{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T00:14:54Z","timestamp":1790727294492,"version":"4.1.0"},"reference-count":32,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2025,9,5]],"date-time":"2025-09-05T00:00:00Z","timestamp":1757030400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["R01\u2010DK087727"],"award-info":[{"award-number":["R01\u2010DK087727"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["R01\u2010DK128068"],"award-info":[{"award-number":["R01\u2010DK128068"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005294","name":"Massachusetts General Hospital","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100005294","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J Hematol"],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    The bone morphogenetic protein (BMP)\u2010SMAD signaling pathway is central to regulating hepcidin, the master regulator of systemic iron homeostasis. We have previously demonstrated that BMP6, BMP2, and, to a lesser extent, BMP5 are the major ligands contributing to hepcidin and iron homeostasis regulation in\u00a0vivo. Hemojuvelin (HJV) and homeostatic iron regulator (HFE) are hepcidin modulators that are mutated in hereditary hemochromatosis. Although both HJV and HFE regulate hepcidin, at least partly, by functionally interacting with the BMP\u2013SMAD pathway, the mechanisms are incompletely understood. Notably, both HJV and HFE can regulate hepcidin in a BMP6\u2010independent manner. To understand whether HJV and HFE influence hepcidin regulation by BMP2 and\/or BMP5, we investigated the iron phenotype of mice with combined mutations in endothelial\n                    <jats:italic>Bmp2\/Hjv<\/jats:italic>\n                    and\n                    <jats:italic>Bmp5\/Hfe.<\/jats:italic>\n                    We found that endothelial\n                    <jats:italic>Bmp2\/Hjv<\/jats:italic>\n                    double knockout (KO) mice exhibit more severe hepcidin deficiency and iron overload than single endothelial\n                    <jats:italic>Bmp2<\/jats:italic>\n                    or\n                    <jats:italic>Hjv<\/jats:italic>\n                    KO mice, similar to previous findings in mice with double endothelial\n                    <jats:italic>Bmp2\/Hfe<\/jats:italic>\n                    KO and\n                    <jats:italic>Bmp6\/Hjv<\/jats:italic>\n                    KO, or a functional loss of both\n                    <jats:italic>Bmp6<\/jats:italic>\n                    and\n                    <jats:italic>Hfe<\/jats:italic>\n                    . Moreover, we found that iron completely fails to induce hepcidin in both endothelial\n                    <jats:italic>Bmp2\/Hjv<\/jats:italic>\n                    and\n                    <jats:italic>Bmp2\/Hfe<\/jats:italic>\n                    double KO mice. In contrast, a functional loss of BMP5 does not worsen hemochromatosis in\n                    <jats:italic>Hfe<\/jats:italic>\n                    KO mice. Together with other published data, these findings suggest a model whereby BMP2 and BMP6 can signal to hepcidin induction independently of HJV and HFE and vice versa. In contrast, BMP5, HJV, and HFE are all required for iron\u2010mediated hepcidin regulation in the absence of BMP2 and BMP6.\n                  <\/jats:p>","DOI":"10.1002\/ajh.70055","type":"journal-article","created":{"date-parts":[[2025,9,6]],"date-time":"2025-09-06T04:29:56Z","timestamp":1757132996000},"page":"2175-2184","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Hemochromatosis Proteins Hemojuvelin and Homeostatic Iron Regulator\u00a0in Bone Morphogenetic Protein\u2010Mediated Hepcidin Regulation and Iron Homeostasis"],"prefix":"10.1002","volume":"100","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9874-5240","authenticated-orcid":false,"given":"Xia","family":"Xiao","sequence":"first","affiliation":[{"name":"Nephrology Division and Endocrine Unit Massachusetts General Hospital, Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gillian A.","family":"Moschetta","sequence":"additional","affiliation":[{"name":"Nephrology Division and Endocrine Unit Massachusetts General Hospital, Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samit B.","family":"Chowdhury","sequence":"additional","affiliation":[{"name":"Nephrology Division and Endocrine Unit Massachusetts General Hospital, Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sydney","family":"Phillips","sequence":"additional","affiliation":[{"name":"Nephrology Division and Endocrine Unit Massachusetts General Hospital, Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niraj","family":"Ghatpande","sequence":"additional","affiliation":[{"name":"Nephrology Division and Endocrine Unit Massachusetts General Hospital, Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9393-2442","authenticated-orcid":false,"given":"Allison L.","family":"Fisher","sequence":"additional","affiliation":[{"name":"Nephrology Division and Endocrine Unit Massachusetts General Hospital, Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongqiang","family":"Xue","sequence":"additional","affiliation":[{"name":"Nephrology Division and Endocrine Unit Massachusetts General Hospital, Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1228-1551","authenticated-orcid":false,"given":"Jodie L.","family":"Babitt","sequence":"additional","affiliation":[{"name":"Nephrology Division and Endocrine Unit Massachusetts General Hospital, Harvard Medical School  Boston Massachusetts 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