2. Academic Validation
  3. Rspo2 exacerbates rheumatoid arthritis by targeting aggressive phenotype of fibroblast-like synoviocytes and disrupting chondrocyte homeostasis via Wnt/β-catenin pathway

Rspo2 exacerbates rheumatoid arthritis by targeting aggressive phenotype of fibroblast-like synoviocytes and disrupting chondrocyte homeostasis via Wnt/β-catenin pathway

  • Arthritis Res Ther. 2023 Nov 9;25(1):217. doi: 10.1186/s13075-023-03198-1.
Dong Guo # 1 2,  Haoyan Pan # 1 2,  Xueying Lu # 3,  Zhong Chen 4,  Laixi Zhou 5,  Shuxin Chen 5,  Jin Huang 5,  Xinzhi Liang 1 2,  Zhisheng Xiao 1 2,  Hua Zeng 1 2,  Yan Shao 1 2,  Weizhong Qi 6 7,  Denghui Xie 8 9,  Chuangxin Lin 10
Affiliations

Affiliations

  • 1 Department of Orthopedic Surgery, Center for Orthopedic Surgery, The Third Affiliated Hospital of Southern Medical University, Guangzhou, 510630, People's Republic of China.
  • 2 Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases, Guangzhou, 510630, People's Republic of China.
  • 3 Shenzhen Hospital of Beijing University of Chinese Medicine (Longgang), Shenzhen, 518100, People's Republic of China.
  • 4 Department of Orthopedics, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People's Republic of China.
  • 5 Department of Orthopedic Surgery, Shantou Central Hospital, Affiliated Shantou Hospital of Sun Yat-Sen University, Shantou, 515031, People's Republic of China.
  • 6 Department of Orthopedic Surgery, Center for Orthopedic Surgery, The Third Affiliated Hospital of Southern Medical University, Guangzhou, 510630, People's Republic of China. qiwz@smu.edu.cn.
  • 7 Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases, Guangzhou, 510630, People's Republic of China. qiwz@smu.edu.cn.
  • 8 Department of Orthopedic Surgery, Center for Orthopedic Surgery, The Third Affiliated Hospital of Southern Medical University, Guangzhou, 510630, People's Republic of China. smuspine@163.com.
  • 9 Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases, Guangzhou, 510630, People's Republic of China. smuspine@163.com.
  • 10 Department of Orthopedic Surgery, Shantou Central Hospital, Affiliated Shantou Hospital of Sun Yat-Sen University, Shantou, 515031, People's Republic of China. lin0604@126.com.
  • # Contributed equally.
PMID: 37946278 DOI: 10.1186/s13075-023-03198-1
Abstract

Background: The aggressive phenotype of fibroblast-like synoviocytes (FLS) has been identified as a contributing factor to the exacerbation of rheumatoid arthritis (RA) through the promotion of synovitis and cartilage damage. Regrettably, there is currently no effective therapeutic intervention available to address this issue. Recent research has shed LIGHT on the crucial regulatory role of R-spondin-2 (Rspo2) in cellular proliferation, cartilage degradation, and tumorigenesis. However, the specific impact of Rspo2 on RA remains poorly understood. We aim to investigate the function and mechanism of Rspo2 in regulating the aggressive phenotype of FLS and maintaining chondrocyte homeostasis in the context of RA.

Methods: The expression of Rspo2 in knee joint synovium and cartilage were detected in RA mice with antigen-induced arthritis (AIA) and RA patients. Recombinant mouse Rspo2 (rmRspo2), Rspo2 neutralizing antibody (Rspo2-NAb), and recombinant mouse DKK1 (rmDKK1, a potent inhibitor of Wnt signaling pathway) were used to explore the role and mechanism of Rspo2 in the progression of RA, specifically in relation to the aggressive phenotype of FLS and chondrocyte homeostasis, both in vivo and in vitro.

Results: We indicated that Rspo2 expression was upregulated both in synovium and articular cartilage as RA progressed in RA mice and RA patients. Increased Rspo2 upregulated the expression of leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5), as the ligand for Rspo2, and β-catenin in FLS and chondrocytes. Subsequent investigations revealed that intra-articular administration of rmRspo2 caused striking progressive synovitis and articular cartilage destruction to exacerbate RA progress in mice. Conversely, neutralization of Rspo2 or inhibition of the Wnt/β-catenin pathway effectively alleviated experimental RA development. Moreover, Rspo2 facilitated FLS aggressive phenotype and disrupted chondrocyte homeostasis primarily through activating Wnt/β-catenin pathway, which were effectively alleviated by Rspo2-NAb or rmDKK1.

Conclusions: Our data confirmed a critical role of Rspo2 in enhancing the aggressive phenotype of FLS and disrupting chondrocyte homeostasis through the Wnt/β-catenin pathway in the context of RA. Furthermore, the results indicated that intra-articular administration of Rspo2 neutralizing antibody or recombinant DKK1 might represent a promising therapeutic strategy for the treatment of RA.

Keywords

Chondrocyte; Fibroblast-like synoviocyte; Rheumatoid arthritis; Rspo2; Synovitis; Wnt/ β-catenin.

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