Epigenetic and therapeutic implications of dnmt3b in temporomandibular joint osteoarthritis

Yue Zhou, Mo Chen, Regis J. O’Keefe, Jie Shen, Zhi Li, Jian Zhou, Xuedong Zhou, Jeremy J. Mao

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

Temporomandibular joint (TMJ) arthritis causes severe debilitation and has few treatment options. Here, we found a small molecule, DNA methyltransferase 3B (Dnmt3b), as a putative therapeutic target, partially rescued osteoarthritic phenotype. Dnmt3b was detected differentially expressed in cell zones of mandibular condylar cartilage and the expression of Dnmt3b decreased in the progression of TMJ osteoarthritis. Dnmt3b deficiency using conditional knockout mice led to the onset of osteoarthritis-like conditions including cartilage clefts, cartilage matrix loss and premature chondrocyte hypertrophy, which suggested that Dnmt3b functioned as a osteoarthritis suppressor. Dnmt3b gain-of-function in TMJ stem/progenitor cells showed increases in collagen type II but decreases in collagen type X, whereas Dnmt3b knockdown had opposite effects with attenuated collagen type II but increased collagen type X. Dnmt3b acted via Wnt/β-catenin signaling and Dnmt3b regulated TMJ stem/progenitor cells differentiation by inducing their premature progression towards hypertrophic chondrocytes through β-catenin transnucleation and activation. Finally, local Dnmt3b delivery partially rescued cartilage degradation in experimentally induced osteoarthritis. Thus, novel molecules in articular cartilage, such as Dnmt3b, may have therapeutic effects for TMJ osteoarthritis.

Original languageEnglish
Pages (from-to)1736-1747
Number of pages12
JournalAmerican Journal of Translational Research
Volume11
Issue number3
StatePublished - 2019

Keywords

  • Hypertrophy
  • Methyltransferase
  • Osteoarthritis
  • Temporomandibular joint

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