A Stem Cell–Based Approach to Cartilage Repair

TLDR

Osteoarthritis is a degenerative joint disease that destroys articular cartilage and leads to disability, and molecules that direct mesenchymal stem cells to differentiate into chondrocytes could stimulate cartilage repair. The study aims to uncover mechanisms controlling chondrogenesis to enable stem cell–based osteoarthritis therapy. An image‑based high‑throughput screen identified kartogenin, a small molecule that promotes chondrocyte differentiation at 100 nM, protects cartilage in vitro, and is effective in two OA animal models by binding filamin A, disrupting its interaction with CBFβ, and activating the CBFβ‑RUNX1 transcriptional program.

Abstract

Osteoarthritis (OA) is a degenerative joint disease that involves the destruction of articular cartilage and eventually leads to disability. Molecules that promote the selective differentiation of multipotent mesenchymal stem cells (MSCs) into chondrocytes may stimulate the repair of damaged cartilage. Using an image-based high-throughput screen, we identified the small molecule kartogenin, which promotes chondrocyte differentiation (median effective concentration = 100 nM), shows chondroprotective effects in vitro, and is efficacious in two OA animal models. Kartogenin binds filamin A, disrupts its interaction with the transcription factor core-binding factor β subunit (CBFβ), and induces chondrogenesis by regulating the CBFβ-RUNX1 transcriptional program. This work provides new insights into the control of chondrogenesis that may ultimately lead to a stem cell-based therapy for osteoarthritis.