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However, little is known about the role of Fosl2 in hematopoiesis and the possible pathological role of Fosl2 inactivation in the hematopoietic system in arthritis. In this study, we show that Fosl2 maintains hematopoietic stem cell (HSC) quiescence and differentiation while controlling the inflammatory response via macrophages. Fosl2-specific deletion in the hematopoietic system caused the expansion of HSCs and myeloid cell growth while affecting erythroid and B cell differentiation. Fosl2 inactivation enhanced macrophage M1 polarization and stimulated proinflammatory cytokines and myeloid growth factors, skewing HSCs toward myeloid cell differentiation, similar to hematopoietic alterations in arthritic mice. Loss of Fosl2 mediated by Vav-iCre also displays an unexpected deletion in embryonic erythro-myeloid progenitor\u2013derived osteoclasts, leading to osteopetrosis and anemia. The reduced bone marrow cellularity in Vav-iCreFosl2f\/f mice is a consequence of the reduced bone marrow space in osteopetrotic mice rather than a direct role of Fosl2 in hematopoiesis. Thus, Fosl2 is indispensable for erythro-myeloid progenitor\u2013derived osteoclasts to maintain the medullary cavity to ensure normal hematopoiesis. These findings improve our understanding of the pathogenesis of bone-destructive diseases and provide important implications for developing therapeutic approaches for these diseases.<\/jats:p>","DOI":"10.4049\/jimmunol.2300592","type":"journal-article","created":{"date-parts":[[2024,2,21]],"date-time":"2024-02-21T14:28:26Z","timestamp":1708525706000},"page":"1081-1093","source":"Crossref","is-referenced-by-count":2,"title":["Fosl2 Deficiency Predisposes Mice to Osteopetrosis, Leading to Bone Marrow Failure"],"prefix":"10.1093","volume":"212","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-7202-1754","authenticated-orcid":false,"given":"Jinfeng","family":"Chen","sequence":"first","affiliation":[{"name":"Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, College of Life Science, Fujian Normal University , Fuzhou, Fujian ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3211-550X","authenticated-orcid":false,"given":"Yi","family":"Wen","sequence":"additional","affiliation":[{"name":"Shenzhen Key Laboratory of Gene Regulation and Systems Biology, Department of Biology, School of Life Sciences, Southern University of Science and Technology , Shenzhen ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lili","family":"Lin","sequence":"additional","affiliation":[{"name":"Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, College of Life Science, Fujian Normal University , Fuzhou, Fujian ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-9286-426X","authenticated-orcid":false,"given":"Yuchen","family":"Cui","sequence":"additional","affiliation":[{"name":"Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, College of Life Science, Fujian Normal University , Fuzhou, Fujian ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenyu","family":"Chen","sequence":"additional","affiliation":[{"name":"Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, College of Life Science, Fujian Normal University , Fuzhou, Fujian ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Gao","sequence":"additional","affiliation":[{"name":"Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, College of Life Science, Fujian Normal University , Fuzhou, Fujian ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-3993-9844","authenticated-orcid":false,"given":"Yifang","family":"Zhuang","sequence":"additional","affiliation":[{"name":"Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, College of Life Science, Fujian Normal University , Fuzhou, Fujian ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Chen","sequence":"additional","affiliation":[{"name":"Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, College of Life Science, Fujian Normal University , Fuzhou, Fujian ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,2,21]]},"reference":[{"key":"2025020405475009800_r1","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1016\/j.cell.2008.01.025","article-title":"Hematopoiesis: an evolving paradigm for stem cell biology","volume":"132","author":"Orkin","year":"2008","journal-title":"Cell"},{"key":"2025020405475009800_r2","doi-asserted-by":"crossref","first-page":"784","DOI":"10.1126\/science.1105786","article-title":"Bone resorption restored in osteopetrotic mice by transplants of normal bone marrow and spleen cells","volume":"190","author":"Walker","year":"1975","journal-title":"Science"},{"key":"2025020405475009800_r3","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1038\/283669a0","article-title":"Osteoclasts derived from haematopoietic stem cells","volume":"283","author":"Ash","year":"1980","journal-title":"Nature"},{"key":"2025020405475009800_r4","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1016\/0012-1606(78)90132-X","article-title":"The developmental relationship between osteocytes and osteoblasts: a study using the quail-chick nucleus marker in endochondrial ossefication","volume":"63","author":"Jotereau","year":"1978","journal-title":"Dev. 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