The SOX11 Transcription Factor Upregulates Growth Differentiation Factor‐5 During Joint Formation Through a Downstream Enhancer Element

Abstract

The direct molecular mechanism underlying joint formation and remodeling has been studied for decades yet still is not fully understood. Growth differentiation factor 5 (GDF5), a critical joint-associated transcription factor linked to accelerated osteoarthritis, has been shown to be one of the intermediate markers for precursors of joint associated cells. Understanding the mechanisms regulating GDF5 expression will further illuminate some of the key steps of joint development. Previously, we identified a GDF5 Associated Regulatory Region (GARR) with putative Sox binding sites; the SOX11 transcription factor has been shown to upregulate GDF5. Hence, we hypothesize that SOX11 (SOXC family) is necessary for GARR-mediated expression of GDF5 during joint development and maintenance. We previously demonstrated that site-directed mutagenesis of the putative Sox binding sites in a GARR reporter construct markedly reduced activity. To confirm the role of SOX11 we performed over expression experiments in transformed chicken fibroblast (DF1) cells, a primary limb bud micromass culture, and in ovo in the developing chicken wing. Co-transfection studies demonstrated increased GARR activity both in vivo and in vitro with over expression of SOX11. Taken together, these data suggest that SOX11 may play a role in the regulation of GDF5 through GARR.