image: During the process of endochondral ossification in growth plate cartilage, hypertrophic genes are marked by both H3K27me3 and H3K4me3 to enable rapid activation when needed. In articular cartilage, which shares a common origin with growth plate cartilage, these hypertrophic genes remain in a bivalent state. Under physiological conditions, these genes are transcriptionally repressed. However, under pathological conditions of osteoarthritis (OA), the repressive mark H3K27me3 is lost, leading to the activation of hypertrophic genes, which promotes cartilage matrix degradation and contributes to OA progression.
Credit: ©Science China Press
OA affects as much as 40% of the elderly population, representing the largest cause of age-related disability. The high susceptibility to OA suggests an intrinsic and systemic characteristic in articular chondrocytes that makes cartilage prone to degeneration.
Epigenetic bivalency, which means coexist of repressive (H3K27me3) and activating (H3K4me3) histone marks, are considered to poise expression of developmental genes in embryonic stem cells, allowing timely activation while maintaining repression in the absence of differentiation signals. Surprisingly, in this paper, researchers reported bivalency for hypertrophy related genes (eg. ADAMTS2 and COL1A1) in normal articular chondrocytes. This bivalency is needed for the activation of hypertrophic genes in growth plate chondrocytes for extracellular matrix degradation and ossification but are left as a “bomb” for degeneration in articular chondrocytes.
In healthy cartilage, hypertrophic genes remain bivalency and repressed. However, in OA cartilage, inflammatory factors trigger the upregulation of an enzyme called KDM6B, which removes H3K27me3, leading to the unwanted activation of these genes, driving cartilage breakdown.
"This study not only explains why articular cartilage is so vulnerable to degeneration but also provides a potential therapeutic strategy to halt OA progression," said Professor Shishu Huang, corresponding author of the study. "By targeting the epigenetic enzyme KDM6B, we can potentially prevent the activation of genes that drive cartilage breakdown."
The findings also have broader implications for understanding how developmental epigenetic features can predispose tissues to disease. "This is a prime example of how developmental legacy can influence disease susceptibility," added Dr Hao Du (first author). "We believe this concept could extend to other tissues and diseases."
Journal
Science China Life Sciences
Method of Research
Experimental study