Osteosclerosis owing to notch gain of function is solely Rbpj-dependent

Jianning Tao, Shan Chen, Tao Yang, Brian Dawson, Elda Munivez, Terry Bertin, Brendan Lee

Research output: Contribution to journalArticlepeer-review

49 Scopus citations

Abstract

Osteosclerosis is a pathologic bone disease characterized by an increase in bone formation over bone resorption. Genetic factors that contribute to the pathogenesis of this disease are poorly understood. Dysregulation or mutation in many components of the Notch signaling pathway results in a wide range of human developmental disorders and cancers, including bone diseases. Our previous study found that activation of the Notch signaling in osteoblasts promotes cell proliferation and inhibits differentiation, leading to an osteosclerotic phenotype in transgenic mice. In this study we report a longer-lived mouse model that also develops osteosclerosis and a genetic manipulation that completely rescues the phenotype. Conditionally cre-activated expression of Notch1 intracellular domain (NICD) in vivo exclusively in committed osteoblasts caused massive osteosclerosis with growth retardation and abnormal vertebrae. Importantly, selective deletion of a Notch nuclear effector - Rbpj - in osteoblasts completely suppressed the osteosclerotic and growth-retardation phenotypes. Furthermore, cellular and molecular analyses of bones from the rescued mice confirmed that NICD-dependent molecular alterations in osteoblasts were completely reversed by removal of the Rbpj pathway. Together, our observations show that the osteosclerosis owing to activation of Notch signaling in osteoblasts is canonical in nature because it depends solely on Rbpj signaling. As such, it identifies Rbpj as a specific target for manipulating Notch signaling in a cell-autonomous fashion in osteoblasts in bone diseases where Notch may be dysregulated.

Original languageEnglish (US)
Pages (from-to)2175-2183
Number of pages9
JournalJournal of Bone and Mineral Research
Volume25
Issue number10
DOIs
StatePublished - Oct 2010
Externally publishedYes

Keywords

  • Genetic mouse model
  • Notch signaling
  • Osteoblast
  • Osteosclerosis
  • Therapeutics

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Orthopedics and Sports Medicine

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