ArticleArthritis research & therapy2024
Small heterodimer partner-interacting leucine zipper protein suppresses pain and cartilage destruction in an osteoarthritis model by modulating the AMPK/STAT3 signaling pathway.
Article in Arthritis research & therapy, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed.
- Small heterodimer partner protects against osteoarthritis by inhibiting IKKβ/NF-κB-mediated matrix-degrading enzymes in chondrocytes.Nature communications · 2026Article
- Multimodal modulation of metal-based nanomaterials in osteoarthritis immunotherapy: current landscape and future paradigms.Frontiers in immunology · 2026Review
- Recent Developments in Osteoarthritis Research: Innovative Therapeutic Approaches and the Role of Polyphenols and Nanotechnology.International journal of molecular sciences · 2025Review
- Mechanistic insights into Sanbi Decoction for osteoarthritis treatment based on network pharmacology and experimental validation.Scientific reports · 2025Article
- Classification and regulatory interactions of key transcription factors in COVID-19.Frontiers in cellular and infection microbiology · 2025Review
- Key Role of STAT3 in Osteoarthritis: From Pathogenic Mechanisms to Targeted Therapy.International journal of nanomedicine · 2025Review
- Undercarboxylated OCN Inhibits Chondrocyte Hypertrophy and Osteoarthritis Development through GPRC6A/HIF-1α Cascade.International journal of biological sciences · 2025Article
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Abstract
objectiveOsteoarthritis (OA) is a degenerative joint disease caused by the breakdown of joint cartilage and adjacent bone. Joint injury, being overweight, differences in leg length, high levels of joint stress, abnormal joint or limb development, and inherited factors have been implicated in the etiology of OA. In addition to physical damage to the joint, a role for inflammatory processes has been identified as well. Small heterodimer partner-interacting leucine zipper protein (SMILE) regulates transcription and many cellular functions. Among the proteins activated by SMILE is the peroxisome proliferator-activated receptor (PPAR) γ, which mediates the activities of CD4 + T helper cells, including Th1, Th2, and Th17, as well as Treg cells. PPAR-γ binds to STAT3 to inhibit its transcription, thereby suppressing the expression of the NF-κB pathway, and in turn, the expression of the inflammatory cytokines interferon (IFN), interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α, which are sub-signals of STAT3 and NF-κB.
methodsOA was induced in control C57BL/6 mice and in C57BL/6-derived SMILE-overexpressing transgenic (SMILE Tg) mice. The protein expression levels in the joint and spleen tissues were analyzed by immunohistochemistry and immunofluorescence images. In addition, flow cytometry was performed for detecting changes of the changes of immune cells.
resultsLess cartilage damage and significantly reduced levels of OA biomarkers (MMP13, TIMP3 and MCP-1) were observed in SMILE Tg mice. Immunohistochemistry performed to identify the signaling pathway involved in the link between SMILE expression and OA revealed decreased levels of IL-1β, IL-6, TNF-α, and phosphorylated AMPK in synovial tissues as well as a significant decrease in phosphorylated STAT3 in both cartilage and synovium. Changes in systemic immune cells were investigated via flow cytometry to analyze splenocytes isolated from control and SMILE Tg mice. SMILE Tg mice had elevated proportions of CD4 + IL-4 + cells (Th2) and CD4 + CD25 + Foxp3 + cells (Treg) and a notable decrease in CD4 + IL-17 + cells (Th17).
conclusionOur results show that overexpressed SMILE attenuates the symptoms of OA, by increasing AMPK signaling and decreasing STAT3, thus reducing the levels of inflammatory immune cells.
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