Bone marrow adiposity during pathologic bone loss: molecular mechanisms underlying the cellular events

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.

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

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00764.2010 ◽

2011 ◽

Vol 300 (5) ◽

pp. R1250-R1260 ◽

Cited By ~ 20

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.

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Greater Bone Marrow Adiposity Predicts Bone Loss in Older Women

Journal of Bone and Mineral Research ◽

10.1002/jbmr.3895 ◽

2019 ◽

Vol 35 (2) ◽

pp. 326-332 ◽

Cited By ~ 5

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

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

International Journal of Molecular Sciences ◽

10.3390/ijms222010988 ◽

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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Adipsin promotes bone marrow adiposity by priming mesenchymal stem cells

10.1101/2021.04.13.439598 ◽

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).

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Adipsin promotes bone marrow adiposity by priming mesenchymal stem cells

eLife ◽

10.7554/elife.69209 ◽

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).

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Inhibition of PPARγ prevents type I diabetic bone marrow adiposity but not bone loss

Journal of Cellular Physiology ◽

10.1002/jcp.20804 ◽

2006 ◽

Vol 209 (3) ◽

pp. 967-976 ◽

Cited By ~ 79

Author(s):

Sergiu Botolin ◽

Laura R. McCabe

Keyword(s):

Bone Marrow ◽

Bone Loss ◽

Type I ◽

Marrow Adiposity

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Combination chemotherapy with cyclophosphamide, epirubicin and 5-fluorouracil causes trabecular bone loss, bone marrow cell depletion and marrow adiposity in female rats

Journal of Bone and Mineral Metabolism ◽

10.1007/s00774-015-0679-x ◽

2015 ◽

Vol 34 (3) ◽

pp. 277-290 ◽

Cited By ~ 16

Author(s):

Chiaming Fan ◽

Kristen R. Georgiou ◽

Ross A. McKinnon ◽

Dorothy M. K. Keefe ◽

Peter R. C. Howe ◽

...

Keyword(s):

Bone Marrow ◽

Bone Loss ◽

Trabecular Bone ◽

Bone Marrow Cell ◽

Combination Chemotherapy ◽

Marrow Cell ◽

Female Rats ◽

Cell Depletion ◽

Marrow Adiposity ◽

Trabecular Bone Loss

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

Acta Radiologica ◽

10.1177/0284185120986937 ◽

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.

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