Epigenetic and therapeutic implications of dnmt3b in temporomandibular joint osteoarthritis

American Journal of Translational Research

Mo Chen¹  Jie Shen²  Zhi Li³  Regis J O’Keefe⁴  Yue Zhou⁵ 

[1] Center for Craniofacial Regeneration, Columbia University Medical Center, New York, NY 10032, USA;Columbia University College of Dental Medicine, New York, NY 10032, USA;Department of Orthopedic Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA;Shanghai Engineering Research Center of Tooth Restoration and Regeneration, School and Hospital of Stomatology, Tongji University, Shanghai 200072, China;State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, West China School of Stomatology, Sichuan University, Chengdu 610041, China

关键词: Temporomandibular joint;    osteoarthritis;    methyltransferase;    hypertrophy;   

DOI  :  

学科分类：医学（综合）

来源: e-Century Publishing Corporation

【 摘 要 】

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.

【 授权许可】

CC BY-NC