Sp2 Transcription Factor Alleviates Chondrocyte Loss in Osteoarthritis by Repressing the DVL1-Dependent Wnt/β-Catenin Signaling Pathway

Osteoarthritis (OA) ranks as the most prevalent condition affecting the musculoskeletal system, where chondrocyte loss or dysfunction plays a crucial pathogenic role. This study is aimed at investigating key molecular cascades implicated in chondrocyte loss and cartilage injury in OA.

A mouse model of OA was generated by destabilization of the medial meniscus. Histological staining was performed to evaluate the pathological changes in the knee joint tissue, the cartilage morphology, and the osteoblast population. A high-throughput sequencing analysis was performed to analyze aberrantly expressed genes in OA cartilage. Gain- or loss-of-function assays of dishevelled segment polarity protein 1 (DVL1) and Sp2 transcription factor (SP2) were carried out to analyze their effects on cartilage injury in mice and chondrocyte apoptosis in vitro. The interaction between SP2 and DVL1 was verified by chromatin immunoprecipitation and luciferase assays.

DVL1 was expressed at aberrantly high levels in the cartilage of OA mice. Its knockdown suppressed protein levels and transcriptional activity of β-catenin, thereby reducing cartilage damage and loss in mice. In vitro, chondrocyte apoptosis was inhibited upon DVL1 silencing. SP2, poorly expressed in OA cartilage, was found to repress DVL1 transcription by binding to its promoter. Overexpression of SP2 similarly alleviated cartilage injury and chondrocyte loss; however, these effects were negated by the additional DVL1 overexpression.

This study demonstrates that SP2 represses DVL1 transcription and inactivates the Wnt/β-catenin signaling, thus alleviating chondrocyte loss and cartilage injury in OA mice.