{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T18:26:27Z","timestamp":1792002387372,"version":"4.4.0"},"reference-count":40,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2022,4,27]],"date-time":"2022-04-27T00:00:00Z","timestamp":1651017600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100003844","name":"Inamori Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003844","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["17H06816"],"award-info":[{"award-number":["17H06816"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["18H02926"],"award-info":[{"award-number":["18H02926"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008880","name":"Kanae Foundation for the Promotion of Medical Science","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100008880","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["DE019420"],"award-info":[{"award-number":["DE019420"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007449","name":"Takeda Science Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007449","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2022,6]]},"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Hypoxia occurs in tumors, infections, and sites of inflammation, such as in the affected joints of patients with rheumatoid arthritis (RA). It alleviates inflammatory responses and increases bone resorption in inflammatory arthritis by enhancing osteoclastogenesis. The mechanism by which the hypoxia response is linked to osteoclastogenesis and inflammatory bone resorption is unclear. This study was undertaken to evaluate whether the protein lysine\u2010specific demethylase 1 (LSD1) metabolically integrates inflammatory osteoclastogenesis and bone resorption in a state of inflammatory arthritis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      LSD1\u2010specific inhibitors and gene silencing with small interfering RNAs were used to inhibit the expression of LSD1 in human osteoclast precursor cells derived from CD14\u2010positive monocytes, with subsequent assessment by RNA\u2010sequencing analysis. In experimental mouse models of arthritis, inflammatory osteolysis, or osteoporosis, features of accelerated bone loss and inflammatory osteolysis were analyzed. Furthermore, in blood samples from patients with RA,\n                      <jats:italic>cis<\/jats:italic>\n                      \u2010acting expression quantitative trait loci (\n                      <jats:italic>cis<\/jats:italic>\n                      \u2010eQTL) were analyzed for association with the expression of hypoxia\u2010inducible factor 1\u03b1 (HIF\u20101\u03b1), and associations between HIF\u20101\u03b1 allelic variants and extent of bone erosion were evaluated.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      In human osteoclast precursor cells, RANKL induced the expression of LSD1 in a mechanistic target of rapamycin\u2013dependent manner. Expression of LSD1 was higher in synovium from RA patients than in synovium from osteoarthritis patients. Inhibition of LSD1 in human osteoclast precursors suppressed osteoclast differentiation. Results of transcriptome analysis identified several LSD1\u2010mediated hypoxia and cell\u2010cycle pathways as key genetic pathways involved in human osteoclastogenesis. Furthermore, HIF\u20101\u03b1 protein, which is rapidly degraded by the proteasome in a normoxic environment, was found to be expressed in RANKL\u2010stimulated osteoclast precursor cells. Induction of LSD1 by RANKL stabilized the expression of HIF\u20101\u03b1 protein, thereby promoting glycolysis, in conjunction with up\u2010regulation of the transcription factor E2F1. Analyses of\n                      <jats:italic>cis<\/jats:italic>\n                      \u2010eQTL revealed that higher HIF\u20101\u03b1 expression was associated with increased bone erosion in patients with RA. Inhibition of LSD1 decreased pathologic bone resorption in mice, both in models of accelerated osteoporosis and models of arthritis and inflammatory osteolysis.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>LSD1 metabolically regulates osteoclastogenesis in an energy\u2010demanding inflammatory environment. These findings provide potential new therapeutic strategies targeting osteoclasts in the management of inflammatory arthritis, including in patients with RA.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/art.42074","type":"journal-article","created":{"date-parts":[[2022,1,25]],"date-time":"2022-01-25T09:03:30Z","timestamp":1643101410000},"page":"948-960","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":68,"title":["Role of\n                    <scp>Lysine\u2010Specific<\/scp>\n                    Demethylase 1 in Metabolically Integrating Osteoclast Differentiation and Inflammatory Bone Resorption Through\n                    <scp>Hypoxia\u2010Inducible<\/scp>\n                    Factor 1\u03b1 and\n                    <scp>E2F1<\/scp>"],"prefix":"10.1002","volume":"74","author":[{"given":"Kohei","family":"Doi","sequence":"first","affiliation":[{"name":"Kyoto University Graduate School of Medicine  Kyoto 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