2. Academic Validation
  3. CRLF1/CLCF1 heterodimer involvement in intervertebral disc degeneration via exacerbation of extracellular matrix degradation and nucleus pulposus cell senescence

CRLF1/CLCF1 heterodimer involvement in intervertebral disc degeneration via exacerbation of extracellular matrix degradation and nucleus pulposus cell senescence

  • Osteoarthritis Cartilage. 2025 Feb 20:S1063-4584(25)00798-8. doi: 10.1016/j.joca.2025.02.773.
Jian Zhu 1,  Yuming Huang 2,  Linchuan Lei 3,  Zhuoyang Zhao 3,  Hua Wang 1,  Zemin Li 1,  Hui Liu 1,  Jianru Wang 1,  Zhaomin Zheng 4
Affiliations

Affiliations

  • 1 Department of Spine Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, PR China; Guangdong Province Key Laboratory of Orthopaedics and Traumatology, Guangzhou 510080, PR China.
  • 2 The First Affiliated Hospital of Fujian Medical University, Fuzhou 350000, PR China.
  • 3 Department of Spine Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, PR China; Guangdong Province Key Laboratory of Orthopaedics and Traumatology, Guangzhou 510080, PR China; Laboratory of General Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, PR China.
  • 4 Department of Spine Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, PR China; Guangdong Province Key Laboratory of Orthopaedics and Traumatology, Guangzhou 510080, PR China; Pain Research Center, Sun Yan Sen University, Guangzhou 510080, PR China. Electronic address: zhzhaom@mail.sysu.edu.cn.
PMID: 39986601 DOI: 10.1016/j.joca.2025.02.773
Abstract

Objective: Low back pain (LBP) is one of the most prevalent musculoskeletal disorders and has a significant global impact. Intervertebral disc degeneration (IVDD) is an important cause of LBP. The aim of this study was to test a hypothesis that elucidates the potential role and molecular mechanisms of cytokine receptor-like factor 1 (CRLF1) in IVDD and LBP.

Methods: We identified dysregulated genes in normal and degenerative discs via microarray profiles. We verified the correlation between CRLF1 and the progression of IVDD in animal models and cellular models and further explored the effect of increased CRLF1 on nucleus pulposus cells (NPCs) and its mechanism by RNA-seq. Finally, the ameliorative effect of CRLF1 knockdown on degenerated NPCs was elucidated by in vivo and in vitro experiments.

Results: We verified the close relationship between senescent NPCs and IVDD. We determined that elevated CRLF1 is associated with the progression of NPC senescence and IVDD in animal and cellular models. In addition, fluorescence colocalization and coimmunoprecipitation analysis revealed that CRLF1 forms a heterodimer with cardiac dystrophin-like cytokine 1 (CLCF1), which together activate JAK/STAT3 signaling. This activation enhances the production of senescence-associated secretory phenotype (SASPs) and accelerates NPC senescence. In vitro studies have shown that targeting CRLF1 reduces extracellular matrix (ECM) degradation and alleviates NPC senescence. Correspondingly, in vivo and pain-behavior tests showed that CRLF1 knockdown reduces IVDD and LBP.

Conclusion: The CRLF1/CLCF1 heterodimer is involved in IVDD, and CRLF1 may be an effective therapeutic target for treating IVDD progression and associated LBP.

Keywords

Cardiac dystrophy-like cytokine 1; Cytokine receptor-like factor 1; Intervertebral disc degeneration; Low back pain; Senescence-associated secretory phenotype.

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