CRTAC1 derived from senescent FLSs induces chondrocyte mitochondrial dysfunction <i>via</i> modulating NRF2/SIRT3 axis in osteoarthritis progression.

Xiang CHEN; Wang GONG; Pan ZHANG; Chengzhi WANG; Bin LIU; Xiaoyan SHAO; Yi HE; Na LIU; Jiaquan LIN; Jianghui QIN; Qing JIANG; Baosheng GUO

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CRTAC1 derived from senescent FLSs induces chondrocyte mitochondrial dysfunction via modulating NRF2/SIRT3 axis in osteoarthritis progression.

Author: Xiang CHEN ¹ ; Wang GONG ¹ ; Pan ZHANG ¹ ; Chengzhi WANG ¹ ; Bin LIU ¹ ; Xiaoyan SHAO ¹ ; Yi HE ¹ ; Na LIU ¹ ; Jiaquan LIN ¹ ; Jianghui QIN ¹ ; Qing JIANG ¹ ; Baosheng GUO ¹
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1. Division of Sports Medicine and Adult Reconstructive Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China.
Publication Type:Journal Article
Keywords: Acetylation; CRTAC1; Cartilage degradation; FOXO3a; Mitochondrial dysfunction; Osteoarthritis (OA); SIRT3; Senescent FLS
From: Acta Pharmaceutica Sinica B 2025;15(11):5803-5816
CountryChina
Language:English
Abstract: Osteoarthritis (OA), the most prevalent joint disease of late life, is closely linked to cellular senescence. Previously, we found that the senescence of fibroblast-like synoviocytes (FLS) played an essential role in the degradation of cartilage. In this work, single-cell sequencing data further demonstrated that cartilage acidic protein 1 (CRTAC1) is a critical secreted factor of senescent FLS, which suppresses mitophagy and induces mitochondrial dysfunction by regulating SIRT3 expression. In vivo, deletion of SIRT3 in chondrocytes accelerated cartilage degradation and aggravated the progression of OA. Oppositely, intra-articular injection of adeno-associated virus expressing SIRT3 effectively alleviated OA progression in mice. Mechanistically, we demonstrated that elevated CRTAC1 could bind with NRF2 in chondrocytes, which subsequently suppresses the transcription of SIRT3 in vitro. In addition, SIRT3 reduction could promote the acetylation of FOXO3a and result in mitochondrial dysfunction, which finally contributes to the degradation of chondrocytes. To conclude, this work revealed the critical role and underlying mechanism of senescent FLSs-derived CRTAC1 in OA progression, which provided a potential strategy for the OA therapy.