001037","article-title":"Cartilage-gut-microbiome axis: a new paradigm for novel therapeutic opportunities in osteoarthritis","volume":"5","author":"Berthelot","year":"2019","journal-title":"RMD Open"},{"key":"B4","doi-asserted-by":"publisher","first-page":"1099","DOI":"10.1016\/j.biopha.2018.03.062","article-title":"Sodium butyrate abolishes the degradation of type II collagen in human chondrocytes","volume":"102","author":"Bo","year":"2018","journal-title":"Biomed. Pharmacother."},{"key":"B5","doi-asserted-by":"publisher","first-page":"4881","DOI":"10.1038\/s41467-019-12873-4","article-title":"Intestinal microbiome composition and its relation to joint pain and inflammation","volume":"10","author":"Boer","year":"2019","journal-title":"Nat. Commun."},{"key":"B6","doi-asserted-by":"publisher","first-page":"883","DOI":"10.1016\/j.cmet.2015.05.016","article-title":"AMPK activation of muscle autophagy prevents fasting-induced hypoglycemia and myopathy during aging","volume":"21","author":"Bujak","year":"2015","journal-title":"Cel Metab."},{"key":"B7","doi-asserted-by":"publisher","first-page":"1331","DOI":"10.1016\/S0140-6736(11)60752-6","article-title":"Knee replacement","volume":"379","author":"Carr","year":"2012","journal-title":"Lancet"},{"key":"B8","doi-asserted-by":"publisher","first-page":"1224","DOI":"10.3892\/ijmm.2017.2934","article-title":"Role of autophagy in the progression of osteoarthritis: the autophagy inhibitor, 3-methyladenine, aggravates the severity of experimental osteoarthritis","volume":"39","author":"Cheng","year":"2017","journal-title":"Int. J. Mol. Med."},{"key":"B9","doi-asserted-by":"publisher","first-page":"S17","DOI":"10.1016\/j.joca.2010.05.025","article-title":"The OARSI histopathology initiative-recommendations for histological assessments of osteoarthritis in the mouse","volume":"18","author":"Glasson","year":"2010","journal-title":"Osteoarthritis Cartilage"},{"key":"B10","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1016\/j.joca.2008.05.009","article-title":"Diminished mitochondrial DNA integrity and repair capacity in OA chondrocytes","volume":"17","author":"Grishko","year":"2009","journal-title":"Osteoarthritis Cartilage"},{"key":"B11","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1016\/j.mam.2015.08.002","article-title":"AMPK and autophagy in glucose\/glycogen metabolism","volume":"46","author":"Ha","year":"2015","journal-title":"Mol. Aspects Med."},{"key":"B12","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1016\/j.bbrc.2019.04.111","article-title":"Sodium butyrate induces autophagic apoptosis of nasopharyngeal carcinoma cells by inhibiting Akt\/mTOR signaling","volume":"514","author":"Huang","year":"2019","journal-title":"Biochem. Biophy. Res. Commun."},{"key":"B13","doi-asserted-by":"publisher","first-page":"1745","DOI":"10.1016\/S0140-6736(19)30417-9","article-title":"Osteoarthritis","volume":"393","author":"Hunter","year":"2019","journal-title":"Lancet"},{"key":"B14","doi-asserted-by":"publisher","first-page":"26035","DOI":"10.3390\/ijms161125943","article-title":"Chondrocyte apoptosis in the pathogenesis of osteoarthritis","volume":"16","author":"Hwang","year":"2015","journal-title":"Int. J. Mol. Sci."},{"key":"B15","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1038\/s41584-018-0123-4","article-title":"Intra-articular treatment options for knee osteoarthritis","volume":"15","author":"Jones","year":"2019","journal-title":"Nat. Rev. Rheumatol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"474","DOI":"10.1016\/j.semarthrit.2019.05.007","article-title":"A cross talk between dysbiosis and gut-associated immune system governs the development of inflammatory arthropathies","volume":"49","author":"Kalinkovich","year":"2019","journal-title":"Semin. Arthritis Rheum."},{"key":"B17","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1080\/15548627.2016.1147886","article-title":"Guidelines for the use and interpretation of assays for monitoring autophagy(3rd edition)","volume":"12","author":"Klionsky","year":"2016","journal-title":"Autophagy"},{"key":"B18","doi-asserted-by":"publisher","first-page":"1767","DOI":"10.1172\/JCI133473","article-title":"Parathyroid hormone-dependent bone formation requires butyrate production by intestinal microbiota","volume":"130","author":"Li","year":"2020","journal-title":"J. Clin. Invest."},{"key":"B19","doi-asserted-by":"publisher","first-page":"1257","DOI":"10.1016\/j.joca.2019.05.009","article-title":"Gut microbiota and obesity-associated osteoarthritis","volume":"27","author":"Liu","year":"2019","journal-title":"Osteoarthritis Cartilage"},{"key":"B20","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1038\/s41467-017-02490-4","article-title":"Short-chain fatty acids regulate systemic bone mass and protect from pathological bone loss","volume":"9","author":"Lucas","year":"2018","journal-title":"Nat. Commun."},{"key":"B21","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1159\/000070573","article-title":"Pathophysiological mechanisms in osteoarthritis lead to novel therapeutic strategies","volume":"174","author":"Malemud","year":"2003","journal-title":"Cells Tissues Organs"},{"key":"B22","doi-asserted-by":"publisher","first-page":"1069","DOI":"10.1038\/nature06639","article-title":"Autophagy fights disease through cellular self-digestion","volume":"451","author":"Mizushima","year":"2008","journal-title":"Nature"},{"key":"B23","doi-asserted-by":"publisher","first-page":"269","DOI":"10.3389\/fphar.2018.00269","article-title":"Halofuginone attenuates osteoarthritis by rescuing bone remodeling in subchondral bone through oral gavage","volume":"9","author":"Mu","year":"2018","journal-title":"Front. Pharmacol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1016\/j.micpath.2018.03.021","article-title":"Gut microbiota and mTOR signaling: insight on a new pathophysiological interaction","volume":"118","author":"Noureldein","year":"2018","journal-title":"Microb. Pathog."},{"key":"B25","doi-asserted-by":"publisher","first-page":"228","DOI":"10.1159\/000495203","article-title":"Butyrate modulates inflammation in chondrocytes via GPR43 receptor","volume":"51","author":"Pirozzi","year":"2018","journal-title":"Cell Physiol Biochem."},{"key":"B26","doi-asserted-by":"publisher","first-page":"531","DOI":"10.1016\/j.semarthrit.2014.10.012","article-title":"Socio-economic costs of osteoarthritis: a systematic review of cost-of-illness studies","volume":"44","author":"Puig-Junoy","year":"2015","journal-title":"Semin. Arthritis Rheum."},{"key":"B27","doi-asserted-by":"publisher","first-page":"1920","DOI":"10.1002\/art.34323","article-title":"Autophagy modulates osteoarthritis-related gene expression in human chondrocytes","volume":"64","author":"Sasaki","year":"2012","journal-title":"Arthritis Rheum."},{"key":"B28","doi-asserted-by":"publisher","first-page":"7","DOI":"10.4161\/auto.26679","article-title":"Boning up on autophagy: the role of autophagy in skeletal biology","volume":"10","author":"Shapiro","year":"2014","journal-title":"Autophagy"},{"key":"B29","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1016\/B978-0-12-800100-4.00003-9","article-title":"The role of short-chain fatty acids in health and disease","volume":"121","author":"Tan","year":"2014","journal-title":"Adv. Immunol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"1116","DOI":"10.1016\/j.immuni.2018.10.013","article-title":"The microbial metabolite butyrate stimulates bone formation via T regulatory cell-mediated regulation of WNT10B expression","volume":"49","author":"Tyagi","year":"2018","journal-title":"Immunity"},{"key":"B31","doi-asserted-by":"publisher","first-page":"3507","DOI":"10.1002\/jcb.23298","article-title":"ADAMTS-4 and ADAMTS-5: key enzymes in osteoarthritis","volume":"112","author":"Verma","year":"2011","journal-title":"J. Cel. Biochem."},{"key":"B32","doi-asserted-by":"publisher","first-page":"1252","DOI":"10.1016\/j.biopha.2017.01.130","article-title":"Inhibition of PI3K\/Akt\/mTOR signaling pathway promotes autophagy of articular chondrocytes and attenuates inflammatory response in rats with osteoarthritis","volume":"89","author":"Xue","year":"2017","journal-title":"Biomed. Pharmacother."},{"key":"B33","doi-asserted-by":"publisher","first-page":"666","DOI":"10.1038\/cr.2007.64","article-title":"Expanding mTOR signaling","volume":"17","author":"Yang","year":"2007","journal-title":"Cell Res."},{"key":"B34","doi-asserted-by":"publisher","first-page":"3018","DOI":"10.1172\/JCI128521","article-title":"The gut-bone axis: how bacterial metabolites bridge the distance","volume":"129","author":"Zaiss","year":"2019","journal-title":"J. Clin. Invest."},{"key":"B35","doi-asserted-by":"publisher","first-page":"144","DOI":"10.1016\/j.jbspin.2014.10.003","article-title":"Role of HIF-1\u03b1 and HIF-2\u03b1 in osteoarthritis","volume":"82","author":"Zhang","year":"2015","journal-title":"Jt. Bone Spine"},{"key":"B36","doi-asserted-by":"publisher","first-page":"e0147218","DOI":"10.1371\/journal.pone.0147218","article-title":"Sodium butyrate induces endoplasmic reticulum stress and autophagy in colorectal cells: implications for apoptosis","volume":"11","author":"Zhang","year":"2016","journal-title":"Plos One"},{"key":"B37","doi-asserted-by":"publisher","first-page":"1432","DOI":"10.1136\/annrheumdis-2013-204599","article-title":"Cartilage-specific deletion of mTOR upregulates autophagy and protects mice from osteoarthritis","volume":"74","author":"Zhang","year":"2015","journal-title":"Ann. Rheum. Dis."},{"key":"B38","doi-asserted-by":"publisher","first-page":"858","DOI":"10.1038\/s41419-018-0909-y","article-title":"TFEB, a potential therapeutic target for osteoarthritis via autophagy regulation","volume":"9","author":"Zheng","year":"","journal-title":"Cell Death Dis"},{"key":"B39","doi-asserted-by":"publisher","first-page":"1454","DOI":"10.1039\/c7fo01892d","article-title":"Monascin inhibits IL-1\u03b2 induced catabolism in mouse chondrocytes and ameliorates murine osteoarthritis","volume":"9","author":"Zheng","year":"","journal-title":"Food Funct."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2021.659597\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,4,9]],"date-time":"2021-04-09T05:44:23Z","timestamp":1617947063000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2021.659597\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,9]]},"references-count":39,"alternative-id":["10.3389\/fphar.2021.659597"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2021.659597","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,9]]},"article-number":"659597"}}