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FBXO21 is a subunit of ubiquitin E3 ligases that degrades P\u2010glycoprotein and EID1 by ubiquitination and activates the JNK and p38 pathways; however, its role in OA remains unknown. Here, the main objective of this study was to evaluate the potential effects and mechanism of FBXO21 in OA degeneration, we revealed that FBXO21 is upregulated in the cartilage of patients with OA, aging, and monosodium iodoacetate\u2010induced OA rats, and chondrocytes treated with interleukin\u20101\u03b2, tumor necrosis factor\u2010\u03b1, and lipopolysaccharide. Moreover, the in vivo and in vitro knockdown of FBXO21 suppressed OA\u2010related cartilage degeneration, as evidenced by activated autophagy, upregulated anabolism, alleviated apoptosis, and downregulated catabolism. In contrast, its overexpression promoted OA\u2010related cartilage degeneration. In addition, using mass spectrometry and co\u2010immunoprecipitation assay, we demonstrated that the downstream mechanism of FBXO21 inhibits autophagy by interacting with and phosphorylating ERK. Furthermore, FBXO21 alleviated anabolism and enhanced apoptosis and catabolism by inhibiting autophagy in rat chondrocytes. Interestingly, for its upstream mechanism, JUNB promoted FBXO21 expression by directly targeting the FBXO21 promoter, thus further accelerating cartilage degeneration in SW1353 cells and rat chondrocytes. Overall, our findings reveal that the JUNB\u2010FBXO21\u2010ERK axis regulates OA apoptosis and cartilage matrix metabolism by inhibiting autophagy. Therefore, FBXO21 is an attractive target for regulating OA pathogenesis, and its knockdown may provide a novel targeted therapy for OA.<\/jats:p>","DOI":"10.1111\/acel.13306","type":"journal-article","created":{"date-parts":[[2021,1,16]],"date-time":"2021-01-16T00:40:19Z","timestamp":1610757619000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":96,"title":["JUNB\u2010FBXO21\u2010ERK axis promotes cartilage degeneration in osteoarthritis by inhibiting autophagy"],"prefix":"10.1111","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4494-7629","authenticated-orcid":false,"given":"Zhiming","family":"Lin","sequence":"first","affiliation":[{"name":"Department of Orthopedics Shengjing Hospital of China Medical University Shenyang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianing","family":"Miao","sequence":"additional","affiliation":[{"name":"Medical Research Center\/Liaoning Key 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University Shenyang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2215-345X","authenticated-orcid":false,"given":"Lunhao","family":"Bai","sequence":"additional","affiliation":[{"name":"Department of Orthopedics Shengjing Hospital of China Medical University Shenyang China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,1,15]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.4161\/auto.3424"},{"issue":"1","key":"e_1_2_9_3_1","first-page":"D87","article-title":"JASPAR 2020: Update of the open\u2010access database of transcription factor binding profiles","volume":"48","author":"Fornes O.","year":"2020","journal-title":"Nucleic Acids 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