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DNA methyltransferase 3b regulates articular cartilage homeostasis by altering metabolism
Jie Shen, … , Audrey McAlinden, Regis J. O’Keefe
Jie Shen, … , Audrey McAlinden, Regis J. O’Keefe
Published June 15, 2017
Citation Information: JCI Insight. 2017;2(12):e93612. https://doi.org/10.1172/jci.insight.93612.
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Research Article Bone biology

DNA methyltransferase 3b regulates articular cartilage homeostasis by altering metabolism

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Abstract

Osteoarthritis (OA) is the most common form of arthritis worldwide. It is a complex disease affecting the whole joint but is generally characterized by progressive degradation of articular cartilage. Recent genome-wide association screens have implicated distinct DNA methylation signatures in OA patients. We show that the de novo DNA methyltransferase (Dnmt) 3b, but not Dnmt3a, is present in healthy murine and human articular chondrocytes and its expression decreases in OA mouse models and in chondrocytes from human OA patients. Targeted deletion of Dnmt3b in murine articular chondrocytes results in an early-onset and progressive postnatal OA-like pathology. RNA-Seq and methylC-Seq analyses of Dnmt3b loss-of-function chondrocytes show that cellular metabolic processes are affected. Specifically, TCA metabolites and mitochondrial respiration are elevated. Importantly, a chondroprotective effect was found following Dnmt3b gain of function in murine articular chondrocytes in vitro and in vivo. This study shows that Dnmt3b plays a significant role in regulating postnatal articular cartilage homeostasis. Cellular pathways regulated by Dnmt3b in chondrocytes may provide novel targets for therapeutic approaches to treat OA.

Authors

Jie Shen, Cuicui Wang, Daofeng Li, Taotao Xu, Jason Myers, John M. Ashton, Ting Wang, Michael J. Zuscik, Audrey McAlinden, Regis J. O’Keefe

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Figure 1

Dnmt3b expression in murine and human knee joint cartilage.

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Dnmt3b expression in murine and human knee joint cartilage.
(A) Represen...
(A) Representative images showing that Dnmt3a is not expressed in chondrocytes from 3-month-old WT articular cartilage (Dnmt3a expression in pancreas served as a positive control), while robust expression of Dnmt3b is seen in chondrocytes of 3-month-old WT articular cartilage, with lower expression in underlying growth plate cartilage (n = 3); the magnified images of the dashed and solid boxed areas of articular cartilage are in separate panels. (B) Representative images showing Dnmt3b expression in 3-month-old (n = 3) versus 27-month-old (n = 3) WT murine knee articular cartilage. (C) Representative images showing Dnmt3b expression in 14-week-old murine articular cartilage following meniscal ligament injury (MLI) surgery (n = 3) or cartilage from sham control knees (n = 3). (D) Representative images showing Dnmt3b expression in 14-week-old murine articular cartilage in mice fed a high-fat diet (HFD) (n = 3) or controls (Ctrl) fed a normal diet (n = 3). (E) Two representative images showing DNMT3B expression in human healthy (ND) articular cartilage (n = 11) or osteoarthritic (OA) cartilage tissue sections (n = 71). (F) Reduced DNMT3B expression in human primary OA chondrocytes compared with healthy chondrocytes (n = 3). (G) Induction of human primary chondrocytes (n = 3) with IL-1β results in decreased expression of DNMT3B mRNA and protein levels. Scale bars: 100 μm. *P < 0.05 by 2-tailed Student’s t test.

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