{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T01:27:39Z","timestamp":1790558859140,"version":"4.1.0"},"reference-count":39,"publisher":"National Academy of Sciences","issue":"45","license":[{"start":{"date-parts":[[2022,11,2]],"date-time":"2022-11-02T00:00:00Z","timestamp":1667347200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000069","name":"HHS | NIH | National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["K99AR079558"],"award-info":[{"award-number":["K99AR079558"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Uplifting Athletes","award":["funding for rare disease research"],"award-info":[{"award-number":["funding for rare disease research"]}]},{"DOI":"10.13039\/100000738","name":"U.S. Department of Veterans Affairs","doi-asserted-by":"publisher","award":["5IK6BX004984-03"],"award-info":[{"award-number":["5IK6BX004984-03"]}],"id":[{"id":"10.13039\/100000738","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000069","name":"HHS | NIH | National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["R00DE031148-02"],"award-info":[{"award-number":["R00DE031148-02"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100019823","name":"University of Maryland, Baltimore","doi-asserted-by":"publisher","award":["start-up funds"],"award-info":[{"award-number":["start-up funds"]}],"id":[{"id":"10.13039\/100019823","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000069","name":"HHS | NIH | National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["intramural research program funding"],"award-info":[{"award-number":["intramural research program funding"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","award":["1726346"],"award-info":[{"award-number":["1726346"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Kentucky Nephrology Research Fund","award":["Kentucky Nephrology Research Fund"],"award-info":[{"award-number":["Kentucky Nephrology Research Fund"]}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2022,11,8]]},"abstract":"<jats:p>\n                    Citrate is a critical metabolic substrate and key regulator of energy metabolism in mammalian cells. It has been known for decades that the skeleton contains most (&gt;85%) of the body\u2019s citrate, but the question of why and how this metabolite should be partitioned in bone has received singularly little attention. Here, we show that osteoblasts use a specialized metabolic pathway to regulate uptake, endogenous production, and the deposition of citrate into bone. Osteoblasts express high levels of the membranous Na\n                    <jats:sup>+<\/jats:sup>\n                    -dependent citrate transporter\n                    <jats:italic>solute carrier family 13 member 5<\/jats:italic>\n                    (\n                    <jats:italic>Slc13a5<\/jats:italic>\n                    ) gene. Inhibition or genetic disruption of\n                    <jats:italic>Slc13a5<\/jats:italic>\n                    reduced osteogenic citrate uptake and disrupted mineral nodule formation. Bones from mice lacking\n                    <jats:italic>Slc13a5<\/jats:italic>\n                    globally, or selectively in osteoblasts, showed equivalent reductions in cortical thickness, with similarly compromised mechanical strength. Surprisingly, citrate content in mineral from\n                    <jats:italic>\n                      Slc13a5\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    <\/jats:italic>\n                    osteoblasts was increased fourfold relative to controls, suggesting the engagement of compensatory mechanisms to augment endogenous citrate production. Indeed, through the coordinated functioning of the apical membrane citrate transporter SLC13A5 and a mitochondrial zinc transporter protein (ZIP1; encoded by\n                    <jats:italic>Slc39a1<\/jats:italic>\n                    ), a mediator of citrate efflux from the tricarboxylic acid cycle, SLC13A5 mediates citrate entry from blood and its activity exerts homeostatic control of cytoplasmic citrate. Intriguingly,\n                    <jats:italic>Slc13a5<\/jats:italic>\n                    -deficient mice also exhibited defective tooth enamel and dentin formation, a clinical feature, which we show is recapitulated in primary teeth from children with\n                    <jats:italic>SLC13A5<\/jats:italic>\n                    mutations. Together, our results reveal the components of an osteoblast metabolic pathway, which affects bone strength by regulating citrate deposition into mineral hydroxyapatite.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2212178119","type":"journal-article","created":{"date-parts":[[2022,11,2]],"date-time":"2022-11-02T14:50:06Z","timestamp":1667400606000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":55,"title":["A specialized metabolic pathway partitions citrate in hydroxyapatite to impact mineralization of bones and teeth"],"prefix":"10.1073","volume":"119","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6507-8106","authenticated-orcid":false,"given":"Naomi","family":"Dirckx","sequence":"first","affiliation":[{"name":"Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21205"},{"name":"Department of Orthopaedics, University of Maryland School of Medicine, Baltimore, MD 21201"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21205"},{"name":"Department of Nutrition and Health, China Agricultural University, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily Y.","family":"Chu","sequence":"additional","affiliation":[{"name":"Department of General Dentistry, Operative Division, University of Maryland School of Dentistry, Baltimore, MD 21201"},{"name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5856-5758","authenticated-orcid":false,"given":"Robert J.","family":"Tower","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21205"},{"name":"Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX 75390"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhu","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21205"},{"name":"Department of Orthopaedics, University of Maryland School of Medicine, Baltimore, MD 21201"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3032-2153","authenticated-orcid":false,"given":"Shenghao","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Johns Hopkins University Whiting School of Engineering, Baltimore, MD 21218"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shichen","family":"Yuan","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Brandeis University, Waltham, MA 02453"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pratik A.","family":"Khare","sequence":"additional","affiliation":[{"name":"Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cissy","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0203-279X","authenticated-orcid":false,"given":"Angela","family":"Verardo","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21205"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucy O.","family":"Alejandro","sequence":"additional","affiliation":[{"name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9470-660X","authenticated-orcid":false,"given":"Angelina","family":"Park","sequence":"additional","affiliation":[{"name":"Department of General Dentistry, Operative Division, University of Maryland School of Dentistry, Baltimore, MD 21201"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie-Claude","family":"Faugere","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Kentucky, Lexington, KY 40506"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen L.","family":"Helfand","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI 02906"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4819-6079","authenticated-orcid":false,"given":"Martha 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Orthopaedics, University of Maryland School of Medicine, Baltimore, MD 21201"},{"name":"Research and Development Service, The Baltimore Veterans Administration Medical Center, Baltimore, MD  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