TY - JOUR
T1 - Osteoclasts adapt to physioxia perturbation through DNA demethylation
AU - Nishikawa, Keizo
AU - Seno, Shigeto
AU - Yoshihara, Toshitada
AU - Narazaki, Ayako
AU - Sugiura, Yuki
AU - Shimizu, Reito
AU - Kikuta, Junichi
AU - Sakaguchi, Reiko
AU - Suzuki, Norio
AU - Takeda, Norihiko
AU - Semba, Hiroaki
AU - Yamamoto, Masamichi
AU - Okuzaki, Daisuke
AU - Motooka, Daisuke
AU - Kobayashi, Yasuhiro
AU - Suematsu, Makoto
AU - Koseki, Haruhiko
AU - Matsuda, Hideo
AU - Yamamoto, Masayuki
AU - Tobita, Seiji
AU - Mori, Yasuo
AU - Ishii, Masaru
N1 - Funding Information:
This work was supported by Grants‐in‐Aid for Scientific Research (B) from the Japan Society for the Promotion of Science (JSPS) (18H02614 to KN); Grants‐in‐Aid for Scientific Research on Innovative Areas from the JSPS (17H05530 to KN); CREST, Japan Science and Technology Agency (to MI); Grants‐in‐Aid for Scientific Research (S) from the JSPS (19H05657 to MI); Grants‐in‐Aid for Scientific Research on Innovative Areas from the JSPS (26111001 and 26111004 to YM); grants from the Takeda Science Foundation (to KN and MI); Toray Science Foundation (to KN); the Nakatani Foundation (to KN); Yamada Science Foundation (to KN); LOTTE Foundation (to KN); Suzuken Memorial Foundation (to KN); Terumo Life Science Foundation (to KN); and infrastructure of metabolomics was partly supported by JST ERATO Suematsu Gas Biology Project (to MS).
Publisher Copyright:
©2021 The Authors. Published under the terms of the CC BY NC ND 4.0 license
PY - 2021/12/6
Y1 - 2021/12/6
N2 - 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.
AB - 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.
KW - bone metabolism
KW - epigenetic regulation
KW - intravital imaging
KW - osteoclast
KW - oxygen
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U2 - 10.15252/embr.202153035
DO - 10.15252/embr.202153035
M3 - Article
C2 - 34661337
AN - SCOPUS:85117100298
SN - 1469-221X
VL - 22
JO - EMBO Reports
JF - EMBO Reports
IS - 12
M1 - e53035
ER -