The circUbqln1, regulated by XBP1s, interplays with 14-3-3ζ to inhibit collagen synthesis and promote osteoarthritis by controlling PRODH activity and proline metabolism

Naibo Feng; Yuanlan Ye; Yiming Pan; Biao Kuang; Yu Du; Nana Geng; Cheng Chen; Kaiwen Liu; Li Liang; Menglin Xian; Yuyou Yang; Xingyue Li; Lin Deng; Fengmei Zhang; Liang Kuang; Mengtian Fan; Yangli Xie; Fengjin Guo

doi:10.1016/j.jare.2024.01.007

The circUbqln1, regulated by XBP1s, interplays with 14-3-3ζ to inhibit collagen synthesis and promote osteoarthritis by controlling PRODH activity and proline metabolism

J Adv Res. 2024 Jan 12:S2090-1232(24)00007-9. doi: 10.1016/j.jare.2024.01.007. Online ahead of print.

Authors

Naibo Feng¹, Yuanlan Ye¹, Yiming Pan¹, Biao Kuang², Yu Du², Nana Geng¹, Cheng Chen³, Kaiwen Liu¹, Li Liang¹, Menglin Xian¹, Yuyou Yang¹, Xingyue Li¹, Lin Deng¹, Fengmei Zhang¹, Liang Kuang⁴, Mengtian Fan¹, Yangli Xie⁴, Fengjin Guo⁵

Affiliations

¹ State Key Laboratory of Ultrasound in Medicine and Engineering, School of Basic Medical Sciences, The Second Affiliated Hospital of Chongqing Medical University, Chongqing Medical University, Chongqing, China.
² Department of Orthopedics, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
³ Department of Orthopedics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
⁴ Department of Wound Repair and Rehabilitation Medicine, Center of Bone Metabolism and Repair (CBMR), State Key Laboratory of Trauma and Chemical Poisoning, Daping Hospital, Army Medical University, Chongqing, China.
⁵ State Key Laboratory of Ultrasound in Medicine and Engineering, School of Basic Medical Sciences, The Second Affiliated Hospital of Chongqing Medical University, Chongqing Medical University, Chongqing, China. Electronic address: guo.fengjin@cqmu.edu.cn.

PMID: 38219870
DOI: 10.1016/j.jare.2024.01.007

Abstract

Introduction: Osteoarthritis (OA) is a degenerative bone disease associated with ageing, characterized by joint pain, stiffness, swelling and deformation. Currently, pharmaceutical options for the clinical treatment of OA are very limited. Circular RNAs(cirRNAs) have garnered significant attention in OA and related drug development due to their unique RNA sequence characteristics.Therefore,exploring the role of cirRNAs in the occurrence and development of OA is of paramount importance for the development of effective medications for OA.

Objectives: To identify a novel circRNA, circUbqln1, for treating osteoarthritis and elucidate its pathophysiological role and mechanisms in the treatment of OA.

Methods: The circUbqln1 expression and distribution were determined by qRT-PCR and FISH. XBP1 gene knockout(XBP1 cKO) spontaneous OA and DMM model and WT mouse CIOA model were used to explore the role of XBP1 and circUbqln1 in OA.Overexpression or knockdown of circUbqln1 lentivirus was used to observe the impacts of circUbqln1 on primary chondrocytes,C28/I2 and mice in vitro and in vivo.Chromatin immunoprecipitation,luciferase reporter assay,RNA pulldown,mass spectrometry,RNA immunoprecipitation,fluorescence in situ hybridization,and flow cytometry to explore the molecular mechanisms of circUbqln1.

Results: It was found that cartilage-specific XBP1 cKO mice exhibited a faster OA progression compared to normal's.Importantly,transcript factor XBP1s has the capacity to impede the biogenesis of circUbqln1,derived from Ubqln1. The circUbqln1 promotes cartilage catabolism and inhibits anabolism, therefore accelerates the occurrence of OA.Mechanismly,circUbqln1 can translocate to the chondrocyte nucleus with the assistance of phosphorylated 14-3-3ζ, upregulate the transcriptional activity of the proline dehydrogenase(Prodh) promoter and PRODH enzyme activity. Consequently, this leads to the promotion of proline degradation and the inhibition of collagen synthesis,ultimately culminating in the impairment of cartilage and its structural integrity.

Conclusion: CircUbqln1 plays a crucial role in the occurrence and development of OA, indicating that the inhibition of circUbqln1 holds promise as a significant approach for treating OA in the future.

Keywords: Cartilage; Circubqln1; Osteoarthritis; PRODH; Proline; XBP1s.