Premium
Osteoclasts adapt to physioxia perturbation through DNA demethylation
Author(s) -
Nishikawa Keizo,
Seno Shigeto,
Yoshihara Toshitada,
Narazaki Ayako,
Sugiura Yuki,
Shimizu Reito,
Kikuta Junichi,
Sakaguchi Reiko,
Suzuki Norio,
Takeda Norihiko,
Semba Hiroaki,
Yamamoto Masamichi,
Okuzaki Daisuke,
Motooka Daisuke,
Kobayashi Yasuhiro,
Suematsu Makoto,
Koseki Haruhiko,
Matsuda Hideo,
Yamamoto Masayuki,
Tobita Seiji,
Mori Yasuo,
Ishii Masaru
Publication year - 2021
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.202153035
Subject(s) - frontier , library science , medical school , medicine , medical education , political science , computer science , law
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.