{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T19:42:24Z","timestamp":1789846944619,"version":"4.0.1"},"reference-count":62,"publisher":"American Physiological Society","issue":"2","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Endocrinology and Metabolism"],"published-print":{"date-parts":[[2016,1,15]]},"abstract":"<jats:p> Activation of Notch1 in cells of the osteoblastic lineage inhibits osteoblast differentiation\/function and causes osteopenia, whereas its activation in osteocytes causes a distinct osteopetrotic phenotype. To explore mechanisms responsible, we established the contributions of canonical Notch signaling (Rbpj\u03ba dependent) to osteocyte function. Transgenics expressing Cre recombinase under the control of the dentin matrix protein-1 ( Dmp1) promoter were crossed with Rbpj\u03ba conditional mice to generate Dmp1-Cre<jats:sup> +\/\u2212<\/jats:sup>; Rbpj\u03ba<jats:sup> \u0394\/\u0394<\/jats:sup> mice. These mice did not have a skeletal phenotype, indicating that Rbpj\u03ba is dispensable for osteocyte function. To study the Rbpj\u03ba contribution to Notch activation, Rosa<jats:sup> Notch<\/jats:sup> mice, where a loxP-flanked STOP cassette is placed between the Rosa26 promoter and the NICD coding sequence, were crossed with Dmp1-Cre transgenic mice and studied in the context ( Dmp1-Cre<jats:sup> +\/\u2212<\/jats:sup>; Rosa<jats:sup> Notch<\/jats:sup>; Rbpj\u03ba<jats:sup> \u0394\/\u0394<\/jats:sup>) or not ( Dmp1-Cre<jats:sup> +\/\u2212<\/jats:sup>; Rosa<jats:sup> Notch<\/jats:sup>) of Rbpj\u03ba inactivation. Dmp1-Cre<jats:sup> +\/\u2212<\/jats:sup>; Rosa<jats:sup> Notch<\/jats:sup> mice exhibited increased femoral trabecular bone volume and decreased osteoclasts and bone resorption. The phenotype was reversed in the context of the Rbpj\u03ba inactivation, demonstrating that Notch canonical signaling was accountable for the phenotype. Notch activation downregulated Sost and Dkk1 and upregulated Axin2, Tnfrsf11b, and Tnfsf11 mRNA expression, and these effects were not observed in the context of the Rbpj\u03ba inactivation. In conclusion, Notch activation in osteocytes suppresses bone resorption and increases bone volume by utilization of canonical signals that also result in the inhibition of Sost and Dkk1 and upregulation of Wnt signaling. <\/jats:p>","DOI":"10.1152\/ajpendo.00395.2015","type":"journal-article","created":{"date-parts":[[2015,11,18]],"date-time":"2015-11-18T03:18:30Z","timestamp":1447816710000},"page":"E171-E182","source":"Crossref","is-referenced-by-count":46,"title":["Canonical Notch activation in osteocytes causes osteopetrosis"],"prefix":"10.1152","volume":"310","author":[{"given":"Ernesto","family":"Canalis","sequence":"first","affiliation":[{"name":"Department of Orthopedic Surgery and the University of Connecticut Musculoskeletal Institute, Farmington, Connecticut; and"},{"name":"Department of Medicine, University of Connecticut Health, Farmington, 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