A selective c-Fos/AP-1 inhibitor prevents cartilage destruction and subsequent osteophyte formation

• Published in: Biochemical and biophysical research communications Vol. 497; no. 2; pp. 756 - 761
• Main Authors: Motomura, Hiraku, Seki, Shoji, Shiozawa, Shunichi, Aikawa, Yukihiko, Nogami, Makiko, Kimura, Tomoatsu
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 04.03.2018
• Subjects: Articular cartilage; c-Fos/AP-1 inhibitor; Inflammatory cytokines; Matrix metalloproteinase; Osteoarthritis; Osteophyte; Osteophyte; Inflammatory cytokines; Matrix metalloproteinase; Articular cartilage; Osteoarthritis; c-Fos/AP-1 inhibitor
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2018.02.147

The objective of the present study is to demonstrate that a newly developed selective c-Fos/activator protein (AP)-1 inhibitor, T-5224, inhibits the expression of matrix metalloproteinases (MMPs) in human articular chondrocytes, and prevents cartilage destruction in an osteoarthritis (OA)-induced mouse model. First, we examined the effect of T-5224 on MMP and inflammatory cytokine expression by real-time polymerase chain reaction in human articular chondrocytes. We created an OA model by destabilization of the medial meniscus (DMM) in mice. T-5224 was orally administered once a day and the OA pathology was assessed by histological, immunohistochemical, and micro-computed tomography (CT) analyses. T-5224 inhibited the mRNA expression levels of MMP-1, 3, and 13, and interleukin (IL)-1β, tumor necrosis factor (TNF)-α and IL-6 in IL-1-stimulated human chondrocytes. Oral administration of T-5224 to OA-induced mice prevented cartilage destruction. The histological scores for OA were significantly better in the T-5224-treated group than the vehicle-treated group. Type X collagen and MMP-13 were not increased in the T-5224-treated group by immunohistochemical staining. Micro-CT analysis showed mild but apparent osteophyte development in the femoral condyle and antero-medial aspect of the tibia in the vehicle-treated group but not in the T-5224-treated group. Taken together, specific inhibition of c-Fos/AP-1 and the resulting inhibition of the transactivation of a broad spectrum of downstream MMPs, along with inflammatory cytokines, effectively prevented cartilage destruction and osteophyte formation. •T-5224 inhibits matrix metalloproteinase mRNA and inflammatory cytokine expression.•T-5224 prevents articular cartilage destruction in an osteoarthritis (OA) model.•T-5224 inhibits matrix metalloproteinase-13 expression in an OA model.•T-5224 prevents osteophyte formation in an osteoarthritis (OA) model.