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However, the mechanisms leading to inappropriate increases in osteoclastic bone resorption are only partially understood. Here, we show that exposure to multiple fractions of low-doses (10 fractions of 0.4 Gy total body irradiation [TBI]\/week, i.e., fractionated exposure) and\/or a single exposure to the same total dose of 4 Gy TBI causes a decrease in trabecular, but not cortical, bone mass in young adult male mice. This damaging effect was associated with highly activated bone resorption. Both osteoclast differentiation and maturation increased in cultures of bone marrow-derived macrophages from mice exposed to either fractionated or singular TBI. IR also increased the expression and enzymatic activity of mitochondrial deacetylase Sirtuin-3 (Sirt3)\u2014an essential protein for osteoclast mitochondrial activity and bone resorption in the development of osteoporosis. Osteoclast progenitors lacking Sirt3 exposed to IR exhibited impaired resorptive activity. Taken together, targeting impairment of osteoclast mitochondrial activity could be a novel therapeutic strategy for IR-induced bone loss, and Sirt3 is likely a major mediator of this effect.<\/jats:p>","DOI":"10.3390\/ijms23020675","type":"journal-article","created":{"date-parts":[[2022,1,9]],"date-time":"2022-01-09T20:29:26Z","timestamp":1641760166000},"page":"675","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Ionizing Radiation Activates Mitochondrial Function in Osteoclasts and Causes Bone Loss in Young Adult Male Mice"],"prefix":"10.3390","volume":"23","author":[{"given":"Kimberly K.","family":"Richardson","sequence":"first","affiliation":[{"name":"Center for Musculoskeletal Disease Research and Center for Osteoporosis and Metabolic Bone Diseases, Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"Ling","sequence":"additional","affiliation":[{"name":"Center for Musculoskeletal Disease Research and Center for Osteoporosis and Metabolic Bone Diseases, Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimberly","family":"Krager","sequence":"additional","affiliation":[{"name":"Division of Radiation Health, Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiang","family":"Fu","sequence":"additional","affiliation":[{"name":"Center for Musculoskeletal Disease Research and Center for Osteoporosis and Metabolic Bone Diseases, Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1783-3610","authenticated-orcid":false,"given":"Stephanie D.","family":"Byrum","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6239-301X","authenticated-orcid":false,"given":"Rupak","family":"Pathak","sequence":"additional","affiliation":[{"name":"Division of Radiation Health, Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8574-4102","authenticated-orcid":false,"given":"Nukhet","family":"Aykin-Burns","sequence":"additional","affiliation":[{"name":"Division of Radiation Health, Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2498-6700","authenticated-orcid":false,"given":"Ha-Neui","family":"Kim","sequence":"additional","affiliation":[{"name":"Center for Musculoskeletal Disease Research and Center for Osteoporosis and Metabolic Bone Diseases, Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,1,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1002\/mpo.10338","article-title":"Radiation-therapy effects on bone density","volume":"41","author":"Hopewell","year":"2003","journal-title":"Med. 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