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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 6

Mitochondrial function and cellular homeostasis in Dnmt3b GOF chondrocytes.

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Mitochondrial function and cellular homeostasis in Dnmt3b GOF chondrocyt...
(A) Gene expression in chondrocytes isolated from 10-week-old Ctrl or Dnmt3b gain-of-function (GOF) mice (n = 3). (B) Mitochondrial respiration, as measured by the oxygen consumption rate (OCR), in primary articular chondrocytes isolated from 2-month-old Col2a1Cre; Rosa-rtTAfl/+; Dnmt3b-tg mice, treated with vehicle (Ctrl) or doxycycline (Dnmt3b GOF) for 48 hours (n = 3). Mitochondrial respiration was measured by the Seahorse XF Extracellular Flux Analyzer. *P < 0.05 by 2-tailed Student’s t test.

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