Long noncoding RNA GCH1 mediates mitophagy via the PTEN-induced kinase 1/Parkin pathway to drive chondrocyte dysfunction and cartilage degeneration in osteoarthritis

Abstract

Background: Osteoarthritis (OA) is a common degenerative joint disease characterized by the progressive degradation of articular cartilage. Mitochondrial dysfunction and autophagy, including mitophagy, have been implicated in OA pathogenesis. Long noncoding RNAs (lncRNA) are emerging as key regulators in various cellular processes, but their roles in OA, particularly in chondrocytes, remain poorly understood. This study explores the involvement of lncRNA-GCH1 in regulating mitophagy and its impact on chondrocyte function and cartilage degradation in OA.

Methods: Primary chondrocytes were isolated from the cartilage tissues of OA patients and healthy controls. lncRNA-GCH1 expression was assessed using RNA-seq, reverse transcription quantitative polymerase chain reaction, and RNA fluorescence in situ hybridization. Functional assays, including Cell Counting Kit-8 (CCK-8), colony formation, flow cytometry, and Western blotting, were used to evaluate the effects of lncRNA-GCH1 knockdown on chondrocyte proliferation, apoptosis, cell cycle, and mitophagy. Mitochondrial function was assessed by measuring adenosine triphosphate production, reactive oxygen species levels, and mitochondrial membrane potential. In vivo, a murine OA model was used to examine the impact of lncRNA-GCH1 knockdown on cartilage degradation.

Results: lncRNA-GCH1 was upregulated in OA chondrocytes and localized in the cytoplasm. Knockdown of lncRNA-GCH1 enhanced cell proliferation and arrested cell cycle in G0/G1. It also suppressed mitophagy, improved mitochondrial function, and reduced matrix-degrading enzyme expression—effects that were reversed by rapamycin treatment. Meanwhile, lncRNA-GCH1 knockdown reduced PTEN-induced kinase 1 (PINK1) aggregation and in vivo local inhibition of PINK1 diminished cartilage degradation.

Conclusion: lncRNA-GCH1 regulates mitophagy in OA chondrocytes, influencing mitochondrial function and matrix degradation. Targeting lncRNA-GCH1 may offer a potential therapeutic approach for OA treatment.

Keywords

lncRNA-GCH1 / mitophagy / osteoarthritis / PTEN-induced kinase 1 (PINK1)-Parkin axis

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2025 The Author(s). Animal Models and Experimental Medicine published by John Wiley & Sons Australia, Ltd on behalf of The Chinese Association for Laboratory Animal Sciences.