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Disruption of this balance contributes to the development of osteoporosis, osteoarthritis, impaired skeletal repair, and bone malignancies. Fat mass and obesity-associated protein (FTO), an RNA demethylase that removes N6-methyladenosine (m6A) and related RNA modifications, has emerged as a key context-dependent regulator of skeletal biology. Rather than acting uniformly as either a pro-osteogenic or disease-promoting factor, FTO exerts diverse effects that depend on the cell type, disease stage, target transcript, reader-protein context, and mode of therapeutic modulation. This narrative review summarizes current evidence on the role of FTO in osteoblast differentiation, osteoclast activity, bone marrow mesenchymal stem cell (BMSC) lineage commitment, cartilage homeostasis, osteosarcoma, multiple myeloma, and bone-related metastasis. We highlight areas of consensus, unresolved controversies, the strength of the available evidence, and major translational challenges. Collectively, FTO represents a promising therapeutic target in skeletal diseases; however, the current evidence remains largely preclinical and should be interpreted with caution until its efficacy and safety are validated in clinical settings.<\/jats:p>","DOI":"10.3390\/biom16071035","type":"journal-article","created":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T01:05:07Z","timestamp":1784163907000},"page":"1035","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["FTO in Bone Diseases: Functions, Mechanisms and Therapeutic Potential"],"prefix":"10.3390","volume":"16","author":[{"given":"Haochuan","family":"You","sequence":"first","affiliation":[{"name":"Department of Orthopedics, Lanzhou University Second Hospital, Lanzhou 730030, China"},{"name":"Orthopedic Clinical Medical Research Center and Intelligent Orthopedic Industry Technology Center of Gansu Province, Lanzhou 730030, China"},{"name":"The Second School of Clinical Medical, Lanzhou University, Lanzhou 730030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yixiang","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Lanzhou University Second Hospital, Lanzhou 730030, China"},{"name":"Orthopedic Clinical Medical Research Center and Intelligent Orthopedic Industry Technology Center of Gansu Province, Lanzhou 730030, China"},{"name":"The Second School of Clinical Medical, Lanzhou University, Lanzhou 730030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiuyuan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Lanzhou University Second Hospital, Lanzhou 730030, China"},{"name":"Orthopedic Clinical Medical Research Center and Intelligent Orthopedic Industry Technology Center of Gansu Province, Lanzhou 730030, China"},{"name":"The Second School of Clinical Medical, Lanzhou University, Lanzhou 730030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haotian","family":"He","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Lanzhou University Second Hospital, Lanzhou 730030, China"},{"name":"Orthopedic Clinical Medical Research Center and Intelligent Orthopedic Industry Technology Center of Gansu Province, Lanzhou 730030, China"},{"name":"The Second School of Clinical Medical, Lanzhou University, Lanzhou 730030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dacheng","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Lanzhou University Second Hospital, Lanzhou 730030, China"},{"name":"Orthopedic Clinical Medical Research Center and Intelligent Orthopedic Industry Technology Center of Gansu Province, Lanzhou 730030, China"},{"name":"The Second School of Clinical Medical, Lanzhou University, Lanzhou 730030, China"},{"name":"Key Laboratory of Dunhuang Medicine and Translation, Ministry of Education, Lanzhou 730030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yayi","family":"Xia","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Lanzhou University Second Hospital, Lanzhou 730030, China"},{"name":"Orthopedic Clinical Medical Research Center and Intelligent Orthopedic Industry Technology Center of Gansu Province, Lanzhou 730030, China"},{"name":"The Second School of Clinical Medical, Lanzhou University, Lanzhou 730030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1126\/science.1141634","article-title":"A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity","volume":"316","author":"Frayling","year":"2007","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1311","DOI":"10.1038\/s41401-021-00756-8","article-title":"The m6A demethylase FTO promotes the osteogenesis of mesenchymal stem cells by downregulating PPARG","volume":"43","author":"Chen","year":"2022","journal-title":"Acta Pharmacol. 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