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Updated: Jun 24, 2025
Ameliorating Osteoarthritis in Mice Using Silver Nanoparticles
Published on: June 2, 2023
Inhibition of CC chemokine receptor 1 ameliorates osteoarthritis in mouse by activating PPAR-γ
Hanqing Xu1, Sheng Chen1, Cheng Meng1
1Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, Hubei, China.
Background:
Osteoarthritis (OA) is a degenerative joint disease characterized by cartilage destruction and inflammation. CC chemokine receptor 1 (CCR1), a member of the chemokine family and its receptor family, plays a role in the autoimmune response. The impact of BX471, a specific small molecule inhibitor of CCR1, on CCR1 expression in cartilage and its effects on OA remain underexplored.
Methods:
This study used immunohistochemistry (IHC) to assess CCR1 expression in IL-1β-induced mouse chondrocytes and a medial meniscus mouse model of destabilization of the medial meniscus (DMM). Chondrocytes treated with varying concentrations of BX471 for 24 h were subjected to IL-1β (10 ng/ml) treatment. The levels of the aging-related genes P16INK4a and P21CIP1 were analyzed via western blotting, and senescence-associated β-galactosidase (SA-β-gal) activity was measured. The expression levels of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), aggrecan (AGG), and the transcription factor SOX9 were determined through western blotting and RT‒qPCR. Collagen II, matrix metalloproteinase 13 (MMP13), and peroxisome proliferator-activated receptor (PPAR)-γ expression was analyzed via western blot, RT‒qPCR, and immunofluorescence. The impact of BX471 on inflammatory metabolism-related proteins under PPAR-γ inhibition conditions (using GW-9662) was examined through western blotting. The expression of MAPK signaling pathway-related molecules was assessed through western blotting. In vivo, various concentrations of BX471 or an equivalent medium were injected into DMM model joints. Cartilage destruction was evaluated through Safranin O/Fast green and hematoxylin-eosin (H&E) staining.
Results:
This study revealed that inhibiting CCR1 mitigates IL-1β-induced aging, downregulates the expression of iNOS, COX-2, and MMP13, and alleviates the IL-1β-induced decrease in anabolic indices. Mechanistically, the MAPK signaling pathway and PPAR-γ may be involved in inhibiting the protective effect of CCR1 on chondrocytes. In vivo, BX471 protected cartilage in a DMM model.
Conclusion:
This study demonstrated the expression of CCR1 in chondrocytes. Inhibiting CCR1 reduced the inflammatory response, alleviated cartilage aging, and retarded degeneration through the MAPK signaling pathway and PPAR-γ, suggesting its potential therapeutic value for OA.
Insights
BX471, a CC chemokine receptor 1 (CCR1) inhibitor, reduces osteoarthritis (OA) progression by mitigating inflammation and cartilage aging. This CCR1 inhibition shows therapeutic potential for OA by protecting chondrocytes via the MAPK signaling pathway and PPAR-γ.
Area of Science:
- Biochemistry
- Immunology
- Cell Biology
Background:
- Osteoarthritis (OA) is a degenerative joint disease marked by cartilage breakdown and inflammation.
- CC chemokine receptor 1 (CCR1) is implicated in autoimmune responses, but its role in OA and the effect of its inhibitor BX471 are not fully understood.
Purpose of the Study:
- To investigate the impact of BX471, a CCR1 inhibitor, on chondrocytes and cartilage in OA models.
- To elucidate the molecular mechanisms underlying CCR1's role in OA pathogenesis.
Main Methods:
- Immunohistochemistry (IHC) and Western blotting to assess CCR1 expression and related markers in IL-1β-induced chondrocytes and destabilization of the medial meniscus (DMM) mouse models.
- Analysis of aging markers (P16INK4a, P21CIP1, SA-β-gal), inflammatory mediators (iNOS, COX-2), matrix components (Aggrecan, Collagen II), and matrix-degrading enzymes (MMP13).
- Investigated the involvement of the MAPK signaling pathway and peroxisome proliferator-activated receptor gamma (PPAR-γ) in OA pathogenesis and BX471's effects.
Main Results:
- BX471 treatment mitigated IL-1β-induced chondrocyte aging and inflammation, reducing iNOS, COX-2, and MMP13 expression.
- BX471 treatment counteracted the decrease in anabolic markers and protected cartilage in the DMM mouse model.
- The study suggests that the MAPK signaling pathway and PPAR-γ are involved in CCR1-mediated chondrocyte protection.
Conclusions:
- CCR1 is expressed in chondrocytes and plays a role in OA pathogenesis.
- Inhibiting CCR1 with BX471 reduces inflammation, alleviates cartilage aging, and retards degeneration.
- BX471 demonstrates potential as a therapeutic agent for osteoarthritis, acting through the MAPK signaling pathway and PPAR-γ.
