PMID- 32802182 OWN - NLM STAT- MEDLINE DCOM- 20210601 LR - 20210601 IS - 1838-7640 (Electronic) IS - 1838-7640 (Linking) VI - 10 IP - 20 DP - 2020 TI - CircCDK14 protects against Osteoarthritis by sponging miR-125a-5p and promoting the expression of Smad2. PG - 9113-9131 LID - 10.7150/thno.45993 [doi] AB - Rationale: Osteoarthritis (OA) is the most common joint disease worldwide. Previous studies have identified the imbalance between extracellular matrix (ECM) catabolism and anabolism in cartilage tissue as the main cause. To date, there is no cure for OA despite a few symptomatic treatments. This study aimed to investigate the role of CircCDK14, a novel circRNA factor, in the progression of OA, and to elucidate its underlying molecular mechanisms. Methods: The function of CircCDK14 in OA, as well as the interaction between CircCDK14 and its downstream target (miR-125a-5p) and mRNA target (Smad2), was evaluated by western blot (WB), immunofluorescence (IF), RNA immunoprecipitation (RIP), quantitative RT-PCR, luciferase assay and fluorescence in situ hybridization (FISH). Rabbit models were introduced to examine the function and mechanism of CircCDK14 in OA in vivo. Results: In our present study, we found that CircCDK14, while being down-regulated in the joint wearing position, regulated metabolism, inhibited apoptosis and promoted proliferation in the cartilage. Mechanically, the protective effect of CircCDK14 was mediated by miR-125a-5p sponging, which downregulated the Smad2 expression and led to the dysfunction of TGF-beta signaling pathway. Intra-articular injection of adeno-associated virus-CircCDK14 also alleviated OA in the rabbit model. Conclusion: Our study revealed an important role of CircCDK14/miR-125a-5p/Smad2 axis in OA progression and provided a potential molecular therapeutic strategy for the treatment of OA. CI - (c) The author(s). FAU - Shen, Panyang AU - Shen P AD - Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine. AD - Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province. FAU - Yang, Yute AU - Yang Y AD - Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine. AD - Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province. FAU - Liu, Gang AU - Liu G AD - Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine. AD - Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province. FAU - Chen, Weijie AU - Chen W AD - Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine. AD - Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province. FAU - Chen, Junxing AU - Chen J AD - Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine. AD - Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province. FAU - Wang, Qingxin AU - Wang Q AD - The Hospital of the Marine Police Corps of the Chinese people's Armed Police Force. FAU - Gao, Hongliang AU - Gao H AD - Departments of Orthopedics, Huzhou Central Hospital, Huzhou City, Zhejiang Province. FAU - Fan, Shunwu AU - Fan S AD - Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine. AD - Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province. FAU - Shen, Shuying AU - Shen S AD - Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine. AD - Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province. FAU - Zhao, Xing AU - Zhao X AD - Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine. AD - Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20200711 PL - Australia TA - Theranostics JT - Theranostics JID - 101552395 RN - 0 (MIRN125 microRNA, human) RN - 0 (MicroRNAs) RN - 0 (RNA, Circular) RN - 0 (SMAD2 protein, human) RN - 0 (Smad2 Protein) RN - 0 (Transforming Growth Factor beta) RN - EC 2.7.11.22 (CDK14 protein, human) RN - EC 2.7.11.22 (Cyclin-Dependent Kinases) SB - IM MH - Animals MH - Apoptosis/physiology MH - Cartilage/metabolism MH - Cell Proliferation/physiology MH - Chondrocytes/metabolism MH - Cyclin-Dependent Kinases/*metabolism MH - Disease Models, Animal MH - Disease Progression MH - Down-Regulation/physiology MH - Extracellular Matrix/metabolism MH - Humans MH - In Situ Hybridization, Fluorescence/methods MH - Male MH - MicroRNAs/*metabolism MH - Osteoarthritis/*metabolism MH - RNA, Circular/*metabolism MH - Rabbits MH - Signal Transduction/physiology MH - Smad2 Protein/*metabolism MH - Transforming Growth Factor beta/metabolism PMC - PMC7415803 OTO - NOTNLM OT - CircCDK14 OT - Osteoarthritis OT - Smad2 OT - metabolism OT - miR-125a-5p COIS- Competing Interests: The authors have declared that no competing interest exists. EDAT- 2020/08/18 06:00 MHDA- 2021/06/02 06:00 PMCR- 2020/01/01 CRDT- 2020/08/18 06:00 PHST- 2020/03/13 00:00 [received] PHST- 2020/06/28 00:00 [accepted] PHST- 2020/08/18 06:00 [entrez] PHST- 2020/08/18 06:00 [pubmed] PHST- 2021/06/02 06:00 [medline] PHST- 2020/01/01 00:00 [pmc-release] AID - thnov10p9113 [pii] AID - 10.7150/thno.45993 [doi] PST - epublish SO - Theranostics. 2020 Jul 11;10(20):9113-9131. doi: 10.7150/thno.45993. eCollection 2020.