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Background  The Nkx3.2 transcription factor promotes chondrogenesis by forming a positive regulatory loop with a crucial chondrogenic transcription factor, Sox9. Previous studies have indicated that factors other than Sox9 may promote chondrogenesis directly, but these factors have not been identified. Here, we test the hypothesis that Nkx3.2 promotes chondrogenesis directly by Sox9-independent mechanisms and indirectly by previously characterized Sox9-dependent mechanisms.    Methodology/Principal Findings  C3H10T1/2 pluripotent mesenchymal cells were cultured with bone morphogenetic protein 2 (BMP2) to induce endochondral ossification. Overexpression of wild-type Nkx3.2 (WT-Nkx3.2) upregulated glycosaminoglycan (GAG) production and expression of type II collagen α1 ( Col2a1 ) mRNA, and these effects were evident before WT-Nkx3.2-mediated upregulation of  Sox9 . RNAi-mediated inhibition of  Nkx3.2  abolished GAG production and expression of  Col2a1  mRNA. Dual luciferase reporter assays revealed that WT-Nkx3.2 upregulated  Col2a1  enhancer activity in a dose-dependent manner in C3H10T1/2 cells and also in N1511 chondrocytes. In addition, WT-Nkx3.2 partially restored downregulation of GAG production, Col2 protein expression, and  Col2a1  mRNA expression induced by  Sox9  RNAi. ChIP assays revealed that Nkx3.2 bound to the  Col2a1  enhancer element.    Conclusions/Significance  Nkx3.2 promoted primary chondrogenesis by two mechanisms: Direct and Sox9-independent upregulation of  Col2a1  transcription and upregulation of  Sox9  mRNA expression under positive feedback system.

Nkx3.2 Promotes Primary Chondrogenic Differentiation by Upregulating Col2a1 Transcription