Metabolic reprogramming occurs in response to the cellular environment to mediate differentiation, but the fundamental mechanisms linking metabolic processes to differentiation programs remain to be elucidated. During osteoclast differentiation, a shift toward more oxidative metabolic processes occurs. In this study we identified the de novo DNA methyltransferase 3a (Dnmt3a) as a transcription factor that couples these metabolic changes to osteoclast differentiation. We also found that receptor activator of nuclear factor-κB ligand (RANKL), an essential cytokine for osteoclastogenesis, induces this metabolic shift towards oxidative metabolism, which is accompanied by an increase in S-adenosylmethionine (SAM) production. We found that SAM-mediated DNA methylation by Dnmt3a regulates osteoclastogenesis via epigenetic repression of anti-osteoclastogenic genes. The importance of Dnmt3a in bone homeostasis was underscored by the observations that Dnmt3a-deficient osteoclast precursor cells do not differentiate efficiently into osteoclasts and that mice with an osteoclast-specific deficiency in Dnmt3a have elevated bone mass due to a smaller number of osteoclasts. Furthermore, inhibition of DNA methylation by theaflavin-3,3'-digallate abrogated bone loss in models of osteoporosis. Thus, this study reveals the role of epigenetic processes in the regulation of cellular metabolism and differentiation, which may provide the molecular basis for a new therapeutic strategy for a variety of bone disorders.

Bone homeostasis is regulated by communication between bone-forming mature osteoblasts (mOBs) and bone-resorptive mature osteoclasts (mOCs). However, the spatial–temporal relationship and mode of interaction in vivo remain elusive. Here we show, by using an intravital imaging technique, that mOB and mOC functions are regulated via direct cell–cell contact between these cell types. The mOBs and mOCs mainly occupy discrete territories in the steady state, although direct cell–cell contact is detected in spatiotemporally limited areas. In addition, a pH-sensing fluorescence probe reveals that mOCs secrete protons for bone resorption when they are not in contact with mOBs, whereas mOCs contacting mOBs are non-resorptive, suggesting that mOBs can inhibit bone resorption by direct contact. Intermittent administration of parathyroid hormone causes bone anabolic effects, which lead to a mixed distribution of mOBs and mOCs, and increase cell–cell contact. This study reveals spatiotemporal intercellular interactions between mOBs and mOCs affecting bone homeostasis in vivo.

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These results demonstrate that Sema4A plays an inhibitory role in Th2-type allergic diseases, such as allergic asthma.

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A: Considerable amounts of radioactive substances (mainly 137 Cs and 134 Cs) were released into the environment after the Japanese nuclear disaster in 2011. Some restrictions on residence areas were lifted in April 2017, owing to the successive and effective decontamination operations. However, the distribution of radioactive substances in vast areas of mountain, forest and satoyama close to the city is still unknown; thus, decontamination operations in such areas are being hampered. In this paper, we report on the first aerial gamma-ray imaging of a schoolyard in Fukushima using a drone that carries a high sensitivity Compton camera. We show that the distribution of 137 Cs in regions with a diameter of several tens to a hundred meters can be imaged with a typical resolution of 2-5 m within a 10-20 min flights duration. The aerial gamma-ray images taken 10 m and 20 m above the ground are qualitatively consistent with a dose map reconstructed from the ground-based measurements using a survey meter. Although further quantification is needed for the distance and air-absorption corrections to derive in situ dose map, such an aerial drone system can reduce measurement time by a factor of ten and is suitable for place where ground-based measurement are difficult. K: Dosimetry concepts and apparatus; Photon detectors for UV, visible and IR photons (solid-state) (PIN diodes, APDs, Si-PMTs, G-APDs, CCDs, EBCCDs, EMCCDs etc); Scintillators, scintillation and light emission processes (solid, gas and liquid scintillators) 1Corresponding author.