Abstract
Endochondral bone formation is fundamental for skeletal development. During this process, chondrocytes undergo multiple steps of differentiation and coordinated transition from a proliferating to a hypertrophic stage, which is critical to advance skeletal development. Here, we identified the transcription factor Dmrt2 (double-sex and mab-3 related transcription factor 2) as a Sox9-inducible gene that promotes chondrocyte hypertrophy in pre-hypertrophic chondrocytes. Epigenetic analysis further demonstrated that Sox9 regulates Dmrt2 expression through an active enhancer located 18 kb upstream of the Dmrt2 gene and that this enhancer’s chromatin status is progressively activated through chondrocyte differentiation. Dmrt2-knockout mice exhibited a dwarf phenotype with delayed initiation of chondrocyte hypertrophy. Dmrt2 augmented hypertrophic chondrocyte gene expression including Ihh through physical and functional interaction with Runx2. Furthermore, Dmrt2 deficiency reduced Runx2-dependent Ihh expression. Our findings suggest that Dmrt2 is critical for sequential chondrocyte differentiation during endochondral bone formation and coordinates the transcriptional network between Sox9 and Runx2.
Highlights
Endochondral bone formation is fundamental for skeletal development
To uncover the transcription factors involved in chondrocyte differentiation, we attempted to identify genes induced by Sox[9] and its transcriptional cofactors, Sox[5] and Sox[6] (Sox5/6/9), in primary chondrocytes by RNA-seq analysis (Fig. 1a)
Severe skeletal defects associated with DMRT2 mutations have been reported in humans and mice[20,21,22], little is known about the functional roles of Dmrt[2] in endochondral ossification
Summary
Endochondral bone formation is fundamental for skeletal development. During this process, chondrocytes undergo multiple steps of differentiation and coordinated transition from a proliferating to a hypertrophic stage, which is critical to advance skeletal development. Our findings suggest that Dmrt[2] is critical for sequential chondrocyte differentiation during endochondral bone formation and coordinates the transcriptional network between Sox[9] and Runx[2]. Proliferating chondrocytes stop proliferating and enlarge their cell size to become pre-hypertrophic and hypertrophic chondrocytes[3], which are characterized by the expression of Indian hedgehog (Ihh) and collagen type X alpha 1 chain (Col10a1), respectively[4,5] These late-stage chondrocytes undergo terminal differentiation and produce matrix metalloproteinase 13 (MMP13), which allows vascular invasion into cartilage[6]. Sryrelated HMG-Box gene 9 (Sox9) plays indispensable roles in chondrocyte development and endochondral bone formation[10], and runt-related transcription factor 2 (Runx2) and Runx[3] play essential roles in chondrocyte hypertrophy by directly regulating Ihh expression[9]. Uncovering the target genes of Sox[9] and their functional roles in chondrocyte hypertrophy would deepen our understanding of endochondral bone formation
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