KLF15 deficiency accelerates cartilage destruction in inflammatory arthritis.

OBJECTIVE

Kruppel-like factor 15 (KLF15) is a transcription factor that promotes anabolic pathways and suppresses catabolic signalling in joint tissues. KLF15 regulates adipocyte differentiation through peroxisome proliferator-activated receptor-γ (PPARγ), which suppresses inflammation via the nuclear factor-κB pathway. This study aimed to clarify the effects of KLF15 in a mouse model of collagen antibody-induced arthritis (CAIA).

METHOD: Tamoxifen-induced cartilage-specific KLF15 knockout (KO) mice were generated. Ten-week-old male KO mice (KO group) and wild-type mice (WT group) were treated intraperitoneally with anti-type II collagen antibody to create CAIA mice. At 0, 1, 2, and 4 weeks after antibody administration, the knee joints were collected for histological (safranin-O, haematoxylin-eosin) and immunohistological [PPARγ, phosphor-IκB kinase complex (pIKK) α/β, interleukin-1β (IL-1β), matrix metalloproteinase-3 (MMP3) and MMP13] evaluation and compared. Chondrocytes from KLF15 KO and WT mice were evaluated for KLF15, PPARγ, MMP3, and MMP13 mRNA expression by quantitative polymerase chain reaction, and for pIKKα/β by Western blotting.

RESULTS

The arthropathy score was significantly higher in the KO group at 4 weeks, while the synovitis score showed no difference. Positive cell ratios for PPARγ were decreased in the KO group, and pIKKα/β, IL-1β, MMP3, and MMP13 were significantly increased. Western blotting showed significantly increased pIKKα/β expression in KO cells compared to WT cells.

CONCLUSION

Arthritis induced in cartilage-specific KLF15 KO mice may cause articular cartilage destruction by decreasing PPARγ expression and increasing inflammatory cytokines and MMPs via IKKα/β. Modulation of KLF15 could be a potential therapeutic strategy for the treatment of arthritis, including rheumatoid arthritis.