Deficiency of Krüppel-like factor 15 activates β-catenin and is involved in the development of osteoarthritis

Krüppel-like factor 15 is a metabolism-related transcription factor that has been implicated in the regulation of the Wnt/β-catenin signaling pathway. This study aimed to elucidate its function in cartilage, particularly its interaction with β-catenin, using inducible cartilage-specific knockout mice. Krüppel-like factor 15 knockout mice and control mice underwent destabilization of medial meniscal surgery to induce osteoarthritis. Histological analysis and immunohistochemistry were carried out, along with in vitro co-immunoprecipitation, double immunofluorescence, and subcellular fractionation. The effects of Wnt3A stimulation and treatment with Wnt/β-catenin inhibitors were evaluated. KO mice showed significantly more cartilage degeneration at eight weeks after surgery when compared with control mice. Knockout mice also showed elevated Osteoarthritis Research Society International scores and increased expression of β-catenin, matrix metalloprotease 13, and a disintegrin-like metalloprotease with thrombospondin motifs 5, along with decreased expression of SRY-box transcription factor 9. Krüppel-like factor 15 was seen to physically interact and colocalize with β-catenin in chondrocyte nuclei. Its deficiency promoted Wnt/β-catenin pathway activation and nuclear β-catenin accumulation. Wnt3A stimulation amplified catabolic gene expression and suppressed anabolic factor expression. However, administration of a Wnt/β-catenin signaling inhibitor canceled out these effects. This study indicates that Krüppel-like factor 15 interacts with β-catenin and functions as a negative regulator of Wnt/β-catenin signaling in cartilage, maintaining matrix homeostasis, and suppressing osteoarthritis progression. Deficiency of Krüppel-like factor 15 promotes catabolism and inhibits anabolism mediated by β-catenin in cartilage. These findings suggest that Krüppel-like factor 15 may be a potential therapeutic target for osteoarthritis, either by restoring its function or enhancing its interaction with β-catenin.