{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T09:27:08Z","timestamp":1785403628099,"version":"3.56.0"},"posted":{"date-parts":[[2026,4,17]]},"group-title":"Molecular Biology","reference-count":63,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T00:00:00Z","timestamp":1776384000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"award":["DE025664"],"award-info":[{"award-number":["DE025664"]}],"id":[{"id":"https:\/\/ror.org\/004a2wv92","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,4,17]]},"abstract":"<jats:title>Summary<\/jats:title>\n                <jats:p>\n                  Craniometaphyseal dysplasia (CMD) is a rare genetic disorder characterized by hyperostosis of craniofacial bones and flared metaphyses of long bones. Mutations in ANKH (mouse orthologue ANK), a transmembrane protein mediating ATP and citrate efflux, cause the autosomal dominant form of CMD. How ANK mutations in CMD affect ATP\/citrate homeostasis and downstream targets remains unknown. We determined that cellular ATP export, intracellular ATP levels, and plasma citric acid were significantly reduced in ANK\n                  <jats:sub>F377del<\/jats:sub>\n                  knock-in (\n                  <jats:italic>\n                    Ank\n                    <jats:sup>KI\/KI<\/jats:sup>\n                  <\/jats:italic>\n                  ) mice. Enrichment and pathway analyses of the plasma metabolome suggested the involvement of the citric acid cycle. It is known that AMPK is phosphorylated and activated when ATP is low. Phospho-AMPK was significantly upregulated in fusing\n                  <jats:italic>\n                    Ank\n                    <jats:sup>KI\/KI<\/jats:sup>\n                  <\/jats:italic>\n                  osteoclasts, major contributors to CMD. AMPK inhibitor treatment only during the fusion stage of osteoclasts significantly restored dysfunctional\n                  <jats:italic>\n                    Ank\n                    <jats:sup>KI\/KI<\/jats:sup>\n                  <\/jats:italic>\n                  osteoclasts, partly by modulating actin structures. Systemic administration of the AMPK inhibitor SBI-0206965 improved the positioning of cervical loops of incisors but failed to correct other skeletal abnormalities in\n                  <jats:italic>\n                    Ank\n                    <jats:sup>KI\/KI<\/jats:sup>\n                  <\/jats:italic>\n                  mice. Limitations of systemic administration of SBI-0206965 include its off-target effects on other cell types and the inability to inhibit AMPK only on fusing osteoclasts. Nonetheless, this proof-of-principle study reveals an important role of the ATP-AMPK axis in CMD pathogenesis.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Take-home message<\/jats:title>\n                  <jats:p>Suppression of increased activation of AMPK restores the function of osteoclasts, suggesting that abnormal energy metabolism is an integral component of the disease phenotype in CMD.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.04.15.717889","type":"posted-content","created":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T12:15:14Z","timestamp":1776428114000},"source":"Crossref","is-referenced-by-count":0,"title":["Disturbed ATP and AMPK homeostasis in an Ank\n                  <sub>F377del<\/sub>\n                  mouse model for craniometaphyseal dysplasia"],"prefix":"10.64898","author":[{"given":"Ayano","family":"Hatori","sequence":"first","affiliation":[{"name":"Department of Endodontics, School of Dental Medicine, University of Connecticut Health, Farmington, CT, United States"},{"name":"Department of Regenerative Medicine and Skeletal Development, University of Connecticut Health, Farmington, CT, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shyam Kishor","family":"Sah","sequence":"additional","affiliation":[{"name":"Department of Endodontics, School of Dental Medicine, University of Connecticut Health, Farmington, CT, United States"},{"name":"Department of Regenerative Medicine and Skeletal Development, University of Connecticut Health, Farmington, CT, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koen van de","family":"Wetering","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, and PXE International Center of Excellence in Research and Clinical Care, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ernst J","family":"Reichenberger","sequence":"additional","affiliation":[{"name":"Department of Regenerative Medicine and Skeletal Development, University of Connecticut Health, Farmington, CT, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7349-3091","authenticated-orcid":false,"given":"I-Ping","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Endodontics, School of Dental Medicine, University of Connecticut Health, Farmington, CT, United States"},{"name":"Department of Regenerative Medicine and Skeletal Development, University of Connecticut Health, Farmington, CT, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"issue":"6","key":"2026042106050450000_2026.04.15.717889v1.1","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1001\/archinte.1954.00250060005001","article-title":"Metaphyseal dysplasia, epiphyseal dysplasia, diaphyseal dysplasia, and related conditions. 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