Induction of the Hajdu-Cheney Syndrome Mutation in CD19 B Cells in Mice Alters B-Cell Allocation but Not Skeletal Homeostasis

Yu, Jungeun; Zanotti, Stefano; Schilling, Lauren; Schoenherr, Chris; Economides, Aris N.; Sanjay, Archana; Canalis, Ernesto

doi:10.1016/j.ajpath.2018.02.010

Cited by 5 publications

(5 citation statements)

References 59 publications

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“…This phenotypic difference in HCS compared to NICD1 overexpression can be a result of a constitutively active Notch2 receptor in HCS mice and also due to differences in expression and function of different Notch receptors. An inducible COIN by inversion model for HCS is available, and these will provide a better comparison with our inducible Notch1 findings 31,32 . In line with our data is recent work by Youngstrom et al 17 showing that local delivery of Notch ligand Jagged‐1 at the time of injury promotes regeneration of femoral and calvarial defects in mice and rats, with more physiological tissue formation than what was achieved with BMP2.…”

Section: Discussionsupporting

confidence: 85%

Modulation of Notch1 signaling regulates bone fracture healing

Novak

Roeder

Sinder

et al. 2020

Journal Orthopaedic Research

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Fracture healing involves interactions of different cell types, driven by various growth factors, and signaling cascades. Periosteal mesenchymal progenitor cells give rise to the majority of osteoblasts and chondrocytes in a fracture callus. Notch signaling has emerged as an important regulator of skeletal cell proliferation and differentiation. We investigated the effects of Notch signaling during the fracture healing process. Increased Notch signaling in osteochondroprogenitor cells driven by overexpression of Notch1 intracellular domain (NICD1) (αSMACreERT2 mice crossed with Rosa-NICD1) during fracture resulted in less cartilage, more mineralized callus tissue, and stronger and stiffer bones after 3 weeks. Periosteal cells overexpressing NICD1 showed increased proliferation and migration in vitro. In vivo data confirmed that increased Notch1 signaling caused expansion of alpha-smooth muscle actin (αSMA)-positive cells and their progeny including αSMA-derived osteoblasts in the callus without affecting osteoclast numbers. In contrast, anti-NRR1 antibody treatment to inhibit Notch1 signaling resulted in increased callus cartilage area, reduced callus bone mass, and reduced biomechanical strength. Our study shows a positive effect of induced Notch1 signaling on the fracture healing process, suggesting that stimulating the Notch pathway could be beneficial for fracture repair.

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Section: Discussionsupporting

confidence: 85%

Modulation of Notch1 signaling regulates bone fracture healing

Novak

Roeder

Sinder

et al. 2020

Journal Orthopaedic Research

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“…Notch2 is required for the development of the marginal zone of the spleen, and mouse models of HCS exhibit a reallocation of marginal zone B cells at the expense of follicular cells but do not appear to develop marginal zone lymphomas [50, 51]. The reallocation of marginal zone B cells does not influence skeletal remodeling.…”

Section: Notch and Congenital Disorders Of The Skeletonmentioning

confidence: 99%

“…It is of interest that somatic NOTCH2 mutations causing loss of the PEST domain exhibit enhanced Notch2 activation and have been identified in B cell lymphoma, specifically in marginal zone B lymphoma of the spleen [49]. Notch2 is required for the development of the marginal zone of the spleen, and mouse models of HCS exhibit a reallocation of marginal zone B cells at the expense of follicular cells but do not appear to develop marginal zone lymphomas [50, 51]. The reallocation of marginal zone B cells does not influence skeletal remodeling.…”

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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“…Recently, we demonstrated that Notch2 tm1.1Ecan mice display splenomegaly and reallocation of marginal zone B-cells, but no evidence of T-cell abnormalities or of a generalized inflammatory process [28, 50]. These findings, coupled with the absence of macrophage infiltration in the synovium of sham- or DMM-operated Notch2 tm1.1Ecan mutants, suggest that NOTCH2 activation in joint tissues, and not in immune cells, drives osteoarthritis progression in Notch2 tm1.1Ecan mice.…”

Section: Discussionmentioning

confidence: 99%

Mice harboring a Hajdu Cheney Syndrome mutation are sensitized to osteoarthritis

Zanotti

Bridgewater

et al. 2018

Bone

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Osteoarthritis is a joint disease characterized by cartilage degradation, altered gene expression and inflammation. NOTCH1 and NOTCH2 receptors and the JAGGED1 ligand regulate chondrocyte biology; however, the contribution of Notch signaling to osteoarthritis is controversial. Hajdu Cheney Syndrome (HCS) is a rare genetic disorder affecting the skeleton and associated with NOTCH2 mutations that lead to NOTCH2 gain-of-function. A murine model of the disease (Notch2) was used to test whether the HCS mutation increases the susceptibility to osteoarthritis. The knee of three-month-old Notch2 male mice and control sex-matched littermates was destabilized by resection of the medial meniscotibial ligament, and changes in the joint analyzed two months thereafter. Expression of Notch target genes was increased in the femoral heads of Notch2 mice, documenting Notch signal activation. Periarticular bone and cartilage structures were unaffected in Notch2 mutants subjected to sham surgery, indicating that NOTCH2 gain-of-function had no discernible impact on joint structure under basal conditions. However, destabilization of the medial meniscus increased osteophyte volume and thickened subchondral bone in Notch2 mice compared to wild type littermates. Moreover, destabilized Notch2 mutants exhibited histological signs of moderate to severe cartilage degeneration, demonstrating joint sensitization to the development of osteoarthritis. Chondrocyte cultures from Notch2 mutants expressed increased Il6 mRNA levels following exposure to JAGGED1, possibly explaining the susceptibility of Notch2 mice to osteoarthritis. In conclusion, Notch2 mutants are sensitized to the development of osteoarthritis in destabilized joints and NOTCH2 activation may play a role in the pathogenesis of the disease.

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Induction of the Hajdu-Cheney Syndrome Mutation in CD19 B Cells in Mice Alters B-Cell Allocation but Not Skeletal Homeostasis

Cited by 5 publications

References 59 publications

Modulation of Notch1 signaling regulates bone fracture healing

Modulation of Notch1 signaling regulates bone fracture healing

Notch in skeletal physiology and disease

Mice harboring a Hajdu Cheney Syndrome mutation are sensitized to osteoarthritis

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