scholarly journals miR-6315 Attenuates Methotrexate Treatment-Induced Decreased Osteogenesis and Increased Adipogenesis Potentially through Modulating TGF-β/Smad2 Signalling

Biomedicines ◽  
2021 ◽  
Vol 9 (12) ◽  
pp. 1926
Author(s):  
Ya-Li Zhang ◽  
Liang Liu ◽  
Yu-Wen Su ◽  
Cory J. Xian
Keyword(s):  
Bone Marrow ◽  
Bone Loss ◽  
Bone Marrow Stromal Cells ◽  
Molecular Mechanisms ◽  
Adipogenic Differentiation ◽  
Marrow Fat ◽  
Childhood Malignancies ◽  
Marrow Adiposity ◽  
Underlying Mechanisms

Methotrexate (MTX) treatment for childhood malignancies has shown decreased osteogenesis and increased adipogenesis in bone marrow stromal cells (BMSCs), leading to bone loss and bone marrow adiposity, for which the molecular mechanisms are not fully understood. Currently, microRNAs (miRNAs) are emerging as vital mediators involved in bone/bone marrow fat homeostasis and our previous studies have demonstrated that miR-6315 was upregulated in bones of MTX-treated rats, which might be associated with bone/fat imbalance by directly targeting Smad2. However, the underlying mechanisms by which miR-6315 regulates osteogenic and adipogenic differentiation require more investigations. Herein, we further explored and elucidated the regulatory roles of miR-6315 in osteogenesis and adipogenesis using in vitro cell models. We found that miR-6315 promotes osteogenic differentiation and it alleviates MTX-induced increased adipogenesis. Furthermore, our results suggest that the involvement of miR-6315 in osteogenesis/adipogenesis regulation might be partially through modulating the TGF-β/Smad2 signalling pathway. Our findings indicated that miR-6315 may be important in regulating osteogenesis and adipogenesis and might be a therapeutic target for preventing/attenuating MTX treatment-associated bone loss and marrow adiposity.

scholarly journals miR-542-3p Attenuates Bone Loss and Marrow Adiposity Following Methotrexate Treatment by Targeting sFRP-1 and Smurf2

2021 ◽  
Vol 22 (20) ◽  
pp. 10988
Author(s):  
Ya-Li Zhang ◽  
Liang Liu ◽  
Yu-Wen Su ◽  
Cory J. Xian
Keyword(s):  
Bone Marrow ◽  
Bone Loss ◽  
Target Prediction ◽  
In Vitro Models ◽  
Bone Homeostasis ◽  
Marrow Fat ◽  
Childhood Malignancies ◽  
Marrow Adiposity ◽  
Underlying Mechanisms

Intensive methotrexate (MTX) treatment for childhood malignancies decreases osteogenesis but increases adipogenesis from the bone marrow stromal cells (BMSCs), resulting in bone loss and bone marrow adiposity. However, the underlying mechanisms are unclear. While microRNAs (miRNAs) have emerged as bone homeostasis regulators and miR-542-3p was recently shown to regulate osteogenesis in a bone loss context, the role of miR-542-3p in regulating osteogenesis and adipogenesis balance is not clear. Herein, in a rat MTX treatment-induced bone loss model, miR-542-3p was found significantly downregulated during the period of bone loss and marrow adiposity. Following target prediction, network construction, and functional annotation/ enrichment analyses, luciferase assays confirmed sFRP-1 and Smurf2 as the direct targets of miR-542-3p. miRNA-542-3p overexpression suppressed sFRP-1 and Smurf2 expression post-transcriptionally. Using in vitro models, miR-542-3p treatment stimulated osteogenesis but attenuated adipogenesis following MTX treatment. Subsequent signalling analyses revealed that miR-542-3p influences Wnt/β-catenin and TGF-β signalling pathways in osteoblastic cells. Our findings suggest that MTX treatment-induced bone loss and marrow adiposity could be molecularly linked to miR-542-3p pathways. Our results also indicate that miR-542-3p might be a therapeutic target for preserving bone and attenuating marrow fat formation during/after MTX chemotherapy.

scholarly journals Adipsin promotes bone marrow adiposity by priming mesenchymal stem cells

2021 ◽  
Author(s):  
Li Qiang ◽  
Nicole Aaron ◽  
Michael J. Kraakman ◽  
Qiuzhong Zhou ◽  
Qiongming Liu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Loss ◽  
Calorie Restriction ◽  
Adipogenic Differentiation ◽  
Dependent Manner ◽  
Hormonal Changes ◽  
Healthy Human ◽  
Downstream Effector ◽  
Obesity And Diabetes ◽  
Marrow Adiposity

Background: Bone marrow (BM) adipose tissue (BMAT) has been shown to be vital for regulating metabolism and maintaining skeletal homeostasis in the marrow niche. As a reflection of BM remodeling, BMAT is highly responsive to nutrient fluctuations, hormonal changes and metabolic disturbances such as obesity and diabetes mellitus. Expansion of BMAT has also been strongly associated with bone loss in mice and humans. However, the regulation of BM plasticity remains poorly understood, as does the mechanism that links changes in marrow adiposity with bone remodeling. Methods: Using C57BL/6 mice as a model, we employed the bone-protected PPARg constitutive deacetylation (2KR), Adipsin, and its downstream effector, C3, knockout mice. These mice were challenged to thiazolidinedione treatment, calorie restriction, or aging in order to induce bone loss and MAT expansion. Analysis of bone density and marrow adiposity was performed using a μCT scanner and by RNA analysis to assess adipocyte and osteoblast markers. For in vitro studies, primary bone marrow stromal cells (BMSCs) were isolated and subjected to osteoblastogenic or adipogenic differentiation or chemical treatment followed by morphological and molecular analyses. Clinical data was obtained from samples of a previous clinical trial of fasting and high calorie diet in healthy human volunteers. Results: We have shown that Adipsin is the most up-regulated adipokine during BMAT expansion in mice and humans, in a PPARg acetylation-dependent manner. Ablation of Adipsin in mice specifically inhibited BMAT expansion but not peripheral adipose depots, and improved bone mass during calorie restriction, thiazolidinedione treatment, and aging. These effects were mediated through its downstream effector, complement component C3, to prime common progenitor cells toward adipogenesis rather than osteoblastogenesis through inhibiting Wnt/b-catenin signaling. Conclusions: Adipsin promotes new adipocyte formation and affects skeletal remodeling in the BM niche. Our study reveals a novel mechanism whereby the BM sustains its own plasticity through paracrine and endocrine actions of a unique adipokine. Funding: This work was supported by the National Institutes of Health T32DK007328 (NA), F31DK124926 (NA), R01DK121140 (JCL), R01AR068970 (BZ), R01AR071463 (BZ), R01DK112943 (LQ), and P01HL087123 (LQ).

Olive oil effectively mitigates ovariectomy-induced marrow adiposity assessed by MR spectroscopy in estrogen-deficient rabbits

2021 ◽  
pp. 028418512098693
Author(s):  
Yin Liu ◽  
Huayi Tan ◽  
Can Huang ◽  
Lifeng Li ◽  
Sijie Wu
Keyword(s):  
Bone Marrow ◽  
Bone Loss ◽  
Olive Oil ◽  
Mr Spectroscopy ◽  
Sham Operation ◽  
Dependent Manner ◽  
Mineral Density ◽  
Sequential Effects ◽  
Marrow Fat ◽  
Marrow Adiposity

Background Polyphenols in extra virgin olive oil (EVOO) have been found to reduce the expression of PPARγ2, inhibit adipocyte differentiation, and enhance the formation of osteoblasts from bone marrow stem cells. However, the underlying mechanisms of their action remain unknown. Purpose To determine the sequential effects of EVOO on marrow fat expansion induced by estrogen deprivation using 3.0-T proton magnetic resonance (MR) spectroscopy in an ovariectomy (OVX) rabbit model of postmenopausal bone loss over a six-month period. Material and Methods A total of 45 female New Zealand rabbits were equally divided into sham-operation, OVX controls, and OVX treated with EVOO for six months. Marrow fat fraction was measured by MR spectroscopy at baseline conditions, and three and six months postoperatively, respectively. Serum bone biomarkers, lumbar and femoral bone mineral density, microtomographic parameters, biomechanical properties, and quantitative parameters of marrow adipocytes were studied. Results OVX was associated with marrow adiposity in a time-dependent manner, accompanied with increased bone turnover and impaired bone mass and trabecular microarchitecture. In OVX rabbits, EVOO markedly alleviated trabecular bone loss and reduced the accumulation of lipid droplets including adipocyte size, density, and areas of fat deposits in the bone marrow. EVOO prevented such changes in terms of both marrow adiposity and bone remodeling. Conclusion Early EVOO treatment may exert beneficial effects on bone by modulating marrow adiposity, which would support their protective effect against bone pathologies.

scholarly journals Identification of key genes of human bone marrow stromal cells adipogenesis at an early stage

PeerJ ◽  
2020 ◽  
Vol 8 ◽  
pp. e9484
Author(s):  
Pengyu Chen ◽  
Mingrui Song ◽  
Yutian Wang ◽  
Songyun Deng ◽  
Weisheng Hong ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stromal Cells ◽  
Bone Marrow Stromal Cells ◽  
Early Stage ◽  
Adipogenic Differentiation ◽  
Enrichment Analysis ◽  
Pathway Enrichment ◽  
Key Genes

Background Bone marrow adipocyte (BMA), closely associated with bone degeneration, shares common progenitors with osteoblastic lineage. However, the intrinsic mechanism of cells fate commitment between BMA and osteogenic lineage remains unclear. Methods Gene Expression Omnibus (GEO) dataset GSE107789 publicly available was downloaded and analyzed. Differentially expressed genes (DEGs) were analyzed using GEO2R. Functional and pathway enrichment analyses of Gene Ontology and Kyoto Encyclopedia of Genes and Genomes were conducted by The Database for Annotation, Visualization and Integrated Discovery and Gene set enrichment analysis software. Protein–protein interactions (PPI) network was obtained using STRING database, visualized and clustered by Cytoscape software. Transcriptional levels of key genes were verified by real-time quantitative PCR in vitro in Bone marrow stromal cells (BMSCs) undergoing adipogenic differentiation at day 7 and in vivo in ovariectomized mice model. Results A total of 2,869 DEGs, including 1,357 up-regulated and 1,512 down-regulated ones, were screened out from transcriptional profile of human BMSCs undergoing adipogenic induction at day 7 vs. day 0. Functional and pathway enrichment analysis, combined with modules analysis of PPI network, highlighted ACSL1, sphingosine 1-phosphate receptors 3 (S1PR3), ZBTB16 and glypican 3 as key genes up-regulated at the early stage of BMSCs adipogenic differentiation. Furthermore, up-regulated mRNA expression levels of ACSL1, S1PR3 and ZBTB16 were confirmed both in vitro and in vivo. Conclusion ACSL1, S1PR3 and ZBTB16 may play crucial roles in early regulation of BMSCs adipogenic differentiation

Novel Findings of Anti-cancer Property of Propofol

2018 ◽  
Vol 18 (2) ◽  
pp. 156-165 ◽  
Author(s):  
Jiaqiang Wang ◽  
Chien-shan Cheng ◽  
Yan Lu ◽  
Xiaowei Ding ◽  
Minmin Zhu ◽  
...  
Keyword(s):  
General Anesthesia ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Intravenous Anesthetic ◽  
The Past ◽  
Anti Cancer ◽  
Underlying Mechanisms ◽  
Recent Attention

Background: Propofol, a widely used intravenous anesthetic agent, is traditionally applied for sedation and general anesthesia. Explanation: Recent attention has been drawn to explore the effect and mechanisms of propofol against cancer progression in vitro and in vivo. Specifically, the proliferation-inhibiting and apoptosis-inducing properties of propofol in cancer have been studied. However, the underlying mechanisms remain unclear. Conclusion: This review focused on the findings within the past ten years and aimed to provide a general overview of propofol's malignance-modulating properties and the potential molecular mechanisms.

scholarly journals Human fetal liver MSCs are more effective than adult bone marrow MSCs for their immunosuppressive, immunomodulatory, and Foxp3+ T reg induction capacity

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yi Yu ◽  
Alejandra Vargas Valderrama ◽  
Zhongchao Han ◽  
Georges Uzan ◽  
Sina Naserian ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Immune Responses ◽  
Molecular Mechanisms ◽  
Fetal Liver ◽  
Cytotoxic T Cells ◽  
Cell Contact ◽  
Adult Bone Marrow ◽  
Adult Bone

Abstract Background Mesenchymal stem cells (MSCs) exhibit active abilities to suppress or modulate deleterious immune responses by various molecular mechanisms. These cells are the subject of major translational efforts as cellular therapies for immune-related diseases and transplantations. Plenty of preclinical studies and clinical trials employing MSCs have shown promising safety and efficacy outcomes and also shed light on the modifications in the frequency and function of regulatory T cells (T regs). Nevertheless, the mechanisms underlying these observations are not well known. Direct cell contact, soluble factor production, and turning antigen-presenting cells into tolerogenic phenotypes, have been proposed to be among possible mechanisms by which MSCs produce an immunomodulatory environment for T reg expansion and activity. We and others demonstrated that adult bone marrow (BM)-MSCs suppress adaptive immune responses directly by inhibiting the proliferation of CD4+ helper and CD8+ cytotoxic T cells but also indirectly through the induction of T regs. In parallel, we demonstrated that fetal liver (FL)-MSCs demonstrates much longer-lasting immunomodulatory properties compared to BM-MSCs, by inhibiting directly the proliferation and activation of CD4+ and CD8+ T cells. Therefore, we investigated if FL-MSCs exert their strong immunosuppressive effect also indirectly through induction of T regs. Methods MSCs were obtained from FL and adult BM and characterized according to their surface antigen expression, their multilineage differentiation, and their proliferation potential. Using different in vitro combinations, we performed co-cultures of FL- or BM-MSCs and murine CD3+CD25−T cells to investigate immunosuppressive effects of MSCs on T cells and to quantify their capacity to induce functional T regs. Results We demonstrated that although both types of MSC display similar cell surface phenotypic profile and differentiation capacity, FL-MSCs have significantly higher proliferative capacity and ability to suppress both CD4+ and CD8+ murine T cell proliferation and to modulate them towards less active phenotypes than adult BM-MSCs. Moreover, their substantial suppressive effect was associated with an outstanding increase of functional CD4+CD25+Foxp3+ T regs compared to BM-MSCs. Conclusions These results highlight the immunosuppressive activity of FL-MSCs on T cells and show for the first time that one of the main immunoregulatory mechanisms of FL-MSCs passes through active and functional T reg induction.

scholarly journals Experimental Type 2 Diabetes Differently Impacts on the Select Functions of Bone Marrow-Derived Multipotent Stromal Cells

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 268
Author(s):  
Jonathan Ribot ◽  
Cyprien Denoeud ◽  
Guilhem Frescaline ◽  
Rebecca Landon ◽  
Hervé Petite ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Bone Marrow ◽  
Stromal Cells ◽  
Adipogenic Differentiation ◽  
Therapeutic Modality ◽  
Multipotent Stromal Cells ◽  
Cell Therapies

Bone marrow-derived multipotent stromal cells (BMMSCs) represent an attractive therapeutic modality for cell therapy in type 2 diabetes mellitus (T2DM)-associated complications. T2DM changes the bone marrow environment; however, its effects on BMMSC properties remain unclear. The present study aimed at investigating select functions and differentiation of BMMSCs harvested from the T2DM microenvironment as potential candidates for regenerative medicine. BMMSCs were obtained from Zucker diabetic fatty (ZDF; an obese-T2DM model) rats and their lean littermates (ZL; controls), and cultured under normoglycemic conditions. The BMMSCs derived from ZDF animals were fewer in number, with limited clonogenicity (by 2-fold), adhesion (by 2.9-fold), proliferation (by 50%), migration capability (by 25%), and increased apoptosis rate (by 2.5-fold) compared to their ZL counterparts. Compared to the cultured ZL-BMMSCs, the ZDF-BMMSCs exhibited (i) enhanced adipogenic differentiation (increased number of lipid droplets by 2-fold; upregulation of the Pparg, AdipoQ, and Fabp genes), possibly due to having been primed to undergo such differentiation in vivo prior to cell isolation, and (ii) different angiogenesis-related gene expression in vitro and decreased proangiogenic potential after transplantation in nude mice. These results provided evidence that the T2DM environment impairs BMMSC expansion and select functions pertinent to their efficacy when used in autologous cell therapies.

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