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Targeting thymidine phosphorylase as a potential therapy for bone loss associated periprosthetic osteolysis

ABSTRACT: Targeting thymidine phosphorylase as a potential therapy for bone loss associated periprosthetic osteolysis

PROVIDER: PRJNA720011 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR14150349_1.fastq.gz	Fastqsanger.gz
	SRR14150349_2.fastq.gz	Fastqsanger.gz
	SRR14150350_1.fastq.gz	Fastqsanger.gz
	SRR14150350_2.fastq.gz	Fastqsanger.gz
	SRR14150351_1.fastq.gz	Fastqsanger.gz

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Targeting thymidine phosphorylase as a potential therapy for bone loss associated periprosthetic osteolysis

Project description:The aim of this study was to identify macrophage-derived factors that promote osteoclast differentiation and periprosthetic bone destruction. To achieve this, we examined the effects of 12 macrophage-derived factors that were identified by RNA-seq analysis of stimulated macrophages on osteoclast differentiation. TYMP was found to trigger significant number of osteoclasts that exhibited resorbing activities on dentine slices. TYMP were detected in serum and synovial tissues of patients that had been diagnosed with aseptic loosening. RNA-seq for TYMP-induced-osteoclasts was then performed in an effort to understand action mode of TYMP. TYMP stimulation appeared to activate the tyrosine kinase FYN signaling associated with osteoclast formation. Oral administration of saracatinib, a FYN kinase inhibitor, significantly suppressed formation of bone osteolytic lesions in a polyethylene debris-induced osteolysis model. Our findings highlight a novel molecular target for therapeutic intervention in periprosthetic osteolysis.

2021-06-10 | GSE171542 | GEO

Targeting thymidine phosphorylase as a potential therapy for bone loss associated with periprosthetic osteolysis.

Project description:Macrophages are generally thought to play a key role in the pathogenesis of aseptic loosening through initiating periprosthetic inflammation and pathological bone resorption. The aim of this study was to identify macrophage-derived factors that promote osteoclast differentiation and periprosthetic bone destruction. To achieve this, we examined the effects of 12 macrophage-derived factors that were identified by RNA-seq analysis of stimulated macrophages on osteoclast differentiation. Surprisingly, thymidine phosphorylase (TYMP) was found to trigger significant number of osteoclasts that exhibited resorbing activities on dentine slices. Functionally, TYMP knockdown reduced the number of osteoclasts in macrophages that had been stimulated with polyethylene debris. TYMP were detected in serum and synovial tissues of patients that had been diagnosed with aseptic loosening. Moreover, the administration of TYMP onto calvariae of mice induced pathological bone resorption that was accompanied by an excessive infiltration of inflammatory cells and osteoclasts. The RNA-seq for TYMP-induced-osteoclasts was then performed in an effort to understand action mode of TYMP. TYMP stimulation appeared to activate the tyrosine kinase FYN signaling associated with osteoclast formation. Oral administration of saracatinib, a FYN kinase inhibitor, significantly suppressed formation of bone osteolytic lesions in a polyethylene debris-induced osteolysis model. Our findings highlight a novel molecular target for therapeutic intervention in periprosthetic osteolysis.

| S-EPMC8459589 | biostudies-literature

Gene expression profile of human epidermoid carcinoma KB cells that overexpress thymidine phosphorylase

2014-08-03 | GSE31467 | GEO

Effect of RIG-I activation and thymidine phosphorylase inhibition using Tipiracil on gene expression of human endothelial cells.

Project description:To investigate the role of RIG-I activation and thymidine phosphorylase inhibition human endothelial cells, we used a dsRNA agonist on HUVECs and HMVECs to activate RIG-I signaling, and further treated with tymp inhibitor TPI. We then performed differential gene expression analysis using data obtained from RNA-seq from each treatment group.

2023-05-01 | GSE204809 | GEO

Gene expression profile of human epidermoid carcinoma KB cells that overexpress thymidine phosphorylase

Project description:Thymidine phosphorylase (TP) catalyzes the reversible phosphorolysis of thymidine, deoxyuridine, and their analogs to the respective bases and 2-deoxy-D-ribose-1-phosphate. TP is identical to platelet-derived endothelial cell growth factor (PD-ECGF). TP was reported to induce many angiogenic factors. However, the molecular mechanism of the TP function is still obscure. To elucidate the molecular basis for the TP function in human epidermoid carcinoma KB cells, we performed a whole genome-wide microarray analysis. Genes upregulated in KB cells overexpressing TP are supposed to represent potential molecular targets of TP in KB cells. KB cells (4 M-CM-^W 10^5) in 5 ml of culture media were cultured for 24 hours, then the growth medium was replaced with serum-free medium. These cells were maintained at 37 M-KM-^ZC in a humidified atmosphere of 5% CO2 for 12 hours, then these cells were collected for RNA extraction and quantification of the transcripts by microarray analysis.

2014-08-03 | E-GEOD-31467 | biostudies-arrayexpress

Injectable natural polymer hybrid hydrogel targeting aseptic loosening due to wear particle induced osteolysis

Project description:Aseptic loosening represents a significant factor contributing to joint replacement failure, primarily associated with diminished bone formation and heightened osteoclast-induced osteolysis. Here, a natural polymer-based injectable hydrogel that encapsulates irisin protein (referred to as I-OG hydrogel) is reported. The hierarchical cross-linked structure of the I-OG hydrogel confers favorable mechanical properties, desirable self-healing ability, and acceptable injectability and, more importantly, sustains continuous release of the protein at the interface between the bone and implant prosthesis. The I-OG hydrogel effectively fills the gap between the titanium pin and bone tissue, successfully inhibiting aseptic loosening induced by titanium particles, which outcome confirms the occurrence of irisin protein's slow-release process and its inhibitory effect on osteolysis. Mechanistically, our in vitro experiments demonstrated that irisin released from the I-OG hydrogel upregulates the Wnt/β-catenin signaling pathway in bone marrow stromal cells (BMSCs) through integrin αV, while concurrently downregulating the NF-κB (P65) signaling pathway in osteoblasts. These molecular events ultimately promote osteogenic differentiation and inhibit osteoclast activation. Collectively, our findings establish that the I-OG hydrogel effectively counteracts aseptic loosening by resisting osteolysis caused by titanium particles and enhancing periprosthetic bone formation, and offers promising prospects for the treatment of aseptic loosening in prosthetic implants.

2023-06-17 | GSE234863 | GEO

Thymidine starvation

Project description:Thymidine starvation

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Effect of RIG-I activation and thymidine phosphorylase inhibition using Tipiracil on gene expression of human endothelial cells.

Project description:Effect of RIG-I activation and thymidine phosphorylase inhibition using Tipiracil on gene expression of human endothelial cells.

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Thymidine phosphorylase: A potential new target for treating cardiovascular disease.

Project description:We recently found that thymidine phosphorylase (TYMP), also known as platelet-derived endothelial cell growth factor, plays an important role in platelet activation in vitro and thrombosis in vivo by participating in multiple signaling pathways. Platelets are a major source of TYMP. Since platelet-mediated clot formation is a key event in several fatal diseases, such as myocardial infarction, stroke and pulmonary embolism, understanding TYMP in depth may lead to uncovering novel mechanisms in the development of cardiovascular diseases. Targeting TYMP may become a novel therapeutic for cardiovascular disorders. In this review article, we summarize the discovery of TYMP and the potential molecular mechanisms of TYMP involved in the development of various diseases, especially cardiovascular diseases. We also offer insights regarding future studies exploring the role of TYMP in the development of cardiovascular disease as well as in therapy.

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Osteocyte CIITA Aggravates Osteolytic Bone Lesions in Myeloma

Project description:Osteolytic destruction is a hallmark of multiple myeloma, resulting from activation of osteoclast mediated bone resorption and reduction of osteoblast-mediated bone formation. However, the molecular mechanism underlying the differentiation and activity of osteoclasts and osteoblasts within a myelomatous microenvironment remains unclear. Here, we demonstrate that the osteocyte-expressed major histocompatibility complex class II transactivator (CIITA) contributes to myeloma-induced bone lesions. CIITA upregulates the secretion of osteolytic cytokines from osteocytes through acetylation at histone 3 lysine 14 in the promoter of TNFSF11 (encoding RANKL) and SOST (encoding sclerostin), leading to enhanced osteoclastogenesis and decreased osteoblastogenesis. In turn, myeloma cell–secreted 2-deoxy-D-ribose, the product of thymidine catalyzed by the function of thymidine phosphorylase, upregulates CIITA expression in osteocytes through the STAT1/IRF1 signaling pathway. Our work thus broadens the understanding of myeloma-induced osteolysis and indicates a potential strategy for disrupting tumor-osteocyte interaction to prevent, or treat patients with, myeloma bone disease.

2022-04-23 | GSE200987 | GEO

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