An Antibody to Notch2 Reverses the Osteopenic Phenotype of Hajdu-Cheney Mutant Male Mice

Canalis, Ernesto; Sanjay, Archana; Yu, Jungeun; Zanotti, Stefano

doi:10.1210/en.2016-1787

Cited by 29 publications

(38 citation statements)

References 59 publications

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“…Notch2 itself could be a future target for the treatment of HCS, and the skeletal phenotype of Notch2 tm1.1Ecan mouse mutants was reversed by anti-Notch2 antibodies that target the NRR of Notch2 and prevent the activation of Notch2 [47, 48]. There are no clinical trials on the use of this approach which carries the risk of a generalized downregulation of Notch2 with potential unwanted events.…”

Section: Notch and Congenital Disorders Of The Skeletonmentioning

confidence: 99%

Notch in skeletal physiology and disease

Canalis

2018

Osteoporos Int

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Notch (Notch1 through 4) are transmembrane receptors that play a fundamental role in cell differentiation and function. Notch receptors are activated following interactions with their ligands in neighboring cells. There are five classic ligands termed Jagged (Jag)1 and Jag2 and Delta-like (Dll)1, Dll3, and Dll4. Recent work has established Notch as a signaling pathway that plays a critical role in the differentiation and function of cells of the osteoblast and osteoclast lineages and in skeletal development and bone remodeling. The effects of Notch are cell-context dependent, and the four Notch receptors carry out specific functions in the skeleton. Gain- and loss-of-function mutations of components of the Notch signaling pathway result in a variety of congenital disorders with significant craniofacial and skeletal manifestations. The Notch ligand Jag1 is a determinant of bone mineral density, and Notch plays a role in the early phases of fracture healing. Alterations in Notch signaling are associated with osteosarcoma and with the metastatic potential of carcinoma of the breast and of the prostate. Controlling Notch signaling could prove useful in diseases of Notch gain-of-function and in selected skeletal disorders. However, clinical data on agents that modify Notch signaling are not available. In conclusion, Notch signaling is a novel pathway that regulates skeletal homeostasis in health and disease.

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Section: Notch and Congenital Disorders Of The Skeletonmentioning

confidence: 99%

Notch in skeletal physiology and disease

Canalis

2018

Osteoporos Int

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“…We previously described a positive role of Notch2 pathway in RANKL-induced osteoclastogenesis (Fukushima et al, 2008). Similarly, sustained Notch2 activity in Hajdu-Cheney mouse model ( Notch2 Q2319X ) has been recently shown to enhance osteoclast formation, leading to osteopenia, a characteristic of HCS (Canalis et al, 2017; Canalis et al, 2016). Considering the contribution of FBW7 in the osteopenia phenotype, we generated the human NOTCH2 Q2317X (corresponding to mouse Q2319X) mutant for biochemical analyses and showed that the Q2317X mutant failed to interact with FBW7 (Figure S4A) and exhibited diminished FBW7-mediated ubiquitination in cells (Figure S4B).…”

Section: Resultsmentioning

confidence: 98%

“…HCS is an ideal model to study a physiological function of NOTCH2 as C-terminal truncation mutations in HCS are shown to confer gain-of-function properties to Notch2 in mice (Canalis et al, 2017; Canalis et al, 2016; Vollersen et al, 2017). Moreover, most identified HCS NOTCH2 mutations cluster between the second nuclear localization signal (NLS) and the PEST domain, resulting in C-terminal premature truncation of NOTCH2 that lacks the PEST sequence (Figure 3A).…”

Section: Resultsmentioning

confidence: 99%

“…Recent studies indicate that NOTCH2-dependent osteoclastic bone resorption results in HCS development (Canalis et al, 2017; Canalis et al, 2016; Isidor et al, 2011; Simpson et al, 2011; Vollersen et al, 2017). Notably, the administration of anti-NOTCH2 NRR antibody in the HCS mouse reverses the osteopenia phenotype (Canalis et al, 2017). This study using NOTCH2 neutralization antibody supports our strategy that inhibition of osteoclastogenesis via administration of Notch inhibitors as well as bisphosphonate may become a first-line treatment for HCS.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, knock-in mice harboring the Notch2 Q2319X HCS mutant exhibited osteopenia due to enhanced osteoclast formation, without significantly affecting osteoblast number and activity (Canalis et al, 2016). This phenotype was alleviated by an antibody against Notch2 negative regulatory region (NRR) (Canalis et al, 2017). Thus, osteoclastic bone loss caused by sustained NOTCH2 activity may lead to HCS pathogenesis.…”

Section: Introductionmentioning

confidence: 99%

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NOTCH2 Hajdu-Cheney Mutations Escape SCFFBW7-Dependent Proteolysis to Promote Osteoporosis

et al. 2017

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Summary Hajdu-Cheney syndrome (HCS), a rare autosomal disorder caused by heterozygous mutations in NOTCH2, is clinically characterized by acroosteolysis, severe osteoporosis, short stature, neurological symptoms, cardiovascular defects, and polycystic kidneys. Recent studies identified that aberrant NOTCH2 signaling and consequent osteoclast hyperactivity are closely associated with the bone-related disorder pathogenesis, but the exact molecular mechanisms remain unclear. Here, we demonstrate that sustained osteoclast activity is largely due to accumulation of NOTCH2 carrying a truncated C-terminus that escapes FBW7-mediated ubiquitination and degradation. Mice with osteoclast-specific Fbw7 ablation revealed osteoporotic phenotypes reminiscent of HCS, due to elevated Notch2 signaling. Importantly, administration of Notch inhibitors in Fbw7 conditional knockout mice alleviated progressive bone resorption. These findings highlight the molecular basis of HCS pathogenesis and provide clinical insights into potential targeted therapeutic strategies for skeletal disorders associated with the aberrant FBW7/NOTCH2 pathway as observed in patients with HCS.

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High Bone Turnover in Mice Carrying a Pathogenic Notch2 Mutation Causing Hajdu-Cheney Syndrome

Vollersen

Hermans‐Borgmeyer

Cornils

et al. 2017

Journal of Bone and Mineral Research

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Hajdu-Cheney syndrome (HCS) is a rare autosomal-dominant disorder primarily characterized by acro-osteolysis and early-onset osteoporosis. Genetically, HCS is caused by nonsense or deletion mutations within exon 34 of the NOTCH2 gene, resulting in premature translational termination and production of C-terminally truncated NOTCH2 proteins that are predicted to activate NOTCH2-dependent signaling. To understand the role of Notch2 in bone remodeling, we developed a mouse model of HCS by introducing a pathogenic mutation (6272delT) into the murine Notch2 gene. By mCT and undecalcified histology, we observed generalized osteopenia in two independent mouse lines derived by injection of different targeted embryonic stem (ES) cell clones, yet acro-osteolysis did not occur until the age of 52 weeks. Cellular and dynamic histomorphometry revealed a high bone turnover situation in Notch2 þ/HCS mice, since osteoblast and osteoclast indices were significantly increased compared with wild-type littermates. Whereas ex vivo cultures failed to uncover cell-autonomous gain-of-functions within the osteoclast or osteoblast lineage, an unbiased RNA sequencing approach identified Tnfsf11 and Il6 as Notch-signaling target genes in bone marrow cells cultured under osteogenic conditions. Because we further observed that the high-turnover pathology of Notch2 þ/HCS mice was fully normalized by alendronate treatment, our results demonstrate that mutational activation of Notch2 does not directly control osteoblast activity but favors a pro-osteoclastic gene expression pattern, which in turn triggers high bone turnover.

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An Antibody to Notch2 Reverses the Osteopenic Phenotype of Hajdu-Cheney Mutant Male Mice

Cited by 29 publications

References 59 publications

Notch in skeletal physiology and disease

Notch in skeletal physiology and disease

NOTCH2 Hajdu-Cheney Mutations Escape SCFFBW7-Dependent Proteolysis to Promote Osteoporosis

High Bone Turnover in Mice Carrying a Pathogenic Notch2 Mutation Causing Hajdu-Cheney Syndrome

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