SOX9 and the many facets of its regulation in the chondrocyte lineage

Abstract

SOX9 is a pivotal transcription factor in developing and adult cartilage. Its gene is expressed from the multipotent skeletal progenitor cells and is active throughout chondrocyte differentiation. While it is repressed in hypertrophic chondrocytes in cartilage growth plates, it remains expressed throughout life in permanent chondrocytes of healthy articular cartilage. SOX9 is required for chondrogenesis: it secures chondrocyte lineage commitment, promotes cell survival, and transcriptionally activates the genes for many cartilage-specific structural components and regulatory factors. Since heterozygous mutations within and around SOX9 were shown to cause the severe skeletal malformation syndrome called Campomelic Dysplasia, researchers around the world have worked assiduously to decipher the many facets of SOX9 actions and regulation in chondrogenesis. The more we learn, the more we realize the complexity of the molecular networks in which SOX9 fulfills its functions and is regulated at the levels of its gene, RNA and protein, and the more we measure the many gaps remaining in knowledge. At the same time, new technologies keep giving us more means to push further the frontiers of knowledge. Research efforts must be pursued to fill these gaps and to better understand and treat many types of cartilage diseases in which SOX9 has or could have a critical role. These diseases include chondrodysplasias and cartilage degeneration diseases, namely osteoarthritis, a prevalent and still incurable joint disease. We here review the current state of knowledge of SOX9 actions and regulation in the chondrocyte lineage, and propose new directions for future fundamental and translational research projects.

An Emerging Regulatory Landscape for Skeletal Development

“…These Sox9 targets have been termed Class II targets to distinguish them from non-enhancer mediated interactions [30] (see below). Cooperative interaction between Sox9 and Sox6 was also evident; two-thirds of Sox9-bound regions were also associated with Sox6, which confirmed interactions between Sox9 and Sox5/6 on cartilage enhancers [31] that were observed in a large number of biochemical assays [15, 32, 35] (Fig. 2).…”

“…Prior to recent genome-scale ChIP-seq analyses [29-31], various approaches revealed Sox9-associated enhancers around Sox9 itself plus several genes encoding cartilage growth factors or extracellular matrix proteins, including Ctgf , Col2a1 , Col9a1 , Col10a1 , Col11a2 , Col27a1 , Hapln1 , Matn1 , and Acan [15, 32]. Sox9 is known to dimerize in activating target genes through a quite variable inverted repeat sequence [33, 34].…”

Translational Control of Sox9 RNA by mTORC1 Contributes to Skeletogenesis

“…Although it is well-established that Sox9 /SOX9 is the subject of many types of regulatory mechanisms, including epigenetic and transcriptional regulation of its gene, post-transcriptional regulation of its RNA, and post-translational modifications of its protein (Akiyama and Lefebvre, 2011, Kozhemyakina et al., 2015, Lefebvre and Dvir-Ginzberg, 2017), no previous literature has reported the translational control of Sox9 RNA thus far. Herein, using a battery of well-established biochemical and functional assays, several lines of evidence indicate that the mTORC1/4E-BPs cascade regulates the translation of Sox9 RNA in undifferentiated mesenchymal cells.…”

AP-1 family members act with Sox9 to promote chondrocyte hypertrophy

“…Inactivating mutations in human SOX9 result in campomelic dysplasia, an autosomal dominant disorder characterized by hypoplasia of the endochondral skeleton and bowing of skeletal elements (Foster, 1996;Giordano et al, 2001;Kwok et al, 1995). Molecular studies indicate that Sox9 promotes expression of a broad spectrum of cartilage matrix components, promotes cell division and cell survival, and inhibits chondrocytes from adopting an alternative pathway of osteoblast development (reviewed by Lefebvre and Dvir-Ginzberg, 2016).…”

“…The SRY-box (Sox) transcriptional regulator Sox9 is a central regulator of endochondral skeletal development (reviewed by Akiyama and Lefebvre, 2011;Lefebvre and Dvir-Ginzberg, 2016). Initial Sox9 expression in condensing mesenchymal cells precedes active chondrogenesis (Bi et al, 1999).…”