2. Academic Validation
  3. CIP2A promotes inflammation and exacerbates osteoarthritis by targeting CEMIP

CIP2A promotes inflammation and exacerbates osteoarthritis by targeting CEMIP

  • Cell Mol Biol Lett. 2025 Jun 9;30(1):67. doi: 10.1186/s11658-025-00748-0.
Jingyue Su # 1 2,  Xuying Sun # 3,  Xin Chen 1 2,  Kang Wei 4,  Danni Luo 3,  Shengwu Yang 1 2,  Chunwu Zhang 1 2,  Jian Xu 5,  Zhenhan Deng 6 7
Affiliations

Affiliations

  • 1 Department of Orthopedics, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China.
  • 2 Geriatrics Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China.
  • 3 Department of Orthopaedic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China.
  • 4 Department of Plastic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, Hubei, China.
  • 5 Department of Orthopedics, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, Zhejiang, China. 0022029@zju.edu.cn.
  • 6 Department of Orthopedics, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China. dengzhenhan@wmu.edu.cn.
  • 7 Geriatrics Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China. dengzhenhan@wmu.edu.cn.
  • # Contributed equally.
PMID: 40490703 DOI: 10.1186/s11658-025-00748-0
Abstract

Background: Osteoarthritis (OA) is a chronic joint disease characterized by cartilage degeneration with unclear pathogenic mechanism. This study aims to discuss the regulatory role of cancerous inhibitor of protein Phosphatase 2A (CIP2A) in OA pathogenesis and to elucidate the molecular mechanisms.

Methods: Mouse chondrocytes were induced by interleukin-1β (IL-1β) to mimic OA inflammation, and extracellular matrix (ECM) homeostasis and inflammatory factors were evaluated at mRNA and protein levels. A mouse model of OA was induced by destabilization of medial meniscus (DMM) surgery. Histopathological staining was used to assess the cartilage destruction of human and mouse. Osteophyte formation was observed using micro-computed tomography (CT). Downstream of CIP2A was screened by RNA Sequencing and coimmunoprecipitation coupled with mass spectrometry in mouse chondrocytes.

Results: CIP2A was downregulated in cartilage of patients with OA and DMM mouse models, as well as in IL-1β-induced mouse chondrocytes. However, CIP2A overexpression promoted ECM degradation and inflammatory processes and exacerbated cartilage destruction and osteophyte formation. By contrast, knockdown or pharmacological inhibition of CIP2A alleviated cartilage degeneration to a certain extent, with no improvement in osteophytes formation caused by OA. Mechanistically, CIP2A interacted with its downstream cell migration-inducing protein (CEMIP) and activated the nuclear factor kappa B (NF-κB) signaling pathway, resulting in the imbalance of cartilage anabolic and catabolic factors and the activation of inflammation in the development of OA. In addition, CIP2A was ubiquitinated in mouse chondrocytes, causing it to be degraded, which could be a negative feedback of CIP2A expression in OA.

Conclusions: CIP2A targets CEMIP to activate NF-κB signaling pathway, which in turn aggravates cartilage destruction and inflammation and ultimately accelerates OA development. Our results suggest the potential role of the CIP2A/CEMIP axis as a therapeutic target for OA.

Keywords

CEMIP; CIP2A; Chondrocytes; NF-κB; Osteoarthritis.

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