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

Hiraku Motomura, Shoji Seki*, Shunichi Shiozawa, Yukihiko Aikawa, Makiko Nogami, Tomoatsu Kimura

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)756-761
Number of pages6
JournalBiochemical and Biophysical Research Communications
Volume497
Issue number2
DOIs
StatePublished - 2018/03/04

Keywords

  • Articular cartilage
  • Inflammatory cytokines
  • Matrix metalloproteinase
  • Osteoarthritis
  • Osteophyte
  • c-Fos/AP-1 inhibitor

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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