{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T16:04:10Z","timestamp":1779725050040,"version":"3.53.1"},"reference-count":38,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T00:00:00Z","timestamp":1779321600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"doctoral fellowship from the French Ministry of Research"},{"name":"EuroRETT consortium","award":["JTC2007"],"award-info":[{"award-number":["JTC2007"]}]},{"name":"ANR project \u201cDROS\u201d and the EU Consortium IDEAL","award":["HEALTH-F2-2011-259679"],"award-info":[{"award-number":["HEALTH-F2-2011-259679"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Rett syndrome is a severe neurodevelopmental disorder caused predominantly by loss-of-function mutations in the X-linked gene MECP2. In addition to a vast array of neurological and physiological impairments, patients also frequently develop severe osteopenia with increased fracture risk; however, the mechanisms underlying these skeletal defects are not completely understood. Previous work in Mecp2-null mouse models has suggested that osteopenia is mainly due to impaired osteoblast function and reduced bone formation. Here, we examined bone mass, microarchitecture, and remodeling parameters in a Mecp2-null mouse model during postnatal development, with a particular focus on osteoclast involvement. Microcomputed tomography and histomorphometric analyses showed reduced bone mineral density and trabecular bone volume, which are associated with increased trabecular separation and cortical thinning. These structural alterations were accompanied by increased osteoclast number per bone surface, elevated urinary deoxypyridinoline, and higher expression of osteoclast-associated genes, including Cathepsin K. Furthermore, gene expression analysis revealed an age-dependent shift in bone remodeling. At postnatal day 35, mutant mice showed reduced expression of Dlx5 and Dlx6, consistent with low bone turnover. By postnatal day 55, Rankl and Cathepsin K were markedly upregulated, suggesting an increase in osteoclast resorptive activity, while key osteoblast markers and the RANKL\/OPG ratio did not change significantly. A potential cell-autonomous contribution of Mecp2 to osteoclast maturation is also suggested by the analysis of public transcriptomic datasets on human osteoclast differentiation. Together, our findings identify increased osteoclast activity as a significant contributor to Rett-associated osteopenia and suggest that skeletal pathology in Mecp2 deficiency progresses from an early low-turnover state to a later phase of increased osteoclast resorption.<\/jats:p>","DOI":"10.3390\/cells15100948","type":"journal-article","created":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T15:05:08Z","timestamp":1779721508000},"page":"948","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Increased Osteoclast Activity Contributes to Bone Resorption and Osteopenia in a Rett Syndrome Mouse Model"],"prefix":"10.3390","volume":"15","author":[{"given":"Nadeem","family":"Samee","sequence":"first","affiliation":[{"name":"CNRS UMR7221, Evolution des R\u00e9gulations Endocriniennes, MNHN, Cedex 05, F-75231 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lou","family":"Belz","sequence":"additional","affiliation":[{"name":"CNRS UMR7221, Evolution des R\u00e9gulations Endocriniennes, MNHN, Cedex 05, F-75231 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolas","family":"Narboux-N\u00eame","sequence":"additional","affiliation":[{"name":"CNRS UMR7221, Evolution des R\u00e9gulations Endocriniennes, MNHN, Cedex 05, F-75231 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9721-8844","authenticated-orcid":false,"given":"Jean-Christophe","family":"Roux","sequence":"additional","affiliation":[{"name":"INSERM, Marseille Medical Genetics, Aix Marseille Universit\u00e9, F-13005 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6204-6771","authenticated-orcid":false,"given":"Nicolas","family":"Panayotis","sequence":"additional","affiliation":[{"name":"INSERM, Marseille Medical Genetics, Aix Marseille Universit\u00e9, F-13005 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7041-6787","authenticated-orcid":false,"given":"Giovanni","family":"Levi","sequence":"additional","affiliation":[{"name":"CNRS UMR7221, Evolution des R\u00e9gulations Endocriniennes, MNHN, Cedex 05, F-75231 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1186\/s13643-023-02169-6","article-title":"Global prevalence of Rett syndrome: Systematic review and meta-analysis","volume":"12","author":"Petriti","year":"2023","journal-title":"Syst. 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