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Theranostics 2020; 10(20):9113-9131. doi:10.7150/thno.45993 This issue Cite

Research Paper

CircCDK14 protects against Osteoarthritis by sponging miR-125a-5p and promoting the expression of Smad2

Panyang Shen^1,2*, Yute Yang^1,2*, Gang Liu^1,2*, Weijie Chen^1,2, Junxing Chen^1,2, Qingxin Wang³, Hongliang Gao⁴, Shunwu Fan^1,2✉*, Shuying Shen^1,2✉*, Xing Zhao^1,2✉*

1. Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine.
2. Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province.
3. The Hospital of the Marine Police Corps of the Chinese people's Armed Police Force.
4. Departments of Orthopedics, Huzhou Central Hospital, Huzhou City, Zhejiang Province.
*These authors contributed equally to this work.

✉ Corresponding authors: Xing Zhao, Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine & Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, E-mail: zhaoxedu.cn; Shuying Shen, Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine & Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, E-mail: 11207057edu.cn; Shunwu Fan, Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine & Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, E-mail: 0099203edu.cn. More

Abstract

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-β 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.

Keywords: CircCDK14, Osteoarthritis, miR-125a-5p, Smad2, metabolism

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