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Emerging research underscores the regulatory functions of RNA methylation on bone homeostasis. Here, we show PCIF1, the N6,2\u2032-O-dimethyladenosine (m\n                    <jats:sup>6<\/jats:sup>\n                    Am) methyltransferase, is essential for maintaining bone mass and promoting osteogenic differentiation of MSCs. Multiple complementary analyses\u2014including GWAS, TWAS, and single-cell transcriptomics\u2014collectively point to PCIF1 as a regulator of human bone mineral traits and early-stage mesenchymal differentiation. Global or MSC-specific\n                    <jats:italic>Pcif1<\/jats:italic>\n                    deletion elicits osteoporotic pathology in mice, although myeloid cell-specific\n                    <jats:italic>Pcif1<\/jats:italic>\n                    knockout does not induce femur bone alterations. Mechanistically,\n                    <jats:italic>Pcif1<\/jats:italic>\n                    knockout decreases m\n                    <jats:sup>6<\/jats:sup>\n                    Am signals of Wnt-related genes (\n                    <jats:italic>Wnt11<\/jats:italic>\n                    ,\n                    <jats:italic>Fzd4<\/jats:italic>\n                    , and\n                    <jats:italic>Fgfr2<\/jats:italic>\n                    ) and accelerates mRNA degradation. This down-regulates active \u03b2-Catenin protein, and thus impairs osteogenic function of MSCs. Additionally, the WNT agonist attenuates the osteoporosis-like phenotype induced by\n                    <jats:italic>Pcif1<\/jats:italic>\n                    deletion. These findings highlight the crucial role of PCIF1-mediated m\n                    <jats:sup>6<\/jats:sup>\n                    Am modification in regulating osteogenesis and suggest potential therapeutic implications for bone disorders.\n                  <\/jats:p>","DOI":"10.1371\/journal.pbio.3003739","type":"journal-article","created":{"date-parts":[[2026,4,6]],"date-time":"2026-04-06T17:43:32Z","timestamp":1775497412000},"page":"e3003739","update-policy":"https:\/\/doi.org\/10.1371\/journal.pbio.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["The m6Am methyltransferase PCIF1 promotes osteogenic differentiation of mesenchymal stem cells through stabilization of Wnt-related 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