Previous investigations from our laboratory revealed that Notch plays a critical role in cell differentiation, and its expression in immature osteoblast causes osteopenia secondary to an inhibitory effect on osteoblastogenesis. The effect of Notch is cell context-dependent, and in contrast to the effects observed in osteoblasts, when Notch is expressed in osteocytes under the control of the Dentin matrix protein 1 (Dmp1) promoter it causes a pronounced increase in trabecular and cortical bone volume. In cancellous bone, Notch inhibits bone resorption due to a decrease in the number of osteoclasts. In cortical bone Notch enhances mineral apposition rate and the structure maintains a trabecular appearance. Our observations led to the hypothesis that Notch plays a central role in the regulation of osteocyte function, and Notch effects in osteocytes are unique and distinct from those observed in osteoblasts. Notch induces osteoprotegerin and inhibits the expression of the Wnt antagonist sclerostin enhancing the expression of Wnt target genes. In initial experiments, we discovered that expression of Notch in osteocytes prevents the bone loss that follows muscle paralysis, and we postulate that Notch protects bone from the detrimental effects of unloading.
The aim of the proposed research is to understand the function of Notch in osteocytes and define the mechanisms involved. For this purpose, we will study mouse and cellular models expressing Notch in the osteocyte environment, and models of conditional inactivation of Notch1 and Notch2 in osteocytes.
Our specific aims are: 1) To determine the function of Notch in osteocytes in the adult skeleton by transgenic expression of Notch under the control of the Dmp1 promoter using inducible models of expression and by targeted Notch1 and Notch2 conditional deletion in osteocytes. The skeletal phenotype of mice misexpressing Notch will be compared to that of wild type mice and determined by contact radiography, densitometry, micro CT scanning and histomorphometry. In addition, we will analyze the biochemical and biomechanical properties of bone;2) To determine the mechanism of action of Notch in osteocytes. Mechanisms responsible for the effects of Notch will be established, and we will determine whether the Notch canonical signaling pathway is responsible for the effects of Notch in osteocytes and the role of mechanotransduction on canonical Notch signaling in vivo. The impact of Notch on the expression of sclerostin and osteoprotegerin in osteocytes, their contribution to the phenotype observed and levels of transcriptional and post-transcriptional regulation will be examined in in vivo and in vitro models;and 3) To establish whether Notch protects the skeleton from the detrimental effects of unloading, as it does from those of muscle paralysis.

Public Health Relevance

These investigations will clarify the role of Notch in osteocytes and offer new information on mechanisms involved in the function of osteocytes, mechanotransduction in bone and in the pathogenesis and reversal of disuse osteoporosis.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Skeletal Biology Structure and Regeneration Study Section (SBSR)
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Chen, Faye H
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St. Francis Hospital and Medical Center
United States
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Yu, Jungeun; Zanotti, Stefano; Schilling, Lauren et al. (2018) Induction of the Hajdu-Cheney Syndrome Mutation in CD19 B Cells in Mice Alters B-Cell Allocation but Not Skeletal Homeostasis. Am J Pathol 188:1430-1446
Canalis, Ernesto (2018) MANAGEMENT OF ENDOCRINE DISEASE: Novel anabolic treatments for osteoporosis. Eur J Endocrinol 178:R33-R44
Canalis, Ernesto (2018) Clinical and experimental aspects of notch receptor signaling: Hajdu-Cheney syndrome and related disorders. Metabolism 80:48-56
Canalis, Ernesto; Yu, Jungeun; Schilling, Lauren et al. (2018) The lateral meningocele syndrome mutation causes marked osteopenia in mice. J Biol Chem 293:14165-14177
Zanotti, Stefano; Canalis, Ernesto (2017) Parathyroid hormone inhibits Notch signaling in osteoblasts and osteocytes. Bone 103:159-167
Canalis, Ernesto; Zanotti, Stefano (2017) Hairy and Enhancer of Split-Related With YRPW Motif-Like (HeyL) Is Dispensable for Bone Remodeling in Mice. J Cell Biochem 118:1819-1826
Canalis, Ernesto; Schilling, Lauren; Zanotti, Stefano (2017) Effects of Sex and Notch Signaling on the Osteocyte Cell Pool. J Cell Physiol 232:363-370
Zanotti, Stefano; Canalis, Ernesto (2016) The Dmp1-SOST Transgene Interacts With and Downregulates the Dmp1-Cre Transgene and the Rosa(Notch) Allele. J Cell Biochem 117:1222-32
Zanotti, Stefano; Canalis, Ernesto (2016) Notch Signaling and the Skeleton. Endocr Rev 37:223-53
Adami, Giovanni; Rossini, Maurizio; Gatti, Davide et al. (2016) Hajdu Cheney Syndrome; report of a novel NOTCH2 mutation and treatment with denosumab. Bone 92:150-156

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