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Inhibiting Hh signaling in Gli1+ osteogenic progenitors alleviates TMJOA

ABSTRACT: Inhibiting Hh signaling in Gli1+ osteogenic progenitors alleviates TMJOA

PROVIDER: PRJNA758561 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR15661705.fastq.gz	Fastqsanger.gz
	SRR15661706.fastq.gz	Fastqsanger.gz
	SRR15661707.fastq.gz	Fastqsanger.gz
	SRR15661708.fastq.gz	Fastqsanger.gz
	SRR15661709.fastq.gz	Fastqsanger.gz

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Inhibiting Hh signaling in Gli1+ osteogenic progenitors alleviates TMJOA

Project description:The goal of this study is to investigate the role of Gli1+ osteogenic progenitors in the development of TMJOA.

2021-11-04 | GSE182969 | GEO

Inhibiting Hh Signaling in Gli1<sup>+</sup> Osteogenic Progenitors Alleviates TMJOA.

Project description:The increased prevalence of temporomandibular joint osteoarthritis (TMJOA) in children and adolescents has drawn considerable attention as it may interfere with mandibular condyle growth, resulting in dento-maxillofacial deformities. However, treatments for osteoarthritis have been ineffective at restoring the damaged bone and cartilage structures due to poor understanding of the underlying degenerative mechanism. In this study, we demonstrate that Gli1+ cells residing in the subchondral bone contribute to bone formation and homeostasis in the mandibular condyle, identifying them as osteogenic progenitors in vivo. Furthermore, we show that, in a TMJOA mouse model, derivatives of Gli1+ cells undergo excessive expansion along with increased but uneven distribution of osteogenic differentiation in the subchondral bone, which leads to abnormal subchondral bone remodeling via Hedgehog (Hh) signaling activation and to the development of TMJOA. The selective pharmacological inhibition and specific genetic inhibition of Hh signaling in Gli1+ osteogenic progenitors result in improved subchondral bone microstructure, attenuated local immune inflammatory response in the subchondral bone, and reduced degeneration of the articular cartilage, providing in vivo functional evidence that targeting Hh signaling in Gli1+ osteogenic progenitors can modulate bone homeostasis in osteoarthritis and provide a potential approach for treating TMJOA.

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Empagliflozin alleviates atherosclerotic calcification by inhibiting osteogenic differentiation of vascular smooth muscle cells

Project description:SGLT-2 inhibitors, such as empagliflozin, have been shown to reduce the occurrence of cardiovascular events and delay the progression of atherosclerosis. However, its role in atherosclerotic calcification remains unclear. In this research, ApoE-/- mice were fed with western diet and empagliflozin was added to the drinking water for 24 weeks. Empagliflozin treatment significantly alleviated arterial calcification assessed by alizarin red and von kossa staining in aortic roots and reduced the lipid levels, while had little effect on body weight and blood glucose levels in ApoE-/- mice. In vitro studies, empagliflozin significantly inhibits calcification of primary vascular smooth muscle cells (VSMCs) and aortic rings induced by osteogenic media (OM) or inorganic phosphorus (Pi). RNA sequencing of VSMCs cultured in OM with or without empagliflozin showed that empagliflozin negatively regulated the osteogenic differentiation of VSMCs. And further studies confirmed that empagliflozin significantly inhibited osteogenic differentiation of VSMCs via qRT-PCR. Our study demonstrates that empagliflozin alleviates atherosclerotic calcification by inhibiting osteogenic differentiation of VSMCs, which addressed a critical need for the discovery of a drug-based therapeutic approach in the treatment of atherosclerotic calcification.

2023-11-22 | GSE243752 | GEO

Gli1+ progenitors mediate bone anabolic function of teriparatide via Hh and Igf signaling

Project description:Teriparatide, a bioactive fragment of human parathyroid hormone (PTH), is the most widely prescribed bone anabolic drug in the world, but its cellular targets remain incompletely defined. The Gli1+ metaphyseal mesenchymal progenitors (MMPs) are a main source for osteoblasts in postnatal growing mice, but their potential response to teriparatide is unknown. Here, by lineage tracing we find that teriparatide stimulates both proliferation and osteoblast differentiation of MMPs. Single-cell RNA sequencing reveals heterogeneity among MMPs including a chondrocyte-like osteoprogenitor (herein COP) population that expands in response to teriparatide. COPs express the highest level of Hedgehog (Hh) target genes and the insulin-like growth factor receptor Igf1r. Inhibition of Hh signaling, or selective deletion of Igf1r in MMPs diminishes the proliferative and osteogenic effects of teriparatide. The study therefore identifies MMPs as teriparatide target cells wherein Hh and Igf signaling are critical for osteoblast production.

2021-06-06 | GSE169560 | GEO

Empagliflozin alleviates atherosclerotic calcification by inhibiting osteogenic differentiation of vascular smooth muscle cells

Project description:Empagliflozin alleviates atherosclerotic calcification by inhibiting osteogenic differentiation of vascular smooth muscle cells

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Expression data from regenerating prostates of wild-type or Gli1-/- mutant mice

Project description:Attenuation of Hedgehog (Hh) pathway activity leads to increased prostate branching during adult prostate regeneration. In order to identify genes regulated by the Hh pathway that might be involved in adult prostate branching, we performed transcriptional profiling of regenerating prostates from wild-type or Gli1-/- mutant mice, which have attenuated Hh pathway activity. 6 total samples were analyzed. 3 wild-type prostates and 3 Gli-/- mutant prostates were analyzed.

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Expression data from regenerating prostates of wild-type or Gli1-/- mutant mice

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Next Generation Sequencing (RNA sequencing) of Wild Type and GLI1 knock-out CUTLL1 childhood T lymphoblastic lymphoma cell line

Project description:T-cell acute lymphoblastic leukemia (T-ALL) is a highly malignant pediatric leukemia, where few therapeutic options are available for patients which relapse. The evolutionarily conserved Hedgehog (Hh) pathway plays a crucial role in patterning and organogenesis during early development, in adult tissue maintenance and repairing functions. Once Hh ligands bind to PTCH1/2 on target cells, the inhibition of Patched proteins for Smo is relieved. Smo translocates to the primary cilium and leads to the breakdown of a protein complex formed by Suppressor of Fused (SUFU) and GLI proteins. GLI transcription factors (GLI1-3) are released and translocate to the nucleus, initiating transcription of Hh target genes. GLI2 and GLI3 have transcriptional activation and repression properties, while GLI1 is a strong positive regulator of Hh transcriptional targets. In T-ALL rare hedgehog pathway mutations have been observed and approximately 20% of T-ALL cases present with ectopic expression of Hh pathway ligands and GLI1. However, the function of Hh signaling and in particular GLI transcription factors in T-ALL initiation and/or tumor progression is not well-known. RNA sequencing was performed in the CUTLL1 T-ALL cell line after knocking out GLI1 gene using CRISPR/Cas9 system.

2020-07-03 | GSE153718 | GEO

Keloid fibroproliferative properties are dependent on stem cells modified by the HEDGEHOG-GLI1 pathway [EA1488]

Project description:Keloids are benign fibroproliferative skin tumors caused by aberrant wound healing, the etiology of which is unknown. Although keloids cause life inconveniences and cosmetic problems, the lack of animal models has yet to elucidate their pathogenesis or develop effective treatments. Here, we found that the characteristics of stem cells from keloid lesions and surrounding dermis differ from those of normal skin and that HEDGEHOG (HH) signal and its downstream transcription factor GLI1 were upregulated in keloid patient-derived stem cells. Inhibition of the HH-GLI1 pathway reduced the expression of genes involved in keloids and fibrosis-inducing cytokines, including osteopontin. Moreover, HH-signal inhibitor vismodegib reduced keloid reconstituted tumor size and the expression of keloid related genes in nude mouse, and the collagen bundle and the expression of cytokines characteristic for keloids in ex vivo culture of keloid tissues. These results implicate the HH-GLI1 pathway in keloid pathogenesis and suggest therapeutic target of keloids.

2023-12-13 | GSE218922 | GEO

Keloid fibroproliferative properties are dependent on stem cells modified by the HEDGEHOG-GLI1 pathway [EA1874]

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