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Osteoclasts adapt to physioxia perturbation through DNA demethylation
Authors:Keizo Nishikawa  Shigeto Seno  Toshitada Yoshihara  Ayako Narazaki  Yuki Sugiura  Reito Shimizu  Junichi Kikuta  Reiko Sakaguchi  Norio Suzuki  Norihiko Takeda  Hiroaki Semba  Masamichi Yamamoto  Daisuke Okuzaki  Daisuke Motooka  Yasuhiro Kobayashi  Makoto Suematsu  Haruhiko Koseki  Hideo Matsuda  Masayuki Yamamoto  Seiji Tobita  Yasuo Mori  Masaru Ishii
Abstract:Oxygen plays an important role in diverse biological processes. However, since quantitation of the partial pressure of cellular oxygen in vivo is challenging, the extent of oxygen perturbation in situ and its cellular response remains underexplored. Using two‐photon phosphorescence lifetime imaging microscopy, we determine the physiological range of oxygen tension in osteoclasts of live mice. We find that oxygen tension ranges from 17.4 to 36.4 mmHg, under hypoxic and normoxic conditions, respectively. Physiological normoxia thus corresponds to 5% and hypoxia to 2% oxygen in osteoclasts. Hypoxia in this range severely limits osteoclastogenesis, independent of energy metabolism and hypoxia‐inducible factor activity. We observe that hypoxia decreases ten‐eleven translocation (TET) activity. Tet2/3 cooperatively induces Prdm1 expression via oxygen‐dependent DNA demethylation, which in turn activates NFATc1 required for osteoclastogenesis. Taken together, our results reveal that TET enzymes, acting as functional oxygen sensors, regulate osteoclastogenesis within the physiological range of oxygen tension, thus opening new avenues for research on in vivo response to oxygen perturbation.
Keywords:bone metabolism  epigenetic regulation  intravital imaging  osteoclast  oxygen
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