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<p>Hyaluronan and proteoglycan link protein 1 (HAPLN1) secreted by fibroblast-like synoviocytes (FLSs) plays a critical role in the pathological process of inflammatory arthritis. This study aimed to investigate the impact and underlying mechanisms of HAPLN1 in an inflamed chondrocyte model. IL-1β-treated SW1353 chondrocytes were exposed to recombinant HAPLN1 (rHAPLN1). A transwell coculture system was used to assess interactions between the chondrocytes and FLSs transfected with the HAPLN1 overexpression plasmid. Cell viability and proliferation were evaluated using cell counting kit-8 (CCK-8) assay and 5-ethynyl-2’-deoxyuridine (EdU) assay. RNA sequencing and bioinformatic analyses, including the identification of differentially expressed genes (DEGs), gene functional enrichment and protein–protein interaction analyses were conducted to explore the potential mechanisms. Our fundings revealed that HAPLN also increased the levels of inflammatory mediators (TNF-α, IL-6, MMP1, MMP3, MMP9, and ADAMTS-5) in the inflamed chondrocytes, suggesting its pro-inflammatory effect. However, HAPLN1 enhanced cell viability, and the expression of Collagen II and TGF-β, the restoration effect of extracellular matrix (ECM). Bioinformatics analysis suggested the upregulated DEGs were enriched in the inflammatory processes, and the pathways related to ECM, TNF and IL-6 were activated in inflamed chondrocytes following rHAPLN1 exposure. Additionally, the protein-protein interaction networks indicated that HAPLN1 interacts with the molecules related to ECM, inflammation, and PI3K/AKT/mTOR pathway. Western blot assay further verified that the phosphorylation of PI3K, AKT, and mTOR was elevated in the rHAPLN1-treated chondrocytes. Our findings highlight the dual effects of HAPLN1 on the arthritic chondrocytes, which may be associated with the activation of the PI3K/AKT/mTOR pathway.</p>

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HAPLN1 Exhibits Dual Effects: Facilitating Extracellular Matrix Restoration while Enhancing Inflammatory Mediator Production in Arthritic Chondrocytes

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月19日

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  • Yunting Chen,
  • Chenggen Luo,
  • Kun Huang,
  • Xiaoli Pan,
  • Yulei Ao,
  • Shidan Tian,
  • Mang He,
  • Anmao Li,
  • Yanjuan Chen,
  • Mei Tian,
  • Yong Chen

摘要

Hyaluronan and proteoglycan link protein 1 (HAPLN1) secreted by fibroblast-like synoviocytes (FLSs) plays a critical role in the pathological process of inflammatory arthritis. This study aimed to investigate the impact and underlying mechanisms of HAPLN1 in an inflamed chondrocyte model. IL-1β-treated SW1353 chondrocytes were exposed to recombinant HAPLN1 (rHAPLN1). A transwell coculture system was used to assess interactions between the chondrocytes and FLSs transfected with the HAPLN1 overexpression plasmid. Cell viability and proliferation were evaluated using cell counting kit-8 (CCK-8) assay and 5-ethynyl-2’-deoxyuridine (EdU) assay. RNA sequencing and bioinformatic analyses, including the identification of differentially expressed genes (DEGs), gene functional enrichment and protein–protein interaction analyses were conducted to explore the potential mechanisms. Our fundings revealed that HAPLN also increased the levels of inflammatory mediators (TNF-α, IL-6, MMP1, MMP3, MMP9, and ADAMTS-5) in the inflamed chondrocytes, suggesting its pro-inflammatory effect. However, HAPLN1 enhanced cell viability, and the expression of Collagen II and TGF-β, the restoration effect of extracellular matrix (ECM). Bioinformatics analysis suggested the upregulated DEGs were enriched in the inflammatory processes, and the pathways related to ECM, TNF and IL-6 were activated in inflamed chondrocytes following rHAPLN1 exposure. Additionally, the protein-protein interaction networks indicated that HAPLN1 interacts with the molecules related to ECM, inflammation, and PI3K/AKT/mTOR pathway. Western blot assay further verified that the phosphorylation of PI3K, AKT, and mTOR was elevated in the rHAPLN1-treated chondrocytes. Our findings highlight the dual effects of HAPLN1 on the arthritic chondrocytes, which may be associated with the activation of the PI3K/AKT/mTOR pathway.