{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T14:46:01Z","timestamp":1790693161156,"version":"4.1.0"},"reference-count":40,"publisher":"National Academy of Sciences","issue":"25","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2012,6,19]]},"abstract":"<jats:p>\n                    Osteoclasts are generated from monocyte\/macrophage-lineage precursors in response to colony-stimulating factor 1 (CSF-1) and receptor activator of nuclear factor-\u03baB ligand (RANKL). CSF-1\u2013mutated\n                    <jats:italic>\n                      CSF-1\n                      <jats:sup>op\/op<\/jats:sup>\n                    <\/jats:italic>\n                    mice as well as\n                    <jats:italic>\n                      RANKL\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    <\/jats:italic>\n                    mice exhibit osteopetrosis (OP) caused by osteoclast deficiency. We previously identified RANKL receptor (RANK)\/CSF-1 receptor (CSF-1R) double-positive cells as osteoclast precursors (OCPs), which existed in bone in\n                    <jats:italic>\n                      RANKL\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    <\/jats:italic>\n                    mice. Here we show that OCPs do not exist in bone but in spleen in\n                    <jats:italic>\n                      CSF-1\n                      <jats:sup>op\/op<\/jats:sup>\n                    <\/jats:italic>\n                    mice, and spleen acts as their reservoir. IL-34, a newly discovered CSF-1R ligand, was highly expressed in vascular endothelial cells in spleen in\n                    <jats:italic>\n                      CSF-1\n                      <jats:sup>op\/op<\/jats:sup>\n                    <\/jats:italic>\n                    mice. Vascular endothelial cells in bone also expressed IL-34, but its expression level was much lower than in spleen, suggesting a role of IL-34 in the splenic generation of OCPs. Splenectomy (SPX) blocked CSF-1\u2013induced osteoclastogenesis in\n                    <jats:italic>\n                      CSF-1\n                      <jats:sup>op\/op<\/jats:sup>\n                    <\/jats:italic>\n                    mice. Osteoclasts appeared in aged\n                    <jats:italic>\n                      CSF-1\n                      <jats:sup>op\/op<\/jats:sup>\n                    <\/jats:italic>\n                    mice with up-regulation of IL-34 expression in spleen and bone. Splenectomy blocked the age-associated appearance of osteoclasts. The injection of 2-methylene-19-nor-(20\n                    <jats:italic>S<\/jats:italic>\n                    )-1\u03b1,25(OH)\n                    <jats:sub>2<\/jats:sub>\n                    D\n                    <jats:sub>3<\/jats:sub>\n                    (2MD), a potent analog of 1\u03b1,25-dihidroxyvitamin D\n                    <jats:sub>3<\/jats:sub>\n                    , into\n                    <jats:italic>\n                      CSF-1\n                      <jats:sup>op\/op<\/jats:sup>\n                    <\/jats:italic>\n                    mice induced both hypercalcemia and osteoclastogenesis. Administration of 2MD enhanced IL-34 expression not only in spleen but also in bone through a vitamin D receptor-mediated mechanism. Either splenectomy or siRNA-mediated knockdown of IL-34 suppressed 2MD-induced osteoclastogenesis. These results suggest that IL-34 plays a pivotal role in maintaining the splenic reservoir of OCPs, which are transferred to bone in response to diverse stimuli, in\n                    <jats:italic>\n                      CSF-1\n                      <jats:sup>op\/op<\/jats:sup>\n                    <\/jats:italic>\n                    mice. The present study also suggests that the IL-34 gene in vascular endothelial cells is a unique target of vitamin D.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1207361109","type":"journal-article","created":{"date-parts":[[2012,6,5]],"date-time":"2012-06-05T21:53:00Z","timestamp":1338933180000},"page":"10006-10011","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":68,"title":["Spleen serves as a reservoir of osteoclast precursors through vitamin D-induced IL-34 expression in osteopetrotic\n                    <i>op\/op<\/i>\n                    mice"],"prefix":"10.1073","volume":"109","author":[{"given":"Yuko","family":"Nakamichi","sequence":"first","affiliation":[{"name":"Division of Hard Tissue Research, Institute for Oral Science, and Departments of"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshihide","family":"Mizoguchi","sequence":"additional","affiliation":[{"name":"Division of Hard Tissue Research, Institute for Oral Science, and Departments of"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atsushi","family":"Arai","sequence":"additional","affiliation":[{"name":"Division of Hard Tissue Research, Institute for Oral Science, and Departments of"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuhiro","family":"Kobayashi","sequence":"additional","affiliation":[{"name":"Division of Hard Tissue Research, Institute for Oral Science, and Departments of"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masahiro","family":"Sato","sequence":"additional","affiliation":[{"name":"Conservative Dentistry and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josef M.","family":"Penninger","sequence":"additional","affiliation":[{"name":"Institute of Molecular Biotechnology, Austrian Academy of Sciences, A-1030, Vienna, Austria;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hisataka","family":"Yasuda","sequence":"additional","affiliation":[{"name":"Oriental Yeast Co., Tokyo 174-8505, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shigeaki","family":"Kato","sequence":"additional","affiliation":[{"name":"Laboratory of Nuclear Signaling, Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo 113-0032, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hector F.","family":"DeLuca","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Wisconsin, Madison, WI 53706; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatsuo","family":"Suda","sequence":"additional","affiliation":[{"name":"Research Center for Genomic Medicine, Saitama Medical University, Saitama 350-1241, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nobuyuki","family":"Udagawa","sequence":"additional","affiliation":[{"name":"Biochemistry, School of Dentistry, Matsumoto Dental University, Nagano 399-0781, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoyuki","family":"Takahashi","sequence":"additional","affiliation":[{"name":"Division of Hard Tissue Research, Institute for Oral Science, and Departments of"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2012,6,5]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature01658"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1210\/edrv.20.3.0367"},{"key":"e_1_3_3_3_2","first-page":"15","article-title":"The biology and action of colony stimulating factor-1","volume":"12","author":"Stanley ER","year":"1994","unstructured":"ER Stanley, KL Berg, DB Einstein, PS Lee, YG Yeung, The biology and action of colony stimulating factor-1. 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