H3K36 methyltransferase NSD1 protects against osteoarthritis through regulating chondrocyte differentiation and cartilage homeostasis

Abstract Osteoarthritis (OA) is the most common joint diseases, there are no disease-modifying drugs, and the pathological mechanisms of OA need further study. Here, we show that H3K36 methylations were decreased in senescent chondrocytes and age-induced osteoarthritic cartilage. Transgenic K36M/+; Prrx1-Cre mice showed articular cartilage destruction and osteophytes formation. Conditional knockout Nsd1 Prrx1-Cre mice, but not Nsd2 Prrx1-Cre or Setd2 Prrx1-Cre mice, replicated the phenotype of K36M/+; Prrx1-Cre mice. Immunostaining results showed reduced anabolic and increased catabolism in Nsd1 Prrx1-Cre mice, along with decreased chondrogenic differentiation. Transcriptome and ChIP-seq data revealed Osr2 was a key factor affected by Nsd1 . Intra-articular delivery of Osr2 adenovirus effectively improved the homeostasis of articular cartilage in Nsd1 Prrx1-Cre mice. In human osteoarthritic cartilages, both mRNA and protein levels of NSD1 and OSR2 were decreased. Our results indicate that NSD1 induced H3K36 methylations and OSR2 expression play important roles in articular cartilage homeostasis and osteoarthritis. Targeting H3K36 methylation and OSR2 would be a novel strategy for osteoarthritis treatment.