{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T16:44:06Z","timestamp":1773247446355,"version":"3.50.1"},"reference-count":49,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,5,30]],"date-time":"2025-05-30T00:00:00Z","timestamp":1748563200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["#82071103"],"award-info":[{"award-number":["#82071103"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["#81570958"],"award-info":[{"award-number":["#81570958"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["YSP202317"],"award-info":[{"award-number":["YSP202317"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Young Scientist Program of Beijing Stomatological Hospital, Capital Medical University","award":["#82071103"],"award-info":[{"award-number":["#82071103"]}]},{"name":"Young Scientist Program of Beijing Stomatological Hospital, Capital Medical University","award":["#81570958"],"award-info":[{"award-number":["#81570958"]}]},{"name":"Young Scientist Program of Beijing Stomatological Hospital, Capital Medical University","award":["YSP202317"],"award-info":[{"award-number":["YSP202317"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Gnathodiaphyseal dysplasia (GDD) is a rare autosomal dominant genetic disease, mainly characterized by enlargement of the mandible, osteosclerosis, and frequent fracture of tubular bone. GDD is caused by heterozygous mutations in Anoctamin 5 (ANO5). We have previously generated an Ano5 knockout (KO) mice model and validated the phenotypes consistent with GDD patients, including enhanced bone formation and alkaline phosphatase (ALP) activity. Experiments have identified that Ano5 deficiency elevated the osteogenesis of calvaria-derived osteoblasts (mCOBs). In this study, we found that Ano5 deficiency notably inhibited miR-34c-5p expression. Kr\u00fcppel-Like Factor 4 (Klf4), a target gene of miR-34c-5p confirmed by dual luciferase reporter assay, was up-regulated in Ano5\u2212\/\u2212 mCOBs, accompanied by activated downstream canonical Wnt\/\u03b2-catenin signaling and increased expression of \u03b2-catenin. Overexpression of miR-34c-5p in Ano5\u2212\/\u2212 mCOBs inhibited osteogenic capacity by suppressing proliferative capacity, osteoblast-related factor levels, ALP activity, and matrix calcification through regulating KLF4\/\u03b2-catenin signaling axis. Furthermore, miR-34c-5p adeno-associated virus (AAV) treatment in vivo rescued the abnormally thickened cortical bone and enhanced biomechanical properties in Ano5\u2212\/\u2212 mice. Importantly, the serum level of P1NP, a marker of bone formation, was also significantly declined. We conclude that dysregulation of miR-34c-5p contributes to the enhanced osteogenesis in GDD by excessive activation of KLF4\/\u03b2-catenin signaling axis under Ano5-deficient conditions. This study elucidates the pathogenesis of GDD and provides novel insights into the therapeutic strategies.<\/jats:p>","DOI":"10.3390\/ijms26115267","type":"journal-article","created":{"date-parts":[[2025,5,30]],"date-time":"2025-05-30T06:14:27Z","timestamp":1748585667000},"page":"5267","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Ano5 Deficiency Leads to Abnormal Bone Formation via miR-34c-5p\/KLF4\/\u03b2-Catenin in Gnathodiaphyseal Dysplasia"],"prefix":"10.3390","volume":"26","author":[{"given":"Shengnan","family":"Wang","sequence":"first","affiliation":[{"name":"Beijing Institute of Dental Research, Beijing Stomatological Hospital, Capital Medical University, No.9 Fanjiacun Road, Fengtai District, Beijing 100070, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7319-4091","authenticated-orcid":false,"given":"Shuai","family":"Zhang","sequence":"additional","affiliation":[{"name":"Beijing Institute of Dental Research, Beijing Stomatological Hospital, Capital Medical University, No.9 Fanjiacun Road, Fengtai District, Beijing 100070, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huichong","family":"Xu","sequence":"additional","affiliation":[{"name":"Beijing Institute of Dental Research, Beijing Stomatological Hospital, Capital Medical University, No.9 Fanjiacun Road, Fengtai District, Beijing 100070, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mingyue","family":"Zhang","sequence":"additional","affiliation":[{"name":"Beijing Institute of Dental Research, Beijing Stomatological Hospital, Capital Medical University, No.9 Fanjiacun Road, Fengtai District, Beijing 100070, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiu","family":"Liu","sequence":"additional","affiliation":[{"name":"Beijing Institute of Dental Research, Beijing Stomatological Hospital, Capital Medical University, No.9 Fanjiacun Road, Fengtai District, Beijing 100070, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sirui","family":"Liu","sequence":"additional","affiliation":[{"name":"Beijing Institute of Dental Research, Beijing Stomatological Hospital, Capital Medical University, No.9 Fanjiacun Road, Fengtai District, Beijing 100070, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hongyu","family":"Li","sequence":"additional","affiliation":[{"name":"Beijing Institute of Dental Research, Beijing Stomatological Hospital, Capital Medical University, No.9 Fanjiacun Road, Fengtai District, Beijing 100070, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ying","family":"Hu","sequence":"additional","affiliation":[{"name":"Beijing Institute of Dental Research, Beijing Stomatological Hospital, Capital Medical University, No.9 Fanjiacun Road, Fengtai District, Beijing 100070, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Jin, L., Liu, Y., Sun, F., Collins, M.T., Blackwell, K., Woo, A.S., Reichenberger, E.J., and Hu, Y. 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