Bone-targeting AAV-mediated silencing of Schnurri-3 prevents bone loss in osteoporosis

Yang, Yujing; Xie, Jun; Wang, Dan; Kim, Jung-Min; Tai, Phillip W. L.; Gravallese, Ellen M.; Gao, Guangping; Shim, Jae-Hyuck

doi:10.1038/s41467-019-10809-6

Cited by 93 publications

(86 citation statements)

References 51 publications

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“…Runx2 is regulated by Shn3 through a complex with E3 ubiquitin ligase WWP1 26 . Shn3 regulates the interaction by inhibiting mitogenactivated protein kinase (MAPK) activity and osteogenic differentiation, and the Shn3 expression indirectly regulates osteoclastic bone resorption 27,28 .…”

Section: Introductionmentioning

confidence: 99%

RETRACTED ARTICLE: Schnurri-3 regulates BMP9-induced osteogenic differentiation and angiogenesis of human amniotic mesenchymal stem cells through Runx2 and VEGF

Liu

Tang

et al. 2020

Cell Death Dis

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Human amniotic mesenchymal stem cells (hAMSCs) are multiple potent progenitor cells (MPCs) that can differentiate into different lineages (osteogenic, chondrogenic, and adipogenic cells) and have a favorable capacity for angiogenesis. Schnurri-3 (Shn3) is a large zinc finger protein related to Drosophila Shn, which is a critical mediator of postnatal bone formation. Bone morphogenetic protein 9 (BMP9), one of the most potent osteogenic BMPs, can strongly upregulate various osteogenesis-and angiogenesis-related factors in MSCs. It remains unclear how Shn3 is involved in BMP9-induced osteogenic differentiation coupled with angiogenesis in hAMSCs. In this investigation, we conducted a comprehensive study to identify the effect of Shn3 on BMP9-induced osteogenic differentiation and angiogenesis in hAMSCs and analyze the responsible signaling pathway. The results from in vitro and in vivo experimentation show that Shn3 notably inhibits BMP9-induced early and late osteogenic differentiation of hAMSCs, expression of osteogenesis-related factors, and subcutaneous ectopic bone formation from hAMSCs in nude mice. Shn3 also inhibited BMP9-induced angiogenic differentiation, expression of angiogenesis-related factors, and subcutaneous vascular invasion in mice. Mechanistically, we found that Shn3 prominently inhibited the expression of BMP9 and activation of the BMP/Smad and BMP/MAPK signaling pathways. In addition, we further found activity on runt-related transcription factor 2 (Runx2), vascular endothelial growth factor (VEGF), and the target genes shared by BMP and Shn3 signaling pathways. Silencing Shn3 could dramatically enhance the expression of Runx2, which directly regulates the downstream target VEGF to couple osteogenic differentiation with angiogenesis. To summarize, our findings suggested that Shn3 significantly inhibited the BMP9-induced osteogenic differentiation and angiogenesis in hAMSCs. The effect of Shn3 was primarily seen through inhibition of the BMP/Smad signaling pathway and depressed expression of Runx2, which directly regulates VEGF, which couples BMP9-induced osteogenic differentiation with angiogenesis.

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Section: Introductionmentioning

confidence: 99%

RETRACTED ARTICLE: Schnurri-3 regulates BMP9-induced osteogenic differentiation and angiogenesis of human amniotic mesenchymal stem cells through Runx2 and VEGF

Liu

Tang

et al. 2020

Cell Death Dis

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“…Mrc1 -/mice transfected with AAV-miR-511-3p. AAV, a nonpathogenic small DNA virus, has been utilized to deliver DNA to target cells (67). An AAV serotype 9 (AAV9) vector encoding the enhanced GFP reporter and expressing miR-511-3p (AAV-CMV-miR-511-3p-GFP), driven by the cytomegalovirus (CMV) promoter, was generated in SignaGen Laboratory.…”

Section: Methodsmentioning

confidence: 99%

miR-511-3p protects against cockroach allergen–induced lung inflammation by antagonizing CCL2

Danh¹,

Mu²,

Xia³

et al. 2019

JCI Insight

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“… 178 The latest achievement using such a strategy was the development of bone-homing capsid named AAV9.DSS-Nter. 179 However, the generation of functional capsids through these means are in general difficult. Part of the reason behind this difficulty is that the AAV capsid and it’s role during the viral life cycle is not completely understood, i.e., changes on the capsid may theoretically improve binding of AAV to specific cell receptors, but may negatively impact other aspects, such as vector production or cellular trafficking.…”

Section: Introductionmentioning

confidence: 99%

Viral vector platforms within the gene therapy landscape

Bulcha

Wang

et al. 2021

Sig Transduct Target Ther

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800

572

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Throughout its 40-year history, the field of gene therapy has been marked by many transitions. It has seen great strides in combating human disease, has given hope to patients and families with limited treatment options, but has also been subject to many setbacks. Treatment of patients with this class of investigational drugs has resulted in severe adverse effects and, even in rare cases, death. At the heart of this dichotomous field are the viral-based vectors, the delivery vehicles that have allowed researchers and clinicians to develop powerful drug platforms, and have radically changed the face of medicine. Within the past 5 years, the gene therapy field has seen a wave of drugs based on viral vectors that have gained regulatory approval that come in a variety of designs and purposes. These modalities range from vector-based cancer therapies, to treating monogenic diseases with life-altering outcomes. At present, the three key vector strategies are based on adenoviruses, adeno-associated viruses, and lentiviruses. They have led the way in preclinical and clinical successes in the past two decades. However, despite these successes, many challenges still limit these approaches from attaining their full potential. To review the viral vector-based gene therapy landscape, we focus on these three highly regarded vector platforms and describe mechanisms of action and their roles in treating human disease.

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Bone-targeting AAV-mediated silencing of Schnurri-3 prevents bone loss in osteoporosis

Cited by 93 publications

References 51 publications

RETRACTED ARTICLE: Schnurri-3 regulates BMP9-induced osteogenic differentiation and angiogenesis of human amniotic mesenchymal stem cells through Runx2 and VEGF

RETRACTED ARTICLE: Schnurri-3 regulates BMP9-induced osteogenic differentiation and angiogenesis of human amniotic mesenchymal stem cells through Runx2 and VEGF

miR-511-3p protects against cockroach allergen–induced lung inflammation by antagonizing CCL2

Viral vector platforms within the gene therapy landscape

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