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Inhibition of CC chemokine receptor 1 ameliorates osteoarthritis in mouse by activating PPAR-γ.
Xu, Hanqing; Chen, Sheng; Meng, Cheng; He, Yi; Huang, Xiao-Jian; You, Hong-Bo.
Affiliation
  • Xu H; Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, Hubei, China.
  • Chen S; Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, Hubei, China.
  • Meng C; Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, Hubei, China.
  • He Y; Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, Hubei, China.
  • Huang XJ; Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, Hubei, China. 939251163@qq.com.
  • You HB; Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, Hubei, China. hbyou360@hotmail.com.
Mol Med ; 30(1): 74, 2024 Jun 03.
Article de En | MEDLINE | ID: mdl-38831316
ABSTRACT

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-1ß-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-1ß (10 ng/ml) treatment. The levels of the aging-related genes P16INK4a and P21CIP1 were analyzed via western blotting, and senescence-associated ß-galactosidase (SA-ß-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-1ß-induced aging, downregulates the expression of iNOS, COX-2, and MMP13, and alleviates the IL-1ß-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.
Sujet(s)
Mots clés

Texte intégral: 1 Collection: 01-internacional Base de données: MEDLINE Sujet principal: Arthrose / Chondrocytes / Récepteur PPAR gamma / Modèles animaux de maladie humaine / Récepteurs CCR1 Limites: Animals Langue: En Journal: Mol Med Sujet du journal: BIOLOGIA MOLECULAR Année: 2024 Type de document: Article Pays d'affiliation: Chine Pays de publication: Royaume-Uni

Texte intégral: 1 Collection: 01-internacional Base de données: MEDLINE Sujet principal: Arthrose / Chondrocytes / Récepteur PPAR gamma / Modèles animaux de maladie humaine / Récepteurs CCR1 Limites: Animals Langue: En Journal: Mol Med Sujet du journal: BIOLOGIA MOLECULAR Année: 2024 Type de document: Article Pays d'affiliation: Chine Pays de publication: Royaume-Uni