EZH1 and EZH2 promote skeletal growth by repressing inhibitors of chondrocyte proliferation and hypertrophy

Abstract

Histone methyltransferases EZH1 and EZH2 catalyse the trimethylation of histone H3 at lysine 27 (H3K27), which serves as an epigenetic signal for chromatin condensation and transcriptional repression. Genome-wide associated studies have implicated EZH2 in the control of height and mutations in EZH2 cause Weaver syndrome, which includes skeletal overgrowth. Here we show that the combined loss of Ezh1 and Ezh2 in chondrocytes severely impairs skeletal growth in mice. Both of the principal processes underlying growth plate chondrogenesis, chondrocyte proliferation and hypertrophy, are compromised. The decrease in chondrocyte proliferation is due in part to derepression of cyclin-dependent kinase inhibitors Ink4a/b, while ineffective chondrocyte hypertrophy is due to the suppression of IGF signalling by the increased expression of IGF-binding proteins. Collectively, our findings reveal a critical role for H3K27 methylation in the regulation of chondrocyte proliferation and hypertrophy in the growth plate, which are the central determinants of skeletal growth.

Epigenetics as a New Frontier in Orthopedic Regenerative Medicine and Oncology

“…Complete knockout of EZH2 in mice produced nonviable embryos with abnormal accumulation of mesodermal cells . EZH2 also has key roles in skeletal development as conditional loss of EZH2 , affects skeletal patterning as well as skeletal growth and bone formation . For example, conditional loss of EZH2 in neural crest–derived tissues (using the Wnt1‐Cre driver) causes craniofacial defects .…”

“…However, EZH1 partially compensates for loss of EZH2 during skeletal development. Dual inactivation of EZH1 and EZH2 in chondrocytes delays skeletal growth . The most dramatic skeletal phenotypic changes were observed in mice with a conditional null mutation in EED, a scaffolding protein that is required for PRC2 complexes that contain either EZH1 or EZH2 as active enzymatic subunits in the sites .…”

“…EZH1 appears to be expressed at different times of skeletal development. EZH2 is most abundant in proliferating uncommitted mesenchymal stem cells, while EZH1 is expressed most prominently in postproliferative lineage‐committed cells . Hence, EZH1 and EZH2 are expressed in different spatio‐temporal patterns and may have distinct mechanistic activities during mesenchymal differentiation and skeletal development.…”

Ezh2 Ameliorates Osteoarthritis by Activating TNFSF13B

“…It was recently revealed that epigenetic regulation is involved in OA pathology and skeletal growth disorders . Our group recently found that the H3K27 (lysine 27 on histone H3) demethylase KDM6B regulated chondrocyte anabolic metabolism in vivo .…”

Recent Advances in Scaffold Design and Material for Vascularized Tissue‐Engineered Bone Regeneration

“…Osteoblasts trapped in the matrix become osteocytes and the bone‐like material calcifies to form a bone matrix, forming the earliest bone tissue. During cartilage osteogenesis, mesenchymal stem cells aggregate and differentiate into chondrocytes and then the chondrocytes proliferate and secrete cartilage matrix rich in type II collagen and proteoglycans . Under stimulation with certain signals, these cells stop proliferating and enter a state of hypertrophy, secreting a matrix rich in type V collagen.…”