ESPE Yearbook of Paediatric Endocrinology

Proc Natl Acad Sci USA 2021 Feb 23;118(8):e2019152118. Abstract: https://pubmed.ncbi.nlm.nih.gov/33597301/

In brief: Sox9 is the key transcription factor and master regulator of chondrocyte differentiation during skeletal development. This paper demonstrates that SOX9 also has a key role during postnatal life to maintain open growth plates and healthy articular cartilage by preventing dedifferentiation of chondrocytes into skeletal progenitors and their subsequent differentiation into osteoblasts.

Comment: Haseeb et al. investigated the essential role of the transcription factor SOX9 in growth plate and articular cartilage. During development chondrocytes undergo differentiation programs to form growth plate cartilage that drives skeletal growth, but also to form permanent articular cartilage at the joint surfaces. It is well-established that SOX9 is essential during embryonic chondrogenesis, but its role during postnatal life is still elusive.

The authors used conditional knock-out mice and high-throughput sequencing analyses and showed that SOX9 prevents growth plate closures at postnatal level as well as deterioration of articular cartilage in an osteoarthritic microenvironment. In absence of SOX9, growth plates are rapidly fused as chondrocytes differentiate to hypertrophic chondrocytes or revert to a dedifferentiated progenitor state, followed by upregulation of osteogenic specific genes and differentiation toward osteoblast cells. Pathway analysis revealed that SOX9 controls TGFβ and BMP signaling during this cell lineage transition. SOX9 deficiency did not alter articular cartilage differentiation, except in the load-bearing regions, in which the chondrocyte-to-osteoblast transition occurred.

In summary, the findings reveal that SOX9 is crucial to maintain cells in the chondrocytic state, prevent hypertrophy and also restrain plasticity towards dedifferentiation to the progenitor state, as well as toward osteoblast differentiation. This highlights the essential role of SOX9 in maintaining healthy growth plate and articular cartilage, improving our understanding of the functional mechanisms underlying cartilage skeletal disorders and points towards a potential target for novel therapeutic approaches for growth regulation as well as for the prevention of osteoarthritis.