Chondrocytes are cartilage-resident cells that can build and repair cartilage and are generated from MSCs. Thus, directing the differentiation of MSCs into chondrocytes to stimulate joint repair could be a potential therapeutic strategy for osteoarthritis. Using this rationale, Johnson et al. screened 22,000 compounds and found that only one, kartogenin, could promote the differentiation of primary human MSCs into chondrocytes. When injected into the joints of rats following surgical or collagenase-induced damage, kartogenin restored cartilage and joint function. By coupling a derivative of kartogenin to biotin and a photoactivatable crosslinker and analyzing the MSC proteins bound to this kartogenin construct after ultraviolet irradiation, the researchers identified filamin A as the target of kartogenin. Filamin A crosslinks actin filaments, but this function was unaffected by kartogenin. Instead, the authors found that the kartogenin-binding region of filamin A also binds core-binding factor-β (CBF-β), the regulatory subunit of the CBF-β–RUNX transcription factor complex. They showed that kartogenin disrupts the binding of filamin A to CBF-β, resulting in the translocation of CBF-β to the nucleus, where it can then bind RUNX and regulate the transcription of chondrogenic genes. Silencing of CBF-β or RUNX1 inhibited the ability of kartogenin to differentiate MSCs into chondrocytes.
The RUNX proteins have previously been implicated in chondrocyte proliferation or differentiation, and the identification of kartogenin provides a new tool to regulate their activity by modifying the subcellular localization of their binding partner CBF-β. In addition, the study provides insight into the potential of MSCs to repair damaged joints that may help inform the development of future stem cell therapies for osteoarthritis in humans.
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