SOX9 keeps growth plates and articular cartilage healthy by inhibiting chondrocyte dedifferentiation/osteoblastic redifferentiation

Abstract

Cartilage is essential throughout vertebrate life. It starts developing in embryos when osteochondroprogenitor cells commit to chondrogenesis, activate a pancartilaginous program to form cartilaginous skeletal primordia, and also embrace a growth-plate program to drive skeletal growth or an articular program to build permanent joint cartilage. Various forms of cartilage malformation and degeneration diseases afflict humans, but underlying mechanisms are still incompletely understood and treatment options suboptimal. The transcription factor SOX9 is required for embryonic chondrogenesis, but its postnatal roles remain unclear, despite evidence that it is down-regulated in osteoarthritis and heterozygously inactivated in campomelic dysplasia, a severe skeletal dysplasia characterized postnatally by small stature and kyphoscoliosis. Using conditional knockout mice and high-throughput sequencing assays, we show here that SOX9 is required postnatally to prevent growth-plate closure and preosteoarthritic deterioration of articular cartilage. Its deficiency prompts growth-plate chondrocytes at all stages to swiftly reach a terminal/dedifferentiated stage marked by expression of chondrocyte-specific (Mgp) and progenitor-specific (Nt5e and Sox4) genes. Up-regulation of osteogenic genes (Runx2, Sp7, and Postn) and overt osteoblastogenesis quickly ensue. SOX9 deficiency does not perturb the articular program, except in load-bearing regions, where it also provokes chondrocyte-to-osteoblast conversion via a progenitor stage. Pathway analyses support roles for SOX9 in controlling TGFβ and BMP signaling activities during this cell lineage transition. Altogether, these findings deepen our current understanding of the cellular and molecular mechanisms that specifically ensure lifelong growth-plate and articular cartilage vigor by identifying osteogenic plasticity of growth-plate and articular chondrocytes and a SOX9-countered chondrocyte dedifferentiation/osteoblast redifferentiation process.

Primary cilia drive postnatal tidemark patterning in articular cartilage by coordinating responses to Indian Hedgehog and mechanical load

“…3Dc), as visualized by DIC imaging (Fig. S2a-c), and is consistent with a recent report of Sox9 function in AC (Haseeb et al, 2021). Mutant tissues at 8 weeks continued to express Sox9 broadly in non-mineralized chondrocytes (Fig.…”

Effects of Berberine on the Chondrogenic Differentiation of Embryonic Limb Skeletal Progenitors

“…However, the histological appearance of the cultures together with the twofold increased expression of Scleraxis , and the overexpression of Ccn1 ( Cyr61 ) genes, that are associated with the differentiation of progenitors in the contour of the developing cartilage, 54 indicate that chondrogenic intensification was not fully dependent of a hypertrophic progression of cartilage differentiation. Consistent with this interpretation Sox9 gene, that is believed to counteract cartilage hypertrophy in the growth plate of long bones, 55 is maintained at high expression levels.…”

Single-Cell RNA-Seq Reveals Transcriptomic Heterogeneity and Post-Traumatic Osteoarthritis-Associated Early Molecular Changes in Mouse Articular Chondrocytes

“…Next, we compared the gene expression profiles of chondrocytes to all other cell type clusters (clusters 2, 5, 6, 8, 9) to identify genes enriched in healthy chondrocytes compared to other connective tissue-forming cells in the joint (Table S1, Figure S3). The master chondrocyte transcription factor Sox9 [25] and several other transcription factors (Nfatc2, Runx3, Bhlhe40, Bhlhe41, Lef1, Tsc22d1, and Sox5) showed significant enrichment in all chondrocyte clusters, suggesting that these transcription factors play major roles in regulating chondrocyte differentiation or homeostasis (Figure 1E and S3A). Previously, it has been shown that the ECM of articular cartilage is distinct from other types of connective tissues [4].…”

“…Analysis of the remaining 2490 cells resulted in 10 cell clusters with distinct gene expression profiles (Figure 1B and S2A). Cell type identities were assigned based on previously published cell-type specific markers [21,[25][26][27][28][29][30][31][32][33] (Figure 1B). Cells in clusters 0, 1, 3, and 4 expressed high levels of chondrocyte markers Sox9, Col2a1, and Acan [25] and were labeled 'chondrocytes' (Figure 1C,D).…”