Journal
AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM
Volume 310, Issue 2, Pages E171-E182Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpendo.00395.2015
Keywords
Notch; Rbpj kappa; Sost; osteocytes; bone remodeling
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Funding
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) [AR-063049]
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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 kappa dependent) to osteocyte function. Transgenics expressing Cre recombinase under the control of the dentin matrix protein-1 (Dmp1) promoter were crossed with Rbpj kappa conditional mice to generate Dmp1-Cre(+)/(-); Rbpj kappa(Delta/Delta) mice. These mice did not have a skeletal phenotype, indicating that Rbpj kappa is dispensable for osteocyte function. To study the Rbpj kappa contribution to Notch activation, Rosa(Notch) 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(+)/(-); Rosa(Notch); Rbpj kappa(Delta/Delta)) or not (Dmp1-Cre(+)/(-); Rosa(Notch)) of Rbpj kappa inactivation. Dmp1-Cre(+/-); Rosa(Notch) mice exhibited increased femoral trabecular bone volume and decreased osteoclasts and bone resorption. The phenotype was reversed in the context of the Rbpj kappa 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 kappa 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.
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