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

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Nicole Aaron ◽  
Michael J Kraakman ◽  
Qiuzhong Zhou ◽  
Qiongming Liu ◽  
Samantha Costa ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Loss ◽  
Calorie Restriction ◽  
Dependent Manner ◽  
Mineral Density ◽  
Genetic Ablation ◽  
Downstream Effector ◽  
Bm Niche ◽  
Obesity And Diabetes ◽  
Marrow Adiposity

Background:Marrow adipose tissue (MAT) has been shown to be vital for regulating metabolism and maintaining skeletal homeostasis in the bone marrow (BM) niche. As a reflection of BM remodeling, MAT is highly responsive to nutrient fluctuations, hormonal changes, and metabolic disturbances such as obesity and diabetes mellitus. Expansion of MAT 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:We studied deletion of Adipsin, and its downstream effector, C3, in C57BL/6 mice as well as the bone-protected PPARγ constitutive deacetylation 2KR mice to assess BM plasticity. The mice were challenged with thiazolidinedione treatment, calorie restriction, or aging to induce bone loss and MAT expansion. Analysis of bone mineral 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 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 show that Adipsin is the most upregulated adipokine during MAT expansion in mice and humans in a PPARγ acetylation-dependent manner. Genetic ablation of Adipsin in mice specifically inhibited MAT 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/β-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), R24DK092759 (CJR), and P01HL087123 (LQ).

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 CCAAT/enhancer binding protein β-deficiency enhances type 1 diabetic bone phenotype by increasing marrow adiposity and bone resorption

2011 ◽  
Vol 300 (5) ◽  
pp. R1250-R1260 ◽  
Author(s):  
Katherine J. Motyl ◽  
Michelle Raetz ◽  
Srinivasan Arjun Tekalur ◽  
Richard C. Schwartz ◽  
Laura R. McCabe
Keyword(s):  
Bone Marrow ◽  
Type 1 Diabetes ◽  
Bone Resorption ◽  
Bone Loss ◽  
Wild Type ◽  
Bone Stiffness ◽  
Bone Phenotype ◽  
Enhancer Binding Protein ◽  
Marrow Adiposity

Bone loss in type 1 diabetes is accompanied by increased marrow fat, which could directly reduce osteoblast activity or result from altered bone marrow mesenchymal cell lineage selection (adipocyte vs. osteoblast). CCAAT/enhancer binding protein beta (C/EBPβ) is an important regulator of both adipocyte and osteoblast differentiation. C/EBPβ-null mice have delayed bone formation and defective lipid accumulation in brown adipose tissue. To examine the balance of C/EBPβ functions in the diabetic context, we induced type 1 diabetes in C/EBPβ-null (knockout, KO) mice. We found that C/EBPβ deficiency actually enhanced the diabetic bone phenotype. While KO mice had reduced peripheral fat mass compared with wild-type mice, they had 5-fold more marrow adipocytes than diabetic wild-type mice. The enhanced marrow adiposity may be attributed to compensation by C/EBPδ, peroxisome proliferator-activated receptor-γ2, and C/EBPα. Concurrently, we observed reduced bone density. Relative to genotype controls, trabecular bone volume fraction loss was escalated in diabetic KO mice (−48%) compared with changes in diabetic wild-type mice (−22%). Despite greater bone loss, osteoblast markers were not further suppressed in diabetic KO mice. Instead, osteoclast markers were increased in the KO diabetic mice. Thus, C/EBPβ deficiency increases diabetes-induced bone marrow (not peripheral) adipose depot mass, and promotes additional bone loss through stimulating bone resorption. C/EBPβ-deficiency also reduced bone stiffness and diabetes exacerbated this (two-way ANOVA P < 0.02). We conclude that C/EBPβ alone is not responsible for the bone vs. fat phenotype switch observed in T1 diabetes and that suppression of CEBPβ levels may further bone loss and decrease bone stiffness by increasing bone resorption.

scholarly journals Effect of nutritional supplement on bone marrow-derived mesenchymal stem cells from aplastic anaemia

2018 ◽  
Vol 119 (7) ◽  
pp. 748-758
Author(s):  
Shihua Luo ◽  
Yinghai Chen ◽  
Lifen Zhao ◽  
Xia Qi ◽  
Xiaoyan Miao ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Aplastic Anaemia ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Nutritional Supplement ◽  
High Dose ◽  
Intragastric Administration ◽  
Dependent Manner ◽  
Mineral Density

AbstractAplastic anaemia (AA) is characterised by pancytopenia resulting from a marked reduction in haemopoietic stem cells (HSC). The regulation of haemopoiesis depends on the interaction between HSC and various cells of the bone marrow (BM) microenvironment, including BM-derived mesenchymal stromal cells (BMSC). The purpose of this study was to analyse the biological effect of nutritional supplement (NS), a dietary supplement consisting of thirty-six compounds: amino acids, nucleotides, vitamins and micronutrients on the BMSC of AA rats. The AA rat model was established by irradiating X-ray (2·5 Gy) and intraperitoneal injections of cyclophosphamide (35 mg/kg; Sigma) and chloramphenicol (35 mg/kg; Sigma). Then AA rats were fed with NS in a dose-dependent manner (2266·95, 1511·3, 1057·91 mg/kg d) by intragastric administration. The effect of NS on the BMSC of AA rats was analysed. As compared with AA rats, NS treatment significantly improved these peripheral blood parameters and stimulated the proliferation of total femoral nucleated cells. NS treatment affected proliferative behaviour of BMSC and suppressed BMSC differentiation to adipocytes. Furthermore, NS treatment of AA rats accelerated osteogenic differentiation of BMSC and enhanced bone mineral density. Co-incubation of HSC with mesenchymal stromal cells and serum from AA rats subjected to high-dose NS markedly improved the yield of CD34+cells. Protein microarray analysis revealed that there were eleven differentially expressed proteins in the NS group compared with the AA rat group. The identified specific NS might be implicated in rehabilitation of BMSC in AA rats, suggesting their potential of nutritional support in AA treatment.

scholarly journals Greater Bone Marrow Adiposity Predicts Bone Loss in Older Women

2019 ◽  
Vol 35 (2) ◽  
pp. 326-332 ◽  
Author(s):  
Gina N Woods ◽  
Susan K Ewing ◽  
Sigurdur Sigurdsson ◽  
Deborah M Kado ◽  
Gudny Eiriksdottir ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Loss ◽  
Older Women ◽  
Marrow Adiposity

scholarly journals Serum FSH Is Associated with BMD, Bone Marrow Adiposity and Body Composition in the AGES-Reykjavik Study of Older Adults

2020 ◽  
Author(s):  
Annegreet G Veldhuis-Vlug ◽  
Gina N Woods ◽  
Sigurdur Sigurdsson ◽  
Susan K Ewing ◽  
Phuong T Le ◽  
...  
Keyword(s):  
Older Adults ◽  
Bone Marrow ◽  
Body Composition ◽  
Body Fat ◽  
Fat Mass ◽  
Lean Mass ◽  
Mineral Density ◽  
1H Mrs ◽  
Testosterone Levels ◽  
Marrow Adiposity

Abstract Context Follicle stimulating hormone (FSH) concentrations increase during the perimenopausal transition and remain high post menopause. Loss of bone mineral density (BMD) and gain of bone marrow adiposity (BMA) and body fat mass also occur during this time. In mice, blocking the action of FSH increases bone mass and decreases fat mass. Objective To investigate the associations between endogenous FSH levels and BMD, BMA and body composition in older adults, independent of estradiol and testosterone levels. Design, setting and participants Older adults from the AGES-Reykjavik Study, an observational cohort study. Main outcome measures Areal BMD, total body fat, and lean mass were measured with DXA. Lumbar vertebral BMA was measured by 1H-MRS. Volumetric BMD and visceral and subcutaneous adipose tissue (VAT, SAT) areas were measured with QCT. The least squares means procedure was used to determine sex-hormone adjusted associations between quartiles of serum FSH and BMD, BMA, and body composition. Results In women (N=238, mean age 81y), those in the highest FSH quartile, compared with the lowest quartile, had lower adjusted mean spine integral BMD (-8.6%), lower spine compressive strength index (-34.8%), higher BMA (+8.4%), lower weight (-8.4%), lower VAT (-17.6%), lower lean mass (-6.1%), and lower fat mass (-11.9%) (all P &lt; 0.05). In men, FSH level was not associated with any outcome. Conclusions Older postmenopausal women with higher FSH levels have higher BMA, but lower BMD and lower fat and lean mass, independent of estradiol and testosterone levels. Longitudinal studies are needed to better understand the underlying mechanisms.

scholarly journals Osteopenia in Sparc (osteonectin)-deficient mice: characterization of phenotypic determinants of femoral strength and changes in gene expression

2007 ◽  
Vol 32 (1) ◽  
pp. 64-73 ◽  
Author(s):  
Fiona C. Mansergh ◽  
Timothy Wells ◽  
Carole Elford ◽  
Samuel L. Evans ◽  
Mark J. Perry ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Mineral ◽  
Mouse Strains ◽  
Mineral Density ◽  
Background Strain ◽  
Marrow Adiposity ◽  
Strength Tests ◽  
Deficient Mice ◽  
Inactivating Mutations

Sparc null mutants have been generated independently via targeted mutations in exons 4 and 6. Previous studies have identified low-turnover osteopenia in the 129Sv/C57BL/6 exon 4 knockout. Since both Sparc null mutations result in complete absence of Sparc protein, similar phenotypic outcomes are likely. However, genetic background (strain) and/or linkage disequilibrium effects can influence phenotype. Different inactivating mutations should be tested in various mouse strains; similar phenotypic outcomes can then confidently be assigned to the mutated gene. We have evaluated the bone phenotype in the 129Sv/EvSparc tm1cam exon 6 knockout at 4 and 9 mo, using physical measurement, mechanical strength tests, and DXA scanning. We have also quantified bone marrow adiposity and circulating leptin levels to assess adipose tissue metabolism. 129Sv/EvSparc tm1cam null mice show decreased bone mineral density and bone mineral content and increased mechanical fragility of bone, in line with previous studies. Differences were also noted. Increased body weight and levels of bone marrow adiposity but decreased circulating leptin concentrations were identified at 4, but not 9 mo, and 129Sv/EvSparc tm1cam null mice also had shorter femurs. Molecular phenotyping was carried out using mouse HGMP NIA microarrays with cortical femur samples at various ages, using semiquantitative RT-PCR validation. We identified 429 genes highly expressed in normal bone. Six genes (Sparc, Zfp162, Bysl, E2F4, two ESTs) are differentially regulated in 129Sv/EvSparc tm1cam cortical femur vs. 129Sv/Ev controls. We confirm low-turnover osteopenia as a feature of the Sparc null phenotype, identifying the usefulness of this mouse as a model for human osteoporosis.

scholarly journals Improvement of bone properties and enhancement of mineralization by ethanol extract of Fructus Ligustri Lucidi

2008 ◽  
Vol 99 (3) ◽  
pp. 494-502 ◽  
Author(s):  
Yan Zhang ◽  
Ping-Chung Leung ◽  
Chun-Tao Che ◽  
Hung-Kay Chow ◽  
Chun-Fu Wu ◽  
...  
Keyword(s):  
Bone Loss ◽  
Bone Mineral ◽  
Sham Operation ◽  
Dependent Manner ◽  
Aged Rats ◽  
Mineral Density ◽  
Fructus Ligustri Lucidi ◽  
Bone Properties ◽  
Ovx Rats ◽  
Umr 106

Fructus Ligustri Lucidi (FLL), a kidney-tonifying Chinese herb, was shown to regulate Ca balance in ovariectomized (OVX) rats in our previous study. This study investigated whether it could improve bone properties in aged normal and OVX rats and increase osteoblastic differentiation in rat osteoblast-like UMR-106 cells. Ten-month-old aged rats underwent sham-operation or ovariectomy, were orally administered with FLL extracts or its vehicle and fed with diets containing different levels of Ca (LCD, 0·1 % Ca; MCD, 0·6 % Ca; HCD, 1·2 % Ca) for 12 weeks. Ovariectomy induced bone loss at multiple-sites of both tibia and femur in all rats being studied. FLL extract increased bone mineral density and bone mineral content at both tibial and femoral diaphysis as well as the lumbar vertebra (LV-2) in rats fed either LCD or MCD. In addition, FLL increased biomechanical strength of the tibial diaphysis in these rats. Combination of FLL and high-Ca diet significantly improved bone mass of cortical and trabecular bone at appendicular bones and LV-2 and decreased bone loss associated with ovarietomy and low-Ca feeding. Treatment of UMR-106 cells with FLL extracts accelerated the formation of calcified matrix and increased extracellular Ca and P depositions in time- and dose-dependent manner. The level of mineralization reached a maximum by 6 d incubation at the dosage of 10 μg FLL extract/ml. Our study indicated that FLL extract could improve bone properties in aged rats possibly via its direct action on osteoblastic cells by enhancement of the mineralization process.

scholarly journals Neuroskeletal Effects of Chronic Bioelectric Nerve Stimulation in Health and Diabetes

2021 ◽  
Vol 15 ◽  
Author(s):  
Alec T. Beeve ◽  
Ivana Shen ◽  
Xiao Zhang ◽  
Kristann Magee ◽  
Ying Yan ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Sciatic Nerve ◽  
Nerve Regeneration ◽  
Nerve Stimulation ◽  
Unintended Consequences ◽  
Independent Effect ◽  
Mineral Density ◽  
Gait Patterns ◽  
Marrow Adiposity

Background/AimsBioelectric nerve stimulation (eStim) is an emerging clinical paradigm that can promote nerve regeneration after trauma, including within the context of diabetes. However, its ability to prevent the onset of diabetic peripheral neuropathy (DPN) has not yet been evaluated. Beyond the nerve itself, DPN has emerged as a potential contributor to sarcopenia and bone disease; thus, we hypothesized that eStim could serve as a strategy to simultaneously promote neural and musculoskeletal health in diabetes.MethodsTo address this question, an eStim paradigm pre-optimized to promote nerve regeneration was applied to the sciatic nerve, which directly innervates the tibia and lower limb, for 8 weeks in control and streptozotocin-induced type 1 diabetic (T1D) rats. Metabolic, gait, nerve and bone assessments were used to evaluate the progression of diabetes and the effect of sciatic nerve eStim on neuropathy and musculoskeletal disease, while also considering the effects of cuff placement and chronic eStim in otherwise healthy animals.ResultsRats with T1D exhibited increased mechanical allodynia in the hindpaw, reduced muscle mass, decreased cortical and cancellous bone volume fraction (BVF), reduced cortical bone tissue mineral density (TMD), and decreased bone marrow adiposity. Type 1 diabetes also had an independent effect on gait. Placement of the cuff electrode alone resulted in altered gait patterns and unilateral reductions in tibia length, cortical BVF, and bone marrow adiposity. Alterations in gait patterns were restored by eStim and tibial lengthening was favored unilaterally; however, eStim did not prevent T1D-induced changes in muscle, bone, marrow adiposity or mechanical sensitivity. Beyond this, chronic eStim resulted in an independent, bilateral reduction in cortical TMD.ConclusionOverall, these results provide new insight into the pathogenesis of diabetic neuroskeletal disease and its regulation by eStim. Though eStim did not prevent neural or musculoskeletal complications in T1D, our results demonstrate that clinical applications of peripheral neuromodulation ought to consider the impact of device placement and eStim on long-term skeletal health in both healthy individuals and those with metabolic disease. This includes monitoring for compounded bone loss to prevent unintended consequences including decreased bone mineral density and increased fracture risk.

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.

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