title: Synovial joint morphogenesis requires the chondrogenic action of Sox5 and Sox6 in growth plate and articular cartilage.
abstract: The mechanisms underlying synovial joint development remain poorly understood. Here we use complete and cell-specific gene inactivation to identify the roles of the redundant chondrogenic transcription factors Sox5 and Sox6 in this process. We show that joint development aborts early in complete mutants (Sox5(-/-)6(-/-)). Gdf5 and Wnt9a expression is punctual in articular progenitor cells, but Sox9 downregulation and cell condensation in joint interzones are late. Joint cell differentiation is unsuccessful, regardless of lineage, and cavitation fails. Sox5 and Sox6 restricted expression to chondrocytes in wild-type embryos and continued Erg expression and weak Ihh expression in Sox5(-/-)6(-/-) growth plates suggest that growth plate failure contribute to this Sox5(-/-)6(-/-) joint morphogenesis block. Sox5/6 inactivation in specified joint cells and chondrocytes (Sox5(fl/fl)6(fl/fl)Col2Cre) also results in a joint morphogenesis block, whereas Sox5/6 inactivation in specified joint cells only (Sox5(fl/fl)6(fl/fl)Gdf5Cre) results in milder joint defects and normal growth plates. Sox5(fl/fl)6(fl/fl)Gdf5Cre articular chondrocytes remain undifferentiated, as shown by continued Gdf5 expression and pancartilaginous gene downregulation. Along with Prg4 downregulation, these defects likely account for joint tissue overgrowth and incomplete cavitation in adult mice. Together, these data suggest that synovial joint morphogenesis relies on essential roles for Sox5/6 in promoting both growth plate and articular chondrocyte differentiation.
authors.affiliation: Department of Cell Biology, and Orthopaedic and Rheumatologic Research Center, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue (NC-10), Cleveland, OH 44195, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Dy
authors.forename: Patrick
authors.initials: P
authors.lastname: Smits
authors.forename: Amber
authors.initials: A
authors.lastname: Silvester
authors.forename: Alfredo
authors.initials: A
authors.lastname: Penzo-Méndez
authors.forename: Bogdan
authors.initials: B
authors.lastname: Dumitriu
authors.forename: Yu
authors.initials: Y
authors.lastname: Han
authors.forename: Carol A
authors.initials: CA
authors.lastname: de la Motte
authors.forename: David M
authors.initials: DM
authors.lastname: Kingsley
authors.forename: Véronique
authors.initials: V
authors.lastname: Lefebvre
mesh_terms: D000818:Animals; D002358:Cartilage, Articular / Q000254:growth & development* / Q000378:metabolism; D002454:Cell Differentiation; D019902:Chondrocytes / Q000378:metabolism; D020219:Chondrogenesis; D005260:Female; D006132:Growth Plate; D006820:Hyaluronic Acid / Q000378:metabolism; D007596:Joints / Q000254:growth & development*; D008297:Male; D009024:Morphogenesis; D015513:Oncogene Proteins / Q000378:metabolism; D055758:SOX9 Transcription Factor / Q000378:metabolism; D055755:SOXD Transcription Factors / Q000378:metabolism*; D013234:Stem Cells / Q000378:metabolism; D014157:Transcription Factors; D000071230:Transcriptional Regulator ERG
chemical_list: C531115:ERG protein, mouse; D015513:Oncogene Proteins; D055758:SOX9 Transcription Factor; D055755:SOXD Transcription Factors; C089186:Sox5 protein, mouse; C095939:Sox6 protein, mouse; C527933:Sox9 protein, mouse; D014157:Transcription Factors; D000071230:Transcriptional Regulator ERG; D006820:Hyaluronic Acid