The mechanosensitive adhesion G protein-coupled receptor GPR133/ADGRD1 enhances bone formation – a potential new target for osteoporosis treatment
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PROVIDER: PRJNA1271562 | ENA |
REPOSITORIES: ENA
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Project description:Osteoporosis poses an increasing health and socioeconomic burden on aging societies. Current therapeutic options often present potentially severe side effects or lack long-term efficacy, underscoring the need for more effective treatments. Establishing novel drug targets requires an in-depth understanding of their physiological roles. Here, we describe the impact of the adhesion G protein-coupled receptor GPR133/ADGRD1 on osteoblast differentiation and function. Constitutive and osteoblast-specific knockouts of GPR133/ADGRD1 in mice result in reduced cortical bone mass and increased trabecularization in femurs and vertebrae—features characteristic of osteoporosis. Genome-wide association studies in humans link GPR133/ADGRD1 gene variants to differences in bone mineral density and body height. At the molecular level, GPR133/ADGRD1 influences osteoblast function and differentiation through a combined activation mechanism involving interaction with its endogenous ligand PTK7 and mechanical forces. In vitro analysis shows that osteoblast differentiation is driven by cAMP-dependent activation of the b-catenin signaling pathway. Activation of GPR133/ADGRD1 with the receptor-specific ligand AP503 promotes osteoblast function and differentiation both in vitro and in vivo, significantly alleviating osteoporosis in a mouse ovariectomy model. This renders GPR133/ADGRD1 a promising therapeutic target for osteoporosis and other diseases characterized by reduced bone mass.
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Project description:Recent studies have shown that microRNAs (miRNAs) are implicated in the development of postmenopausal osteoporosis, implying potential biomarkers. We performed a microarray-based expression scanning to search for potential circulating miRNA biomarkers for postmenopausal osteoporosis as whole blood obtianed from patients was used. MiRNA expression in the whole blood of 23 Chinese postmenopausal women with osteopenia and that of 25 Chinese postmenopausal women with osteoporosis. After total RNA was extracted, all of the RNA extraction samples were seperately pooled into six subgroups according to the T-score measurement.
2014-12-23 | E-GEOD-64433 | biostudies-arrayexpress
Project description:In the present study we analyzed the effect of primary osteoporosis on the transcriptome of human mesenchymal stem cells (hMSC; alternatively named mesenchymal stromal cells) from human bone marrow. Human MSC of elderly patients suffering from osteoporosis were isolated from femoral heads after low-energy fracture of the femoral neck. Bone marrow of age-matched, non-osteoporotic donors was obtained of femoral heads after total hip arthroplasty. Cells were isolated from human bone marrow according to the previously described protocol (Noth et al., 2002, J Orthop Res, 20/5, 1060-1069) under agreement of the local Ethics Committee of the University of Würzburg. Human MSC of elderly patients suffering from osteoporosis were isolated from femoral heads after low-energy fracture of the femoral neck. Additional criteria for confirming primary osteoporosis in these donors were vertebrae fractures and advanced age. Bone marrow of age-matched, non-osteoporotic donors was obtained of femoral heads after total hip arthroplasty due to osteoarthritis and/or hip dysplasia. RNA samples were taken from passage 1 or passage 2.
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Project description:Investigate genes expression profiles of postmenopausal osteoporosis in bone(femur)
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Project description:Background: Osteoporosis is one of the most common chronic diseases around the world, especially in postmenopausal women. Circular RNAs (circRNAs) are emerging as important regulators in human disease. The aim of the present study was to analyze circRNA expression profiles in osteoporosis and to explore the clinical significance. Methods: The serum samples were collected from osteoporosis patients and healthy people. The circRNA array was performed to screen for differentially expressed circRNAs. The mRNA expression levels of target genes were analyzed by quantitative real-time PCR (qRT-PCR). Results: Hsa_circ_0006859 was identified as one of the most upregulated circRNAs in the microarray analysis. Hsa_circ_0006859 in exosome was upregulated in osteoporosis patients compared with healthy controls. Hsa_circ_0006859 could differentiate osteopenia or osteoporosis patients from healthy controls with high sensitivity and specificity. Conclusion: Exosomal hsa_circ_0006859 is a potential biomarker for postmenopausal osteoporosis.
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Project description:Recent studies have shown that microRNAs (miRNAs) are implicated in the development of postmenopausal osteoporosis, implying potential biomarkers. We performed a microarray-based expression scanning to search for potential circulating miRNA biomarkers for postmenopausal osteoporosis as whole blood obtianed from patients was used.
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Project description:Mechanisms governing cancer metastasis remain poorly understood. Once disseminated tumor cells (DTCs) arrive at a metastatic organ, they remain there, latent, and become seeds of metastasis. However, the clonal composition of DTCs in a latent state remains unclear. Here, we applied high-resolution DNA barcode tracking to a mouse model that recapitulated the metastatic dormancy of head and neck squamous cell carcinoma (HNSCC). We found that clones that had abundant circulating tumor cells (CTCs) but were rare in the primary site dominated DTCs. We obtained a specific subclone that dominated CTCs and subsequent DTCs in lungs and bone marrow. Despite no notable features under static conditions, this clone significantly generated stable cell aggregates that were resistant to anoikis in suspension culture under fluid shear stress conditions. Even as a heterogeneous population, this clone generated almost monoclonal CTC clusters. Via transcriptome analyses, we identified E-cadherin to be indispensable but not sufficient for such stable cell-cell adhesion. Instead, our data indicated that mutual regulation of cortical actin-myosin dynamics according to mechanostress in the cells within each aggregate governed stable adhesion. Furthermore, the gene expression signature of the mechanosensitive clone, which originated clustered CTCs, was associated with locoregional and metastatic recurrence in patients with HNSCC. These results reveal that intrinsically mechanosensitive rare clones in the parental population dominantly colonize distant sites via homotypic CTC cluster formation. This novel clonal selection mechanism based on intrinsic tumor cell mechanosensitivity may lead to promising cancer therapies.
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Project description:Investigate genes expression profiles of postmenopausal osteoporosis with kidney Yin deficiency in peripheral blood By TCM syndrome, 10 patients with postmenopausal osteoporosis were divided into three groups: kidney Yin deficiency (n=4), kidney Yang deficiency (n=3), non-kidney deficiency (n=3), another 3 healthy postmenopausal women also were selected as control group. Whole human genome oligo microarray were applied to explore gene expression difference of the groups. Kidney Yin deficiency group was compared with other three groups respectively.
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