The Hajdu Cheney mutation sensitizes mice to the osteolytic actions of tumor necrosis factor α

Yu, Jungeun; Canalis, Ernesto

doi:10.1074/jbc.ra119.009824

Cited by 14 publications

(25 citation statements)

References 64 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Because cells of the myeloid/osteoclast lineage do not express Notch3 mRNA, NOTCH3 is capable of modulating osteoclastogenesis only by indirect mechanisms regulating the expression of RANKL and osteoprotegerin in the osteoblast lineage ( 16 , 47 ). This is in contrast to NOTCH1 and NOTCH2, which are expressed in the myeloid lineage and have direct, as well as indirect, effects on osteoclastogenesis ( 14 , 17 , 18 , 48 , 49 ), albeit those of NOTCH1 are inhibitory, whereas those of NOTCH2 are stimulatory.…”

Section: Discussionmentioning

confidence: 75%

“…Cells from the last three digestions were pooled and seeded at a density of 10,000 cells/cm 2 and cultured in Dulbecco’s modified Eagle’s medium supplemented with nonessential amino acids (both from Thermo Fisher Scientific), 20 mM Hepes, 100 μg/ml ascorbic acid (both from Sigma-Aldrich), and 10% heat-inactivated fetal bovine serum (Atlanta Biologicals) in a humidified 5% CO 2 incubator at 37 °C. BMMs from wildtype mice were isolated by flushing of the marrow as described ( 48 , 49 ). Cells were centrifuged, and the sediment was suspended in α-MEM (Thermo Fischer Scientific) in the presence of 10% FBS and recombinant human macrophage colony stimulating factor at 30 ng/ml as described ( 48 , 49 ).…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Activation of Notch3 in osteoblasts/osteocytes causes compartment-specific changes in bone remodeling

Canalis

Zanotti

Schilling

et al. 2021

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Notch receptors maintain skeletal homeostasis. NOTCH1 and 2 have been studied for their effects on bone remodeling. Although NOTCH3 plays a significant role in vascular physiology, knowledge about its function in other cellular environments, including bone, is limited. The present study was conducted to establish the function of NOTCH3 in skeletal cells using models of Notch3 misexpression. Microcomputed tomography demonstrated that Notch3 null mice did not have appreciable bone phenotypes. To study the effects of the NOTCH3 activation in the osteoblast lineage, BGLAP-Cre or Dmp1-Cre transgenics were crossed with Rosa Notch3 mice, where the NOTCH3 intracellular domain is expressed following the removal of a loxP -flanked STOP cassette. Microcomputed tomography demonstrated that BGLAP-Cre;Rosa Notch3 and Dmp1-Cre;Rosa Notch3 mice of both sexes exhibited an increase in trabecular bone and in connectivity, with a decrease in cortical bone and increased cortical porosity. Histological analysis revealed a decrease in osteoclast number and bone resorption in trabecular bone and an increase in osteoclast number and void or pore area in cortical bone of Rosa Notch3 mice. Bone formation was either decreased or could not be determined in Cre;Rosa Notch3 mice. NOTCH3 activation in osteoblasts inhibited Alpl (alkaline phosphatase) and Bglap (osteocalcin) and induced Tnfsf11 (RANKL) and Tnfrsf11b (osteoprotegerin) mRNA, possibly explaining the trabecular bone phenotype. However, NOTCH3 induced Tnfsf11 and suppressed Tnfrsf11b in osteocytes, possibly explaining the cortical porosity. In conclusion, basal NOTCH3 is dispensable for skeletal homeostasis, whereas activation of NOTCH3 in osteoblasts/osteocytes inhibits osteoclastogenesis and bone resorption in cancellous bone but increases intracortical remodeling and causes cortical porosity.

show abstract

Section: Discussionmentioning

confidence: 75%

Section: Methodsmentioning

confidence: 99%

Activation of Notch3 in osteoblasts/osteocytes causes compartment-specific changes in bone remodeling

Canalis

Zanotti

Schilling

et al. 2021

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

show abstract

“…In skeletal cells, NOTCH1 inhibits the differentiation of cells of the osteoblast and osteoclast lineages. Instead, NOTCH2 enhances osteoclast differentiation by direct and indirect mechanisms (Bai et al, 2008 ; Engin et al, 2008 ; Fukushima et al, 2008 ; Hilton et al, 2008 ; Canalis et al, 2016 ; Yu and Canalis, 2019 ). NOTCH3 is preferentially expressed by vascular smooth muscle cells and cells of the osteoblast lineage, particularly osteocytes and is not expressed by myeloid cells or osteoclasts (Zanotti and Canalis, 2017 ).…”

Section: Notch Receptors and Ligandsmentioning

confidence: 99%

“…The classic or canonical Notch ligands of the JAG and DLL families are single-pass transmembrane proteins with a conserved extracellular domain that, like Notch, contains multiple tandem EGF-like repeats. Of these ligands, JAG1 is consistently expressed by skeletal cells and its deletion phenocopies models of Notch inactivation suggesting that JAG1 is the most relevant ligand to skeletal homeostasis (Lawal et al, 2017 ; Zanotti and Canalis, 2017 ; Yu and Canalis, 2019 ). A variety of soluble and transmembrane proteins have been reported to interact with Notch receptors.…”

Section: Notch Receptors and Ligandsmentioning

confidence: 99%

The Skeleton of Lateral Meningocele Syndrome

Canalis

2021

Front. Genet.

Self Cite

View full text Add to dashboard Cite

Notch (Notch1 through 4) are transmembrane receptors that determine cell differentiation and function, and are activated following interactions with ligands of the Jagged and Delta-like families. Notch has been established as a signaling pathway that plays a critical role in the differentiation and function of cells of the osteoblast and osteoclast lineages as well as in skeletal development and bone remodeling. Pathogenic variants of Notch receptors and their ligands are associated with a variety of genetic disorders presenting with significant craniofacial and skeletal manifestations. Lateral Meningocele Syndrome (LMS) is a rare genetic disorder characterized by neurological manifestations, meningoceles, skeletal developmental abnormalities and bone loss. LMS is associated with NOTCH3 gain-of-function pathogenic variants. Experimental mouse models of LMS revealed that the bone loss is secondary to increased osteoclastogenesis due to enhanced expression of receptor activator of nuclear factor kappa B ligand by cells of the osteoblast lineage. There are no effective therapies for LMS. Antisense oligonucleotides targeting Notch3 and antibodies that prevent the activation of NOTCH3 are being tested in preclinical models of the disease. In conclusion, LMS is a serious genetic disorder associated with NOTCH3 pathogenic variants. Novel experimental models have offered insight on mechanisms responsible and ways to correct the disease.

show abstract

“…The NOTCH2 gene, located on 1p12-p11 (NM_024408.3), encodes a transmembrane protein critical in skeletal development and bone remodeling by acting on the cells of osteoclast and osteoblast lineage [7]. The NOTCH2 mutation is a gain of function, as it results in a longer half-life for NOTCH2 protein [8,9]. The enhanced NOTCH2 activity promotes osteoclastogenesis and inhibits osteogenesis.…”

Section: Introductionmentioning

confidence: 99%

Distinct severity of phenotype in Hajdu-Cheney syndrome: a case report and literature review

Zeng

Lin

et al. 2020

BMC Musculoskelet Disord

View full text Add to dashboard Cite

Background: Hajdu-Cheney syndrome (HCS) is a rare inherited skeletal disorder caused by pathogenic mutations in exon 34 of NOTCH2. Its highly variable phenotypes make early diagnosis challenging. In this paper, we report a case of early-onset HCS with severe phenotypic manifestations but delayed diagnosis. Case presentation: The patient was born to non-consanguineous, healthy parents of Chinese origin. She presented facial anomalies, micrognathia and skull malformations at birth, and was found hearing impairment, congenital heart disease and developmental delay during her first year of life. Her first visit to our center was at 1 year of age due to cardiovascular repair surgery for patent ductus arteriosus (PDA) and ventricular septal defect (VSD). Skull X-ray showed wormian bones. She returned at 7 years old after she developed progressive skeletal anomalies with fractures. She presented with multiple wormian bones, acro-osteolysis, severe osteoporosis, bowed fibulae and a renal cyst. Positive genetic test of a de novo heterozygous frameshift mutation in exon 34 of NOTCH2 (c.6426dupT) supported the clinical diagnosis of HCS. Conclusion: This is the second reported HCS case caused by the mutation c.6426dupT in NOTCH2, but presenting much earlier and severer clinical expression. Physicians should be aware of variable phenotypes so that early diagnosis and management may be achieved.

show abstract

The Hajdu Cheney mutation sensitizes mice to the osteolytic actions of tumor necrosis factor α

Cited by 14 publications

References 64 publications

Activation of Notch3 in osteoblasts/osteocytes causes compartment-specific changes in bone remodeling

Activation of Notch3 in osteoblasts/osteocytes causes compartment-specific changes in bone remodeling

The Skeleton of Lateral Meningocele Syndrome

Distinct severity of phenotype in Hajdu-Cheney syndrome: a case report and literature review

Contact Info

Product

Resources

About