Antisense oligonucleotides targeting Notch2 ameliorate the osteopenic phenotype in a mouse model of Hajdu-Cheney syndrome

Canalis, Ernesto; Grossman, Tamar R.; Carrer, Michele; Schilling, Lauren; Yu, Jungeun

doi:10.1074/jbc.ra119.011440

Cited by 12 publications

(10 citation statements)

References 76 publications

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“…13 Oxidative Medicine and Cellular Longevity Overexpression of LINC00370 sponge miR-222-3p to enhance RGS4-medicated bone protection [40]. Conversely, as a negative regulator, suppressing HEY2 with Notch2 antisense oligonucleotides (ASO) attenuated the cancellous osteopenia of Notch2 tm1.1Ecan mice [41]. The potential amphoteric effects of bortezomib on RGS4 and HEY2 in OP will be explored in our further work.…”

Section: Discussionmentioning

confidence: 99%

Bortezomib Rescues Ovariectomy-Induced Bone Loss via SMURF-Mediated Ubiquitination Pathway

Fang

Liu

Zhao

et al. 2021

Oxidative Medicine and Cellular Longevity

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A balance between bone formation by osteoblasts and bone resorption by osteoclasts is necessary to maintain bone health and homeostasis. As a cancer of plasma cells, multiple myeloma (MM) is accompanied with rapid bone loss and fragility fracture. Bortezomib has been used as a first-line for treating MM for decades. Recently, the potential protection of bortezomib on osteoporosis (OP) is reported; however, the specific mechanism involving bortezomib-mediated antiosteoporotic effect is undetermined. In the present study, we assessed the effects of in vitro bortezomib treatment on osteogenesis and osteoclastogenesis and the protective effect on bone loss in ovariectomized (OVX) mice. Our results indicated that bortezomib treatment increased osteogenic differentiation of MC3T3-E1 cells as evidenced by increased levels of matrix mineralization and osteoblast-specific markers. In bortezomib-treated bone marrow monocytes (BMMs), osteoclast differentiation was suppressed, substantiated by downregulated tartrate-resistant acid phosphatase- (TRAP-) positive multinucleated cells, areas of actin rings, pit formation, and osteoclast-specific genes. Mechanistically, bortezomib exerted a protective effect against OP through the Smad ubiquitination regulatory factor- (SMURF-) mediated ubiquitination pathway. Furthermore, in vivo intraperitoneal injection of bortezomib attenuated the bone microarchitecture in OVX mice. Accordingly, our findings corroborated that bortezomib might have future applications in the treatment of postmenopausal OP.

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Section: Discussionmentioning

confidence: 99%

Bortezomib Rescues Ovariectomy-Induced Bone Loss via SMURF-Mediated Ubiquitination Pathway

Fang

Liu

Zhao

et al. 2021

Oxidative Medicine and Cellular Longevity

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“…According to data from the Andalusian Tourism Situation Survey [63], tourism declined by 47.5% in the third quarter of 2020 compared to the same period in 2019, falling from 11,425,437 tourists to 6,000,293.…”

Section: Tourist Behaviour In Andalusia Before and During The Covid-1mentioning

confidence: 98%

Using Social Media in Tourist Sentiment Analysis: A Case Study of Andalusia during the Covid-19 Pandemic

2021

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This paper explores the role of social media in tourist sentiment analysis. To do this, it describes previous studies that have carried out tourist sentiment analysis using social media data, before analyzing changes in tourists’ sentiments and behaviors during the COVID-19 pandemic. In the case study, which focuses on Andalusia, the changes experienced by the tourism sector in the southern Spanish region as a result of the COVID-19 pandemic are assessed using the Andalusian Tourism Situation Survey (ECTA). This information is then compared with data obtained from a sentiment analysis based on the social network Twitter. On the basis of this comparative analysis, the paper concludes that it is possible to identify and classify tourists’ perceptions using sentiment analysis on a mass scale with the help of statistical software (RStudio and Knime). The sentiment analysis using Twitter data correlates with and is supplemented by information from the ECTA survey, with both analyses showing that tourists placed greater value on safety and preferred to travel individually to nearby, less crowded destinations since the pandemic began. Of the two analytical tools, sentiment analysis can be carried out on social media on a continuous basis and offers cost savings.

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“…It is possible that the pathogenic variant associated with Lehman Syndrome can be targeted to ameliorate the phenotype associated with the NOTCH3 gain-of-function using an ASO approach. The ASO strategy was recently tested in an experimental mouse model of HCS termed Notch2 tm 1.1 Ecan and characterized by a NOTCH2 gain-of-function and severe osteopenia secondary to increased osteoclastogenesis (Canalis et al, 2020 ). Delivery of Notch2 ASOs in vitro decreased Notch2 wild type and mutant expression, and NOTCH2 activation, and inhibited osteoclastogenesis in Notch2 tm 1.1 Ecan osteoclast precursors.…”

Section: Interventions To Ameliorate the Lateral Meningocele Syndromementioning

confidence: 99%

The Skeleton of Lateral Meningocele Syndrome

Canalis

2021

Front. Genet.

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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.

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Antisense oligonucleotides targeting Notch2 ameliorate the osteopenic phenotype in a mouse model of Hajdu-Cheney syndrome

Cited by 12 publications

References 76 publications

Bortezomib Rescues Ovariectomy-Induced Bone Loss via SMURF-Mediated Ubiquitination Pathway

Bortezomib Rescues Ovariectomy-Induced Bone Loss via SMURF-Mediated Ubiquitination Pathway

Using Social Media in Tourist Sentiment Analysis: A Case Study of Andalusia during the Covid-19 Pandemic

The Skeleton of Lateral Meningocele Syndrome

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