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Liu H, Liu L, Rosen CJ. Bone Marrow Adipocytes as Novel Regulators of Metabolic Homeostasis: Clinical Consequences of Bone Marrow Adiposity. Curr Obes Rep 2025; 14:9. [PMID: 39808256 DOI: 10.1007/s13679-024-00594-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/21/2024] [Indexed: 01/16/2025]
Abstract
PURPOSE OF REVIEW Bone marrow adipose tissue is a distinctive fat depot located within the skeleton, with the potential to influence both local and systemic metabolic processes. Although significant strides have been made in understanding bone marrow adipose tissue over the past decade, many questions remain regarding their precise lineage and functional roles. RECENT FINDINGS Recent studies have highlighted bone marrow adipose tissue's involvement in continuous cross-talk with other organs and systems, exerting both endocrine and paracrine functions that play a crucial role in metabolic homeostasis, skeletal remodeling, hematopoiesis, and the progression of bone metastases. The advancement of imaging techniques, particularly cross-sectional imaging, has profoundly expanded our understanding of the complexities beyond the traditional view of bone marrow adipose tissue as an inert depot. Notably, marrow adipocytes are anatomically and functionally distinct from brown, beige, and classic white adipocytes. Emerging evidence suggests that bone marrow adipocytes, bone marrow adipose tissue originate from the differentiation of bone marrow mesenchymal stromal cells; however, they appear to be a heterogeneous population with varying metabolic profiles, lipid compositions, secretory properties, and functional responses depending on their specific location within the bone marrow. This review provides an up-to-date synthesis of current knowledge on bone marrow adipocytes, emphasizing the relationships between bone marrow adipogenesis and factors such as aging, osteoporosis, obesity, and bone marrow tumors or metastases, thereby elucidating the mechanisms underlying musculoskeletal pathophysiology.
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Affiliation(s)
- Hanghang Liu
- State Key Laboratory of Oral Diseases & National Center for Stomatology &, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, Sichuan, China
- Maine Medical Center Research Institute, Maine Medical Center, 81 Research Drive, Scarborough, ME, 04074, USA
| | - Linyi Liu
- Maine Medical Center Research Institute, Maine Medical Center, 81 Research Drive, Scarborough, ME, 04074, USA
| | - Clifford J Rosen
- Maine Medical Center Research Institute, Maine Medical Center, 81 Research Drive, Scarborough, ME, 04074, USA.
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Cho S, Shin S, Lee S, Rhee Y, Kim HI, Hong N. Differential Impact of Subcutaneous and Visceral Fat on Bone Changes after Gastrectomy. Endocrinol Metab (Seoul) 2024; 39:632-640. [PMID: 39015029 PMCID: PMC11375306 DOI: 10.3803/enm.2024.1956] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Accepted: 05/27/2024] [Indexed: 07/18/2024] Open
Abstract
BACKGRUOUND Osteoporosis and fragility fractures are crucial musculoskeletal complications in long-term survivors of gastric cancer. However, the relationship between changes in body composition after gastrectomy and bone loss has not been investigated. Therefore, this study aimed to explore whether computed tomography (CT)-derived body composition parameters are associated with bone loss after gastrectomy in patients with gastric cancer. METHODS We retrospectively reviewed medical records and abdomen CT scans of patients who underwent gastrectomy at Yonsei University Severance Hospital between 2009 and 2018. Patients with non-metastatic gastric adenocarcinoma and preoperative and postoperative non-contrast CT scans were analyzed. Section area of skeletal muscle (SMA), visceral fat (VFA), and subcutaneous fat (SFA) were assessed using semi-automatic segmentation software. Changes in trabecular bone attenuation of L1 mid-vertebra level (L1 Hounsfield units [HU]) were measured. RESULTS Fifty-seven patients (mean age, 65.5±10.6; 70.2% males) were analyzed, and the median duration was 31 months. Fortyseven patients (82.5%) lost weight after gastrectomy. Baseline SMA and VFA did not differ between the bone loss and preserved groups; however, baseline SFA was significantly higher in the bone preserved group than in the bone loss group (P=0.020). In a multivariable linear regression model adjusted for confounding factors, one standard deviation higher VFA at baseline was associated with greater annualized L1 HU loss (%) (P=0.034). However, higher preoperative SFA was associated with protection against bone loss after gastrectomy (P=0.025). CONCLUSION Higher preoperative SFA exhibited a protective effect against bone loss after gastrectomy in patients with non-metastatic gastric cancer, whereas VFA exhibited a negative effect.
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Affiliation(s)
- Sungjoon Cho
- Department of Internal Medicine, Severance Hospital, Endocrine Research Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Sungjae Shin
- Division of Endocrinology and Metabolism, Department of Internal Medicine, National Health Insurance Service Ilsan Hospital, Goyang, Korea
| | - Seunghyun Lee
- Department of Internal Medicine, Wonju Severance Christian Hospital, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Yumie Rhee
- Department of Internal Medicine, Severance Hospital, Endocrine Research Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Hyoung-Il Kim
- Department of Surgery, Yonsei University College of Medicine, Seoul, Korea
- Gastric Cancer Center, Yonsei Cancer Center, Seoul, Korea
| | - Namki Hong
- Department of Internal Medicine, Severance Hospital, Endocrine Research Institute, Yonsei University College of Medicine, Seoul, Korea
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Zhang X, Tian L, Majumdar A, Scheller EL. Function and Regulation of Bone Marrow Adipose Tissue in Health and Disease: State of the Field and Clinical Considerations. Compr Physiol 2024; 14:5521-5579. [PMID: 39109972 PMCID: PMC11725182 DOI: 10.1002/cphy.c230016] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2025]
Abstract
Bone marrow adipose tissue (BMAT) is a metabolically and clinically relevant fat depot that exists within bone. Two subtypes of BMAT, regulated and constitutive, reside in hematopoietic-rich red marrow and fatty yellow marrow, respectively, and exhibit distinct characteristics compared to peripheral fat such as white and brown adipose tissues. Bone marrow adipocytes (BMAds) are evolutionally preserved in most vertebrates, start development after birth and expand throughout life, and originate from unique progenitor populations that control bone formation and hematopoiesis. Mature BMAds also interact closely with other cellular components of the bone marrow niche, serving as a nearby energy reservoir to support the skeletal system, a signaling hub that contributes to both local and systemic homeostasis, and a final fuel reserve for survival during starvation. Though BMAT and bone are often inversely correlated, more BMAT does not always mean less bone, and the prevention of BMAT expansion as a strategy to prevent bone loss remains questionable. BMAT adipogenesis and lipid metabolism are regulated by the nervous systems and a variety of circulating hormones. This contributes to the plasticity of BMAT, including BMAT expansion in common physiological or pathological conditions, and BMAT catabolism under certain extreme circumstances, which are often associated with malnutrition and/or systemic inflammation. Altogether, this article provides a comprehensive overview of the local and systemic functions of BMAT and discusses the regulation and plasticity of this unique adipose tissue depot in health and disease. © 2024 American Physiological Society. Compr Physiol 14:5521-5579, 2024.
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Affiliation(s)
- Xiao Zhang
- Division of Bone and Mineral Diseases, Department of Medicine, Washington University, St. Louis, Missouri, USA
- Department of Biomedical Engineering, Washington University, St. Louis, Missouri, USA
| | - Linda Tian
- Division of Bone and Mineral Diseases, Department of Medicine, Washington University, St. Louis, Missouri, USA
- Department of Biomedical Engineering, Washington University, St. Louis, Missouri, USA
| | - Anurag Majumdar
- Division of Bone and Mineral Diseases, Department of Medicine, Washington University, St. Louis, Missouri, USA
| | - Erica L. Scheller
- Division of Bone and Mineral Diseases, Department of Medicine, Washington University, St. Louis, Missouri, USA
- Department of Biomedical Engineering, Washington University, St. Louis, Missouri, USA
- Department of Cell Biology and Physiology, Washington University, St. Louis, Missouri, USA
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Gu Y, Song Y, Pan Y, Liu J. The essential roles of m 6A modification in osteogenesis and common bone diseases. Genes Dis 2024; 11:335-345. [PMID: 37588215 PMCID: PMC10425797 DOI: 10.1016/j.gendis.2023.01.032] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Accepted: 01/30/2023] [Indexed: 03/30/2023] Open
Abstract
N6-methyladenosine (m6A) is the most prevalent modification in the eukaryotic transcriptome and has a wide range of functions in coding and noncoding RNAs. It affects the fate of the modified RNA, including its stability, splicing, and translation, and plays an important role in post-transcriptional regulation. Bones play a key role in supporting and protecting muscles and other organs, facilitating the movement of the organism, ensuring blood production, etc. Bone diseases such as osteoarthritis, osteoporosis, and bone tumors are serious public health problems. The processes of bone development and osteogenic differentiation require the precise regulation of gene expression through epigenetic mechanisms including histone, DNA, and RNA modifications. As a reversible dynamic epigenetic mark, m6A modifications affect nearly every important biological process, cellular component, and molecular function, including skeletal development and homeostasis. In recent years, studies have shown that m6A modification is involved in osteogenesis and bone-related diseases. In this review, we summarized the proteins involved in RNA m6A modification and the latest progress in elucidating the regulatory role of m6A modification in bone formation and stem cell directional differentiation. We also discussed the pathological roles and potential molecular mechanisms of m6A modification in bone-related diseases like osteoporosis and osteosarcoma and suggested potential areas for new strategies that could be used to prevent or treat bone defects and bone diseases.
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Affiliation(s)
- Yuxi Gu
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China
| | - Yidan Song
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China
| | - Yihua Pan
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China
| | - Jun Liu
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China
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Li H, Kong D, Zhao Y, Liu X, Xiao F, Li X, Hu J, Chen Y, Li S, Wang B, Chen Y, Jiang Y, Liu X, Feng X, Guo Y, Feng X, Ren J, Wang F, Han Y, Donelan W, Yang L, Xu D, Tang D, Zheng C. Irisin protected hemopoietic stem cells and improved outcome of severe bone marrow failure. Biomed Pharmacother 2023; 169:115863. [PMID: 37952356 DOI: 10.1016/j.biopha.2023.115863] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Revised: 11/05/2023] [Accepted: 11/07/2023] [Indexed: 11/14/2023] Open
Abstract
Acquired aplastic anemia (AA) is a bone marrow failure (BMF) disease, characterized by fatty bone marrow (BM) and BM hypocellularity resulted from auto-immune dysregulated T cells-mediated destruction of BM haemopoietic stem cells (HPSC). The objective of this study was to investigate potential therapeutic effect of irisin, a molecule involved in adipose tissue transition, on AA mouse model. Our results showed that the concentration of irisin in serum was lower in AA patients than in healthy controls, suggesting a role of irisin in the pathogenesis of AA. In the AA mice, irisin administration prolonged the survival rate, prevented or attenuated peripheral pancytopenia, and preserved HPSC in the BM. Moreover, irisin also markedly reduced BM adipogenesis. In vitro results showed that irisin increased both cell proliferation and colony numbers of HPSC. Furthermore, our results demonstrated that irisin upregulated the expression of mitochondrial ATPase Inhibitory Factor 1 (IF1) in HPSC, inhibited the activation of mitochondrial fission protein (DRP1) and enhanced aerobic glycolysis. Taken together, our findings indicate novel roles of irisin in the pathogenesis of AA, and in the protection of HPSC through stimulation of proliferation and regulation of mitochondria function, which provides a proof-of-concept for the application of irisin in AA therapy.
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Affiliation(s)
- Hui Li
- Center for Gene and Immunotherapy, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Dexiao Kong
- Hematology Department, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China; Institute of Biotherapy for Hematological Malignancies, Shandong University, Jinan, China; Shandong University-Karolinska Institute Collaborative Laboratory for Stem Cell Research, Shandong University, Jinan, China
| | - Yi Zhao
- Center for Gene and Immunotherapy, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Xia Liu
- Department of Respiratory Intervention, Qilu Children's Hospital of Shandong University, Jinan, China
| | - Fang Xiao
- Department of Health Care and Geriatrics, the Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Xiaoyan Li
- Hematology Department, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Jianting Hu
- Shandong Pharmaceutical Academy, Shandong Provincial Key Laboratory of Chemical Drugs, Jinan, China
| | - Yingjie Chen
- Department of Clinical Laboratory, The Second Hospital of Shandong University, Jinan, China
| | - Shengli Li
- Department of Hematology of Jining No. 1 People's Hospital, Jining, China
| | - Baozhu Wang
- Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University, Jinan, China
| | - Yuan Chen
- Central Research Laboratory, The second hospital of Shandong University, Jinan, China
| | - Yang Jiang
- Hematology Department, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China; Institute of Biotherapy for Hematological Malignancies, Shandong University, Jinan, China; Shandong University-Karolinska Institute Collaborative Laboratory for Stem Cell Research, Shandong University, Jinan, China
| | - Xiaoli Liu
- Hematology Department, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China; Institute of Biotherapy for Hematological Malignancies, Shandong University, Jinan, China; Shandong University-Karolinska Institute Collaborative Laboratory for Stem Cell Research, Shandong University, Jinan, China
| | - Xiumei Feng
- Shandong University-Karolinska Institute Collaborative Laboratory for Stem Cell Research, Shandong University, Jinan, China
| | - Yanan Guo
- Hematology Department, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Xiaoli Feng
- Department of Clinical Laboratory, The Second Hospital of Shandong University, Jinan, China
| | - Jing Ren
- Hematology Department, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Fang Wang
- Institute of Medical Sciences, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Ying Han
- Institute of Medical Sciences, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - William Donelan
- Department of Urology, College of Medicine, University of Florida, Gainesville, FL, United States
| | - Lijun Yang
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, Gainesville, FL, USA
| | - Dawei Xu
- Shandong University-Karolinska Institute Collaborative Laboratory for Stem Cell Research, Shandong University, Jinan, China; Department of Medicine, Division of Hematology, Center for Molecular Medicine (CMM) and Bioclinicum, Karolinska Institute, Stockholm, Sweden
| | - Dongqi Tang
- Center for Gene and Immunotherapy, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
| | - Chengyun Zheng
- Hematology Department, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China; Institute of Biotherapy for Hematological Malignancies, Shandong University, Jinan, China; Shandong University-Karolinska Institute Collaborative Laboratory for Stem Cell Research, Shandong University, Jinan, China.
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Liu J, Li X, Wang H, Ren Y, Li Y, Guo F. Bavachinin selectively modulates PPAR γ and maintains bone homeostasis in Type 2 Diabetes. Phytother Res 2023; 37:4457-4472. [PMID: 37308719 DOI: 10.1002/ptr.7912] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Revised: 04/25/2023] [Accepted: 05/19/2023] [Indexed: 06/14/2023]
Abstract
Full peroxisome proliferator-activated receptor (PPAR) γ agonists, Thiazolidinediones (TZDs), effectively prevent the process of Type 2 Diabetes Mellitus (T2DM), but their side effects have curtailed use in the clinic, including weight gain and bone loss. Here, we identified that a selective PPAR γ modulator, Bavachinin (BVC), isolated from the seeds of Psoralea Corylifolia L., could potently regulate bone homeostasis. MC3T3-E1 pre-osteoblast cells and C3H10T1/2 mesenchymal stem cells were assessed for osteogenic differentiation activities, and receptor activator of NF-κB ligand (RANKL)-induced RAW 264.7 cells were assessed osteoclasts formation. Leptin receptor-deficient mice and diet-induced obesity mice were applied to evaluate the effect of BVC on bone homeostasis in vivo. Compared to full PPAR γ agonist rosiglitazone, BVC significantly increased the osteogenesis differentiation activities under normal and high glucose conditions in MC3T3-E1 cells. Moreover, BVC could alleviate osteoclast differentiation in RANKL-induced RAW 264.7 cells. In vivo, synthesized BVC prodrug (BN) has been applied to improve water solubility, increase the extent of oral absorption of BVC and prolong its residence time in blood circulation. BN could prevent weight gain, ameliorate lipid metabolism disorders, improve insulin sensitivity, and maintain bone mass and bone biomechanical properties. BVC, a unique PPAR γ selective modulator, could maintain bone homeostasis, and its prodrug (BN) exhibits insulin sensitizer activity while circumventing the side effects of the TZDs, including bone loss and undesirable weight gain.
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Affiliation(s)
- Jingwen Liu
- Experiment Center for Science and Technology, Shanghai University of Traditional Chinese Medicine, Shanghai, People's Republic of China
| | - Xiaoye Li
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, People's Republic of China
| | - Hong Wang
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, People's Republic of China
| | - Yan Ren
- Experiment Center for Science and Technology, Shanghai University of Traditional Chinese Medicine, Shanghai, People's Republic of China
| | - Yiming Li
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, People's Republic of China
| | - Fujiang Guo
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, People's Republic of China
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7
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Duan W, Zou H, Zang N, Ma D, Yang B, Zhu L. Metformin increases bone marrow adipose tissue by promoting mesenchymal stromal cells apoptosis. Aging (Albany NY) 2023; 15:542-552. [PMID: 36645914 PMCID: PMC9925686 DOI: 10.18632/aging.204486] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Accepted: 10/27/2022] [Indexed: 01/18/2023]
Abstract
Bone marrow adipose tissue (MAT) has the potential to exert both local and systemic effects on metabolic homeostasis. As a first-line drug used to treat type 2 diabetes mellitus, metformin has conflicting effects on MAT and bone marrow mesenchymal stem cell (BM-MSC) differentiation. Through a series of experiments in vivo and in vitro, we found that except improving the glucose and lipid metabolism disorder in ob/ob mice, 200 mg/kg metformin increased MAT in mice tibia, and prompted osteogenic genes (RunX2, OPN, OCN) and lipogenic genes (Ppar-γ, Cebpα, Scd1) expression in mice bone marrow. However, metformin promoted osteogenesis and inhibited lipogenesis of MSC in vitro, which is inconsistent with the results in vivo. Given MAT being considered the "filler" of the space after the apoptosis of bone marrow stroma, the effect of metformin on MSC apoptosis was examined. We discovered that metformin induces MSC apoptosis in vivo and in vitro. Therefore, we speculated that the increased MAT in mice tibia may be attributed to the filling of adipose tissue after apoptosis of bone marrow stromal cells induced by metformin. The increased MAT may be involved in the regulation of metformin on glucose, lipid, and bone metabolism in diabetic mice, providing a new way to understand the metabolic regulation of metformin. While increased MAT-associated insulin resistance and metabolic disorders may account for the poorer clinical benefits in patients with intensive glucose control.
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Affiliation(s)
- Wu Duan
- Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, Shandong 250012, China
| | - Huajie Zou
- Department of Endocrinology, The Affiliated Hospital of Qinghai University, Xining 810000, China
| | - Nan Zang
- Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, Shandong 250012, China
| | - Dongxia Ma
- Department of Allergy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Bo Yang
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Lin Zhu
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
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Salmi A, Quacquarelli F, Chauveau C, Clabaut A, Broux O. An integrative bioinformatics approach to decipher adipocyte-induced transdifferentiation of osteoblast. Genomics 2022; 114:110422. [PMID: 35817314 DOI: 10.1016/j.ygeno.2022.110422] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Revised: 06/09/2022] [Accepted: 06/28/2022] [Indexed: 12/25/2022]
Abstract
In human, bone loss is associated with increased marrow adipose tissue and recent data suggest that medullary adipocytes could play a role in osteoporosis by acting on neighboring bone-forming osteoblasts. Supporting this hypothesis, we previously showed, in a coculture model based on human bone marrow stromal cells, that factors secreted by adipocytes induced the conversion of osteoblasts towards an adipocyte-like phenotype. In this work, we employed an original integrative bioinformatics approach connecting proteomic and transcriptomic data from adipocytes and osteoblasts, respectively, to investigate the mechanisms underlying their crosstalk. Our analysis identified a total of 271 predicted physical interactions between adipocyte-secreted proteins and osteoblast membrane protein coding genes and proposed three pathways for their potential contribution to osteoblast transdifferentiation, the PI3K-AKT, the JAK2-STAT3 and the SMAD pathways. Our findings demonstrated the effectiveness of our integrative omics strategy to decipher cell-cell communication events.
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Affiliation(s)
- Ayyoub Salmi
- Univ. Littoral Côte d'Opale F-62200 Boulogne-sur-Mer, France, Univ. Lille F-59000, Marrow Adiposity and Bone Lab - MABLab, ULR 4490 Lille, France
| | - Federica Quacquarelli
- Univ. Littoral Côte d'Opale F-62200 Boulogne-sur-Mer, France, Univ. Lille F-59000, Marrow Adiposity and Bone Lab - MABLab, ULR 4490 Lille, France
| | - Christophe Chauveau
- Univ. Littoral Côte d'Opale F-62200 Boulogne-sur-Mer, France, Univ. Lille F-59000, Marrow Adiposity and Bone Lab - MABLab, ULR 4490 Lille, France
| | - Aline Clabaut
- Univ. Littoral Côte d'Opale F-62200 Boulogne-sur-Mer, France, Univ. Lille F-59000, Marrow Adiposity and Bone Lab - MABLab, ULR 4490 Lille, France
| | - Odile Broux
- Univ. Littoral Côte d'Opale F-62200 Boulogne-sur-Mer, France, Univ. Lille F-59000, Marrow Adiposity and Bone Lab - MABLab, ULR 4490 Lille, France.
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Kim JH, Kim K, Kim I, Seong S, Koh JT, Kim N. The ATF3-OPG Axis Contributes to Bone Formation by Regulating the Differentiation of Osteoclasts, Osteoblasts, and Adipocytes. Int J Mol Sci 2022; 23:ijms23073500. [PMID: 35408860 PMCID: PMC8998270 DOI: 10.3390/ijms23073500] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Revised: 03/21/2022] [Accepted: 03/22/2022] [Indexed: 01/25/2023] Open
Abstract
Activating transcription factor 3 (ATF3) has been identified as a negative regulator of osteoblast differentiation in in vitro study. However, it was not associated with osteoblast differentiation in in vivo study. To provide an understanding of the discrepancy between the in vivo and in vitro findings regarding the function of ATF3 in osteoblasts, we investigated the unidentified roles of ATF3 in osteoblast biology. ATF3 enhanced osteoprotegerin (OPG) production, not only in osteoblast precursor cells, but also during osteoblast differentiation and osteoblastic adipocyte differentiation. In addition, ATF3 increased nodule formation in immature osteoblasts and decreased osteoblast-dependent osteoclast formation, as well as the transdifferentiation of osteoblasts to adipocytes. However, all these effects were reversed by the OPG neutralizing antibody. Taken together, these results suggest that ATF3 contributes to bone homeostasis by regulating the differentiation of various cell types in the bone microenvironment, including osteoblasts, osteoclasts, and adipocytes via inducing OPG production.
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Affiliation(s)
- Jung Ha Kim
- Department of Pharmacology, Chonnam National University Medical School, Gwangju 61469, Korea; (J.H.K.); (K.K.); (I.K.); (S.S.)
- Hard-Tissue Biointerface Research Center, School of Dentistry, Chonnam National University, Gwangju 61186, Korea;
| | - Kabsun Kim
- Department of Pharmacology, Chonnam National University Medical School, Gwangju 61469, Korea; (J.H.K.); (K.K.); (I.K.); (S.S.)
| | - Inyoung Kim
- Department of Pharmacology, Chonnam National University Medical School, Gwangju 61469, Korea; (J.H.K.); (K.K.); (I.K.); (S.S.)
| | - Semun Seong
- Department of Pharmacology, Chonnam National University Medical School, Gwangju 61469, Korea; (J.H.K.); (K.K.); (I.K.); (S.S.)
- Hard-Tissue Biointerface Research Center, School of Dentistry, Chonnam National University, Gwangju 61186, Korea;
| | - Jeong-Tae Koh
- Hard-Tissue Biointerface Research Center, School of Dentistry, Chonnam National University, Gwangju 61186, Korea;
- Department of Pharmacology and Dental Therapeutics, School of Dentistry, Chonnam National University, Gwangju 61186, Korea
| | - Nacksung Kim
- Department of Pharmacology, Chonnam National University Medical School, Gwangju 61469, Korea; (J.H.K.); (K.K.); (I.K.); (S.S.)
- Hard-Tissue Biointerface Research Center, School of Dentistry, Chonnam National University, Gwangju 61186, Korea;
- Correspondence: ; Tel.: +82-61-379-2835
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Wang Z, He J, Bach DH, Huang YH, Li Z, Liu H, Lin P, Yang J. Induction of m 6A methylation in adipocyte exosomal LncRNAs mediates myeloma drug resistance. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2022; 41:4. [PMID: 34980213 PMCID: PMC8722039 DOI: 10.1186/s13046-021-02209-w] [Citation(s) in RCA: 74] [Impact Index Per Article: 24.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Accepted: 12/04/2021] [Indexed: 11/10/2022]
Abstract
Background Therapeutic resistance occurs in most patients with multiple myeloma (MM). One of the key mechanisms for MM drug resistance comes from the interaction between MM cells and adipocytes that inhibits drug-induced apoptosis in MM cells; MM cells reprogram adipocytes to morph into different characterizations, including exosomes, which are important for tumor-stroma cellular communication. However, the mechanism by which exosomes mediate the cellular machinery of the vicious cycle between MM cells and adipocytes remains unclear. Methods Adipocytes were either isolated from bone marrow aspirates of healthy donors or MM patients or derived from mesenchymal stem cells. Co-culturing normal adipocytes with MM cells was used to generate MM-associated adipocytes. Exosomes were collected from the culture medium of adipocytes. Annexin V-binding and TUNEL assays were performed to assess MM cell apoptosis. Methyltransferase activity assay and dot blotting were used to access the m6A methylation activity of methyltransferase like 7A (METTL7A). RIP, MeRIP-seq, and RNA–protein pull down for assessing the interaction between long non-cording RNAs (LncRNAs) and RNA binding proteins were performed. Adipocyte-specific enhancer of zeste homolog 2 (EZH2) knockout mice and MM-xenografted mice were used for evaluating MM therapeutic response in vivo. Results Exosomes collected from MM patient adipocytes protect MM cells from chemotherapy-induced apoptosis. Two LncRNAs in particular, LOC606724 and SNHG1, are significantly upregulated in MM cells after exposure to adipocyte exosomes. The raised LncRNA levels in MM cells are positively correlated to worse outcomes in patients, indicating their clinical relevancy in MM. The functional roles of adipocyte exosomal LOC606724 or SNHG1 in inhibition of MM cell apoptosis are determined by knockdown in adipocytes or overexpression in MM cells. We discovered the interactions between LncRNAs and RNA binding proteins and identified methyltransferase like 7A (METTL7A) as an RNA methyltransferase. MM cells promote LncRNA package into adipocyte exosomes through METTL7A-mediated LncRNA m6A methylation. Exposure of adipocytes to MM cells enhances METTL7A activity in m6A methylation through EZH2-mediated protein methylation. Conclusion This study elucidates an unexplored mechanism of how adipocyte-rich microenvironment exacerbates MM therapeutic resistance and indicates a potential strategy to improve therapeutic efficacy by blocking this vicious exosome-mediated cycle. Supplementary Information The online version contains supplementary material available at 10.1186/s13046-021-02209-w.
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Affiliation(s)
- Zhiming Wang
- Houston Methodist Cancer Center, Research Institute Houston Methodist Hospital, Houston, TX, 77030, USA
| | - Jin He
- Houston Methodist Cancer Center, Research Institute Houston Methodist Hospital, Houston, TX, 77030, USA
| | - Duc-Hiep Bach
- Houston Methodist Cancer Center, Research Institute Houston Methodist Hospital, Houston, TX, 77030, USA
| | - Yung-Hsing Huang
- Houston Methodist Cancer Center, Research Institute Houston Methodist Hospital, Houston, TX, 77030, USA
| | - Zongwei Li
- Houston Methodist Cancer Center, Research Institute Houston Methodist Hospital, Houston, TX, 77030, USA
| | - Huan Liu
- Cancer Research Center, School of Medicine, Xiamen University, Xiamen, 361102, China
| | - Pei Lin
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Jing Yang
- Houston Methodist Cancer Center, Research Institute Houston Methodist Hospital, Houston, TX, 77030, USA.
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11
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Muschler GF, Simmons H, Mantripragada V, Piuzzi NS. Bone Marrow as a Source of Cells for Musculoskeletal Cellular Therapies. ORTHOBIOLOGICS 2022:29-45. [DOI: 10.1007/978-3-030-84744-9_2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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12
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Pan T, Lin SC, Lee YC, Yu G, Song JH, Pan J, Titus M, Satcher RL, Panaretakis T, Logothetis C, Yu-Lee LY, Lin SH. Statins reduce castration-induced bone marrow adiposity and prostate cancer progression in bone. Oncogene 2021; 40:4592-4603. [PMID: 34127814 PMCID: PMC8384136 DOI: 10.1038/s41388-021-01874-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Revised: 05/14/2021] [Accepted: 05/27/2021] [Indexed: 02/05/2023]
Abstract
A fraction of patients undergoing androgen deprivation therapy (ADT) for advanced prostate cancer (PCa) will develop recurrent castrate-resistant PCa (CRPC) in bone. Strategies to prevent CRPC relapse in bone are lacking. Here we show that the cholesterol-lowering drugs statins decrease castration-induced bone marrow adiposity in the tumor microenvironment and reduce PCa progression in bone. Using primary bone marrow stromal cells (BMSC) and M2-10B4 cells, we showed that ADT increases bone marrow adiposity by enhancing BMSC-to-adipocyte transition in vitro. Knockdown of androgen receptor abrogated BMSC-to-adipocyte transition, suggesting an androgen receptor-dependent event. RNAseq analysis showed that androgens reduce the secretion of adipocyte hormones/cytokines including leptin during BMSC-to-adipocyte transition. Treatment of PCa C4-2b, C4-2B4, and PC3 cells with leptin led to an increase in cell cycle progression and nuclear Stat3. RNAseq analysis also showed that androgens inhibit cholesterol biosynthesis pathway, raising the possibility that inhibiting cholesterol biosynthesis may decrease BMSC-to-adipocyte transition. Indeed, statins decreased BMSC-to-adipocyte transition in vitro and castration-induced bone marrow adiposity in vivo. Statin pre-treatment reduced 22RV1 PCa progression in bone after ADT. Our findings with statin may provide one of the mechanisms to the clinical correlations that statin use in patients undergoing ADT seems to delay progression to "lethal" PCa.
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Affiliation(s)
- Tianhong Pan
- Department of Orthopedic Oncology, University of Texas, MD Anderson Cancer Center, Houston, TX, USA
| | - Song-Chang Lin
- Department of Translational Molecular Pathology, University of Texas, MD Anderson Cancer Center, Houston, TX, USA
| | - Yu-Chen Lee
- Department of Translational Molecular Pathology, University of Texas, MD Anderson Cancer Center, Houston, TX, USA
| | - Guoyu Yu
- Department of Translational Molecular Pathology, University of Texas, MD Anderson Cancer Center, Houston, TX, USA
| | - Jian H Song
- Department of Genitourinary Medical Oncology, University of Texas, MD Anderson Cancer Center, Houston, TX, USA
| | - Jing Pan
- Department of Translational Molecular Pathology, University of Texas, MD Anderson Cancer Center, Houston, TX, USA
| | - Mark Titus
- Department of Genitourinary Medical Oncology, University of Texas, MD Anderson Cancer Center, Houston, TX, USA
| | - Robert L Satcher
- Department of Orthopedic Oncology, University of Texas, MD Anderson Cancer Center, Houston, TX, USA
| | - Theocharis Panaretakis
- Department of Genitourinary Medical Oncology, University of Texas, MD Anderson Cancer Center, Houston, TX, USA
| | - Christopher Logothetis
- Department of Genitourinary Medical Oncology, University of Texas, MD Anderson Cancer Center, Houston, TX, USA
| | - Li-Yuan Yu-Lee
- Department of Medicine, Baylor College of Medicine, Houston, TX, USA
| | - Sue-Hwa Lin
- Department of Translational Molecular Pathology, University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
- Department of Genitourinary Medical Oncology, University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
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13
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Blaschke M, Koepp R, Streit F, Beismann J, Manthey G, Seitz MT, Kragl A, Siggelkow H. The rise in expression and activity of 11β-HSD1 in human mesenchymal progenitor cells induces adipogenesis through increased local cortisol synthesis. J Steroid Biochem Mol Biol 2021; 210:105850. [PMID: 33639236 DOI: 10.1016/j.jsbmb.2021.105850] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Revised: 01/20/2021] [Accepted: 01/25/2021] [Indexed: 11/16/2022]
Abstract
11β-Hydroxysteroid dehydrogenase 1 (11β-HSD1) plays an important role in pre-receptor glucocorticoid metabolism. This enzyme is expressed in bone, increases with age, and catalyzes the conversion of the inactive glucocorticoid cortisone into the active glucocorticoid cortisol and vice versa. Here we hypothesized that the physiological activity of 11β-HSD1 to produce cortisol in human mesenchymal progenitor cells (hMSC) is principally sufficient to shift the differentiation potential in the direction of adipogenic. We thus investigated differentiating hMSCs and the mesenchymal stem cell line SCP-1 cultured under osteogenic conditions and stimulated with supra-physiological cortisone levels. The release of active cortisol into the medium was monitored and the influence on cell differentiation analyzed. We revealed an increase in 11β-HSD1 expression followed by increased reductive activity of the enzyme, thereby inducing a more adipogenic phenotype of the cell models via cortisol with negative effects on osteogenesis. Through inhibition experiments with the specific inhibitor 10 j, we proved the enzyme specificity for cortisol synthesis and adipogenic differentiation. Increased expression of 11β-HSD1 followed by higher cortisol levels might thus explain bone marrow adiposity followed by reduced bone quality and stability in old age or in situations of supra-physiological glucocorticoid exposure.
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Affiliation(s)
- Martina Blaschke
- Clinic of Gastroenterology and Gastrointestinal Oncology, University Medical Center Göttingen, Göttingen, 37075, Germany; MVZ Endokrinologikum Göttingen, Von-Siebold-Straße 3, Göttingen, 37075, Germany.
| | - Regine Koepp
- Clinic of Gastroenterology and Gastrointestinal Oncology, University Medical Center Göttingen, Göttingen, 37075, Germany
| | - Frank Streit
- Department of Clinical Chemistry, University Medical Center Göttingen, Göttingen, 37075, Germany
| | - Johannes Beismann
- Clinic of Gastroenterology and Gastrointestinal Oncology, University Medical Center Göttingen, Göttingen, 37075, Germany
| | - Georg Manthey
- Evangelical Hospital Göttingen-Weende, Neu-Mariahilf Site, Göttingen, Germany
| | - Mark-Tilmann Seitz
- Clinic for Trauma Surgery, Orthopedics and Reconstructive Surgery, University Medical Center Göttingen, Göttingen, 37075, Germany
| | - Angelique Kragl
- Institute of Pharmacology, Center of Drug Absorption and Transport (C_DAT), University Medicine Greifswald, Felix-Hausdorff-Str. 3, Greifswald, 17487, Germany
| | - Heide Siggelkow
- Clinic of Gastroenterology and Gastrointestinal Oncology, University Medical Center Göttingen, Göttingen, 37075, Germany; MVZ Endokrinologikum Göttingen, Von-Siebold-Straße 3, Göttingen, 37075, Germany
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14
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Aaron N, Kraakman MJ, Zhou Q, Liu Q, Costa S, Yang J, Liu L, Yu L, Wang L, He Y, Fan L, Hirakawa H, Ding L, Lo J, Wang W, Zhao B, Guo E, Sun L, Rosen CJ, Qiang L. Adipsin promotes bone marrow adiposity by priming mesenchymal stem cells. eLife 2021; 10:69209. [PMID: 34155972 PMCID: PMC8219379 DOI: 10.7554/elife.69209] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Accepted: 06/07/2021] [Indexed: 01/12/2023] Open
Abstract
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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Affiliation(s)
- Nicole Aaron
- Naomi Berrie Diabetes Cente, Columbia UniversityNew YorkUnited States,Department of Pharmacology, Columbia UniversityNew YorkUnited States
| | - Michael J Kraakman
- Naomi Berrie Diabetes Cente, Columbia UniversityNew YorkUnited States,Department of Medicine, Columbia UniversityNew YorkUnited States
| | - Qiuzhong Zhou
- Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical SchoolSingaporeSingapore
| | - Qiongming Liu
- Naomi Berrie Diabetes Cente, Columbia UniversityNew YorkUnited States,Department of Pathology and Cellular Biology, Columbia UniversityNew YorkUnited States
| | - Samantha Costa
- Center for Molecular Medicine, Maine Medical Center Research InstituteScarboroughUnited States,School of Medicine, Tufts UniversityBostonUnited States,Graduate School of Biomedical Science and Engineering, University of MaineOronoUnited States
| | - Jing Yang
- Naomi Berrie Diabetes Cente, Columbia UniversityNew YorkUnited States,Department of Pathology and Cellular Biology, Columbia UniversityNew YorkUnited States
| | - Longhua Liu
- Naomi Berrie Diabetes Cente, Columbia UniversityNew YorkUnited States,Department of Pathology and Cellular Biology, Columbia UniversityNew YorkUnited States
| | - Lexiang Yu
- Naomi Berrie Diabetes Cente, Columbia UniversityNew YorkUnited States,Department of Pathology and Cellular Biology, Columbia UniversityNew YorkUnited States
| | - Liheng Wang
- Naomi Berrie Diabetes Cente, Columbia UniversityNew YorkUnited States,Department of Medicine, Columbia UniversityNew YorkUnited States
| | - Ying He
- Naomi Berrie Diabetes Cente, Columbia UniversityNew YorkUnited States,Department of Pathology and Cellular Biology, Columbia UniversityNew YorkUnited States
| | - Lihong Fan
- Naomi Berrie Diabetes Cente, Columbia UniversityNew YorkUnited States,Department of Pathology and Cellular Biology, Columbia UniversityNew YorkUnited States
| | - Hiroyuki Hirakawa
- Department of Microbiology and Immunology, Columbia UniversityNew YorkUnited States,Department of Rehabilitation and Regenerative Medicine, Vagelos College of Physicians and SurgeonsNew YorkUnited States
| | - Lei Ding
- Department of Microbiology and Immunology, Columbia UniversityNew YorkUnited States,Department of Rehabilitation and Regenerative Medicine, Vagelos College of Physicians and SurgeonsNew YorkUnited States
| | - James Lo
- Weill Center for Metabolic Health, Cardiovascular Research Institute, and Division of Cardiology, Weill Cornell Medical CollegeNew YorkUnited States
| | - Weidong Wang
- Department of Medicine, Division of Endocrinology, Harold Hamm Diabetes Center, The University of Oklahoma Health Science CenterOklahoma CityUnited States
| | - Baohong Zhao
- Arthritis and Tissue Degeneration Program and The David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, Department of Medicine, Weill Cornell Medical College; Graduate Program in Cell & Developmental Biology, Weill Cornell Graduate School of Medical SciencesNew YorkUnited States
| | - Edward Guo
- Department of Biomedical Engineering, Columbia UniversityNew YorkUnited States
| | - Lei Sun
- Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical SchoolSingaporeSingapore
| | - Cliff J Rosen
- Center for Molecular Medicine, Maine Medical Center Research InstituteScarboroughUnited States
| | - Li Qiang
- Naomi Berrie Diabetes Cente, Columbia UniversityNew YorkUnited States,Department of Pathology and Cellular Biology, Columbia UniversityNew YorkUnited States
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15
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Luo G, Tang M, Zhao Q, Lu L, Xie Y, Li Y, Liu C, Tian L, Chen X, Yu X. Bone marrow adipocytes enhance osteolytic bone destruction by activating 1q21.3(S100A7/8/9-IL6R)-TLR4 pathway in lung cancer. J Cancer Res Clin Oncol 2020; 146:2241-2253. [PMID: 32494918 DOI: 10.1007/s00432-020-03277-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Accepted: 05/29/2020] [Indexed: 02/08/2023]
Abstract
PURPOSE Bone metastasis is the result of complex crosstalk between tumor cells and bone marrow cells. Bone marrow adipocytes (BMAs) are the most abundant cell type in adult bone marrow. Therefore, we explore the effects of BMAs on bone metastasis in lung cancer. METHODS RNA-seq was used to compare the mRNA expression level of bone metastatic SBC5 cells and non-bone metastatic SBC3 cells. Rosiglitazone-induced marrow adiposity and intra-femoral injection of SBC5 cells were used to demonstrate the relationship between BMAs and SBC5 cells in vivo. Co-culture system, gene co-expression, gene ontology (GO) enrichment analysis and protein-protein interaction (PPI) network were used to explore the potential mechanism. RESULTS BMAs specially enhance the invasion of bone metastatic SBC5 instead of non-bone metastatic SBC3 in vitro. SBC5 instead of SBC3 promoted osteoblast and osteoclast differentiation as well as de-differentiation of mature BMAs. Rosiglitazone-induced marrow adiposity significantly enhanced osteolytic lesion induced by SBC5 in vivo. RNA-seq revealed that compared with SBC3, S100A9 and S100A8 genes were the most prominent genes up-regulated in SBC5 cells. High expression of S100A8/9 in SBC5 could be responsible for the crosstalk between lung cancer cells and BMAs. More importantly, interleukin 6 receptor (IL6R), which is adjacent to S100A8/A9 in 1q21.3, was significantly up-regulated by BMAs in vitro. S100A8/A9 (1 μg/ml) could obviously enhance the osteoblastic differentiation and inhibit adipogenic differentiation, whereas TLR4 inhibitor TAK242 (10 μmol/l) significantly attenuated this effect. CONCLUSIONS Our study suggested that bone marrow adipocyte may communicate with lung cancer cells via 1q21.3 (S100A8/A9-IL6R)-TLR4 pathway to promote osteolytic bone destruction. 1q21.3 (S100A8/A9-IL6R) is a potential target for the treatment of lung cancer bone metastasis.
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Affiliation(s)
- Guojing Luo
- Laboratory of Endocrinology and Metabolism, Department of Endocrinology and Metabolism, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Mengjia Tang
- Laboratory of Endocrinology and Metabolism, Department of Endocrinology and Metabolism, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Qian Zhao
- Department of General Practice, West China Hospital, Sichuan University, Chengdu, China
| | - Lingyun Lu
- Laboratory of Endocrinology and Metabolism, Department of Endocrinology and Metabolism, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Ying Xie
- Laboratory of Endocrinology and Metabolism, Department of Endocrinology and Metabolism, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Yujue Li
- Laboratory of Endocrinology and Metabolism, Department of Endocrinology and Metabolism, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Chang Liu
- Laboratory of Endocrinology and Metabolism, Department of Endocrinology and Metabolism, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Li Tian
- Laboratory of Endocrinology and Metabolism, Department of Endocrinology and Metabolism, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Xiang Chen
- Laboratory of Endocrinology and Metabolism, Department of Endocrinology and Metabolism, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Xijie Yu
- Laboratory of Endocrinology and Metabolism, Department of Endocrinology and Metabolism, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China.
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16
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Liu L, Yang XL, Zhang H, Zhang ZJ, Wei XT, Feng GJ, Liu J, Peng HP, Hai R, Shen H, Tian Q, Deng HW, Pei YF, Zhang L. Two novel pleiotropic loci associated with osteoporosis and abdominal obesity. Hum Genet 2020; 139:1023-1035. [PMID: 32239398 PMCID: PMC7883472 DOI: 10.1007/s00439-020-02155-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2019] [Accepted: 03/24/2020] [Indexed: 12/11/2022]
Abstract
Aiming to uncover a shared genetic basis of abdominal obesity and osteoporosis, we performed a bivariate GWAS meta-analysis of femoral neck BMD (FNK-BMD) and trunk fat mass adjusted by trunk lean mass (TFMadj) in 11,496 subjects from 6 samples, followed by in silico replication in the large-scale UK Biobank (UKB) cohort. A series of functional investigations were conducted on the identified variants. Bivariate GWAS meta-analysis identified two novel pleiotropic loci 12q15 (lead SNP rs73134637, p = 3.45 × 10-7) and 10p14 (lead SNP rs2892347, p = 2.63 × 10-7) that were suggestively associated and that were replicated in the analyses of related traits in the UKB sample (osteoporosis p = 0.06 and 0.02, BMI p = 0.03 and 4.61 × 10-3, N up to 499,520). Cis-eQTL analysis demonstrated that allele C at rs73134637 was positively associated with IFNG expression in whole blood (N = 369, p = 0.04), and allele A at rs11254759 (10p14, p = 9.49 × 10-7) was negatively associated with PRKCQ expression in visceral adipose tissue (N = 313, p = 0.04) and in lymphocytes (N = 117, p = 0.03). As a proof-of-principle experiment, the function of rs11254759, which is 235 kb 5'-upstream from PRKCQ gene, was investigated by the dual-luciferase reporter assay, which clearly showed that the haplotype carrying rs11254759 regulated PRKCQ expression by upregulating PRKCQ promoter activity (p = 4.60 × 10-7) in an allelic specific manner. Mouse model analysis showed that heterozygous PRKCQ deficient mice presented decreased fat mass compared to wild-type control mice (p = 3.30 × 10-3). Mendelian randomization analysis demonstrated that both FNK-BMD and TFMadj were causally associated with fracture risk (p = 1.26 × 10-23 and 1.18 × 10-11). Our findings may provide useful insights into the genetic association between osteoporosis and abdominal obesity.
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Affiliation(s)
- Lu Liu
- Center for Genetic Epidemiology and Genomics, School of Public Health, Medical College, Soochow University, 199 Ren-ai Rd, Suzhou, 215123, Jiangsu, People's Republic of China
- Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, School of Public Health, Medical College of Soochow University, Suzhou, Jiangsu, People's Republic of China
- Kunshan Hospital of Traditional Chinese Medicine, Suzhou, Jiangsu, People's Republic of China
| | - Xiao-Lin Yang
- Center for Genetic Epidemiology and Genomics, School of Public Health, Medical College, Soochow University, 199 Ren-ai Rd, Suzhou, 215123, Jiangsu, People's Republic of China
- Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, School of Public Health, Medical College of Soochow University, Suzhou, Jiangsu, People's Republic of China
| | - Hong Zhang
- Center for Genetic Epidemiology and Genomics, School of Public Health, Medical College, Soochow University, 199 Ren-ai Rd, Suzhou, 215123, Jiangsu, People's Republic of China
- Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, School of Public Health, Medical College of Soochow University, Suzhou, Jiangsu, People's Republic of China
| | - Zi-Jia Zhang
- People's Hospital of Inner Mongolia Autonomous Region, Hohhot, Inner Mongolia Autonomous Region, People's Republic of China
| | - Xin-Tong Wei
- Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, School of Public Health, Medical College of Soochow University, Suzhou, Jiangsu, People's Republic of China
- Department of Epidemiology and Health Statistics, School of Public Health, Medical College, Soochow University, 199 Ren-ai Rd., Suzhou, 215123, Jiangsu, People's Republic of China
| | - Gui-Juan Feng
- Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, School of Public Health, Medical College of Soochow University, Suzhou, Jiangsu, People's Republic of China
- Department of Epidemiology and Health Statistics, School of Public Health, Medical College, Soochow University, 199 Ren-ai Rd., Suzhou, 215123, Jiangsu, People's Republic of China
| | - Ju Liu
- Kunshan Hospital of Traditional Chinese Medicine, Suzhou, Jiangsu, People's Republic of China
| | - Hui-Ping Peng
- Kunshan Hospital of Traditional Chinese Medicine, Suzhou, Jiangsu, People's Republic of China
| | - Rong Hai
- Health Commission of Inner Mongolia Autonomous Region, Hohhot, Inner Mongolia Autonomous Region, People's Republic of China
| | - Hui Shen
- Tulane Center for Genomics and Bioinformatics, Department of Biostatistics and Bioinformatics, School of Public Health and Tropical Medicine, Tulane University, 1440 Canal St., Suite 2001, New Orleans, LA, 70112, USA
| | - Qing Tian
- Tulane Center for Genomics and Bioinformatics, Department of Biostatistics and Bioinformatics, School of Public Health and Tropical Medicine, Tulane University, 1440 Canal St., Suite 2001, New Orleans, LA, 70112, USA
| | - Hong-Wen Deng
- Tulane Center for Genomics and Bioinformatics, Department of Biostatistics and Bioinformatics, School of Public Health and Tropical Medicine, Tulane University, 1440 Canal St., Suite 2001, New Orleans, LA, 70112, USA.
| | - Yu-Fang Pei
- Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, School of Public Health, Medical College of Soochow University, Suzhou, Jiangsu, People's Republic of China.
- Department of Epidemiology and Health Statistics, School of Public Health, Medical College, Soochow University, 199 Ren-ai Rd., Suzhou, 215123, Jiangsu, People's Republic of China.
| | - Lei Zhang
- Center for Genetic Epidemiology and Genomics, School of Public Health, Medical College, Soochow University, 199 Ren-ai Rd, Suzhou, 215123, Jiangsu, People's Republic of China.
- Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, School of Public Health, Medical College of Soochow University, Suzhou, Jiangsu, People's Republic of China.
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17
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Pham TT, Ivaska KK, Hannukainen JC, Virtanen KA, Lidell ME, Enerbäck S, Mäkelä K, Parkkola R, Piirola S, Oikonen V, Nuutila P, Kiviranta R. Human Bone Marrow Adipose Tissue is a Metabolically Active and Insulin-Sensitive Distinct Fat Depot. J Clin Endocrinol Metab 2020; 105:5822831. [PMID: 32311037 PMCID: PMC7247553 DOI: 10.1210/clinem/dgaa216] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Accepted: 04/17/2020] [Indexed: 01/29/2023]
Abstract
CONTEXT Bone marrow (BM) in adult long bones is rich in adipose tissue, but the functions of BM adipocytes are largely unknown. We set out to elucidate the metabolic and molecular characteristics of BM adipose tissue (BMAT) in humans. OBJECTIVE Our aim was to determine if BMAT is an insulin-sensitive tissue, and whether the insulin sensitivity is altered in obesity or type 2 diabetes (T2DM). DESIGN This was a cross-sectional and longitudinal study. SETTING The study was conducted in a clinical research center. PATIENTS OR OTHER PARTICIPANTS Bone marrow adipose tissue glucose uptake (GU) was assessed in 23 morbidly obese subjects (9 with T2DM) and 9 healthy controls with normal body weight. In addition, GU was assessed in another 11 controls during cold exposure. Bone marrow adipose tissue samples for molecular analyses were collected from non-DM patients undergoing knee arthroplasty. INTERVENTION(S) Obese subjects were assessed before and 6 months after bariatric surgery and controls at 1 time point. MAIN OUTCOME MEASURE We used positron emission tomography imaging with 2-[18F]fluoro-2-deoxy-D-glucose tracer to characterize GU in femoral and vertebral BMAT. Bone marrow adipose tissue molecular profile was assessed using quantitative RT-PCR. RESULTS Insulin enhances GU in human BMAT. Femoral BMAT insulin sensitivity was impaired in obese patients with T2DM compared to controls, but it improved after bariatric surgery. Furthermore, gene expression analysis revealed that BMAT was distinct from brown and white adipose tissue. CONCLUSIONS Bone marrow adipose tissue is a metabolically active, insulin-sensitive and molecularly distinct fat depot that may play a role in whole body energy metabolism.
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Affiliation(s)
- Tam T Pham
- Turku PET Centre, University of Turku, Turku, Finland
| | - Kaisa K Ivaska
- Institute of Biomedicine, University of Turku, Turku, Finland
| | | | | | - Martin E Lidell
- Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Sven Enerbäck
- Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Keijo Mäkelä
- Department of Orthopaedics and Traumatology, Turku University Hospital, Turku, Finland
| | - Riitta Parkkola
- Department of Radiology, Turku University Hospital, Turku, Finland
| | - Sauli Piirola
- Turku PET Centre, University of Turku, Turku, Finland
| | - Vesa Oikonen
- Turku PET Centre, University of Turku, Turku, Finland
| | - Pirjo Nuutila
- Turku PET Centre, University of Turku, Turku, Finland
- Department of Endocrinology, Turku University Hospital, Turku, Finland
| | - Riku Kiviranta
- Institute of Biomedicine, University of Turku, Turku, Finland
- Department of Endocrinology, Turku University Hospital, Turku, Finland
- Correspondence and Reprint Requests: Riku Kiviranta, Institute of Biomedicine, University of Turku, 20520 Turku, Finland. E-mail:
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18
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Ko DS, Kim YH, Goh TS, Lee JS. Altered physiology of mesenchymal stem cells in the pathogenesis of adolescent idiopathic scoliosis. World J Clin Cases 2020; 8:2102-2110. [PMID: 32548139 PMCID: PMC7281031 DOI: 10.12998/wjcc.v8.i11.2102] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Revised: 05/13/2020] [Accepted: 05/23/2020] [Indexed: 02/05/2023] Open
Abstract
Adolescent idiopathic scoliosis is the most common spinal deformity during puberty, especially in females. It is characterized by aberrant skeletal growth and generalized reduced bone density, which is associated with impaired bone mineral metabolism. Despite recent progress in multidisciplinary research to support various hypotheses, the pathogenesis of Adolescent idiopathic scoliosis is still not clearly understood. One of the hypothesis is to study the role of mesenchymal stem cells due to its involvement in the above-mentioned bone metabolic abnormalities. In this review, we will summarize reported literatures on the role of mesenchymal stem cells, particularly in the pathogenesis of Adolescent idiopathic scoliosis. In addition, we will describe the research on mesenchymal stem cells of Adolescent idiopathic scoliosis performed using bioinformatics tools.
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Affiliation(s)
- Dai Sik Ko
- Division of Vascular Surgery, Department of Surgery, Gachon University Gil Medical Center, Incheoz 21565, South Korea
| | - Yun Hak Kim
- Department of Anatomy and Department of Biomedical Informatics, School of Medicine, Pusan National University, Yangsan 50612, South Korea
| | - Tae Sik Goh
- Department of Orthopaedic Surgery and Biomedical Research Institute, Pusan National University Hospital, Busan 49241, South Korea
| | - Jung Sub Lee
- Department of Orthopaedic Surgery and Biomedical Research Institute, Pusan National University Hospital, Busan 49241, South Korea
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19
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Abstract
Unhealthy diet, lack of exercise, psychosocial stress, and insufficient sleep are increasingly prevalent modifiable risk factors for cardiovascular disease. Accumulating evidence indicates that these risk factors may fuel chronic inflammatory processes that are active in atherosclerosis and lead to myocardial infarction and stroke. In concert with hyperlipidemia, maladaptive immune system activities can contribute to disease progression and increase the probability of adverse events. In this review, we discuss recent insight into how the above modifiable risk factors influence innate immunity. Specifically, we focus on pathways that raise systemic myeloid cell numbers and modulate immune cell phenotypes, reviewing hematopoiesis, leukocyte trafficking, and innate immune cell accumulation in cardiovascular organs. Often, relevant mechanisms that begin with lifestyle choices and lead to cardiovascular events span multiple organ systems, including the central nervous, endocrine, metabolic, hematopoietic, immune and, finally, the cardiovascular system. We argue that deciphering such pathways provides not only support for preventive interventions but also opportunities to develop biomimetic immunomodulatory therapeutics that mitigate cardiovascular inflammation.
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Affiliation(s)
- Maximilian J Schloss
- From the Center for Systems Biology, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston (M.J.S., F.K.S., M.N.).,Department of Radiology, Massachusetts General Hospital, Boston (M.J.S., F.K.S., M.N.)
| | - Filip K Swirski
- From the Center for Systems Biology, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston (M.J.S., F.K.S., M.N.).,Department of Radiology, Massachusetts General Hospital, Boston (M.J.S., F.K.S., M.N.)
| | - Matthias Nahrendorf
- From the Center for Systems Biology, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston (M.J.S., F.K.S., M.N.).,Department of Radiology, Massachusetts General Hospital, Boston (M.J.S., F.K.S., M.N.).,Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston (M.N.).,Department of Internal Medicine I, University Hospital Wuerzburg, Germany (M.N.)
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20
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Sieron D, Drakopoulos D, Loebelenz LI, Schroeder C, Ebner L, Obmann VC, Huber AT, Christe A. Correlation between fat signal ratio on T1-weighted MRI in the lower vertebral bodies and age, comparing 1.5-T and 3-T scanners. Acta Radiol Open 2020; 9:2058460120901517. [PMID: 32166041 PMCID: PMC7055425 DOI: 10.1177/2058460120901517] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Accepted: 12/30/2019] [Indexed: 11/28/2022] Open
Abstract
Background The hypothesis was that the fat-dependent T1 signal intensity in vertebral
bodies increases with age due to red-yellow marrow conversion. Purpose To analyze the increasing fatty conversion of red bone marrow with age. Material and Methods A continuous sample of 524 patients (age range 2–96 years) with normal lumbar
spine MRIs (T11–L5) was retrospectively selected in order to get a
representative sample from our 1.5-T and 3-T MRI units (Siemens, Erlangen,
Germany). Four radiologists read the images independently. Absolute T1
signal intensities were measured in the lower vertebral bodies and
standardized by dividing their value by the signal of the subcutaneous fat
on lumbar and sacral level. Results The standardized T1 signal correlated significantly with patients’ age at the
1.5-T unit, with the best correlation demonstrated by thoracic vertebra T11,
followed by lumbar vertebra L1, with correlation coefficients (R) of 0.64
(95% CI 0.53–0.72, P < 0.0001) and 0.49 (95% CI
0.38–0.59, P < 0.0001), respectively. For women and men,
the R values were similar in thoracic vertebra T11 at 0.62 (95% CI
0.49–0.72) and 0.64 (95% CI 0.44–0.77), respectively. The vertebral signal
correlated significantly better with age in the 1.5-T compared to the 3-T
unit on all vertebral levels: the best R value of the 3-T unit was only 0.20
(95% CI 0.09–0.30, P < 0.0001). Our study showed an
average increase of the relative T1 signal in T11 of 10% per decade. Conclusion T1 fat signal ratio increases with age in the vertebral bodies, which could
help estimating the age of a person. Best age correlation was found when
measuring T1 signal in T11, standardized by the sacral subcutaneous fat
signal and using a 1.5-T MRI.
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Affiliation(s)
- Dominik Sieron
- Department of Radiology, Division City and County Hospitals, INSELGROUP, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Dionysios Drakopoulos
- Department of Radiology, Division City and County Hospitals, INSELGROUP, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Laura I Loebelenz
- Department of Radiology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Christophe Schroeder
- Department of Radiology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Lukas Ebner
- Department of Radiology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Verena C Obmann
- Department of Radiology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Adrian T Huber
- Department of Radiology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Andreas Christe
- Department of Radiology, Division City and County Hospitals, INSELGROUP, Bern University Hospital, University of Bern, Bern, Switzerland
- Department of Radiology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
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21
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Ansari MGA, Hussain SD, Wani KA, Yakout SM, Al-Disi D, Alokail MS, Reginster JY, Al-Daghri NM. Influence of bone mineral density in circulating adipokines among postmenopausal Arab women. Saudi J Biol Sci 2019; 27:374-379. [PMID: 31889860 PMCID: PMC6933263 DOI: 10.1016/j.sjbs.2019.10.007] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2019] [Revised: 10/16/2019] [Accepted: 10/20/2019] [Indexed: 12/20/2022] Open
Abstract
Osteoporosis and osteopenia has a significant link with substantial fracture risk. Epidemiological data revealed a protective role of adipose tissue on bone biology in postmenopausal osteoporosis. The current study assessed the associations between select adipokines and bone mineral density (BMD) in postmenopausal women. A total of 175 Saudi postmenopausal women were selected and categorized based on their BMD (normal & low-BMD). Circulating levels of select adipokines (adiponectin, resistin, leptin, and adipsin), insulin, 25(OH)D and RANKl were determined using commercially available assay kits. BMD was measured by dual-energy X-ray absorptiometry (DXA). Overall and among low-BMD subjects, adiponectin consistently showed a significant inverse association with BMD (overall −0.34, p < 0.01; low BMD group −0.34, p < 0.01). In multiple regression, adiponectin (−0.29 ± 0.06, p < 0.00) and resistin (−0.08 ± 0.04, p < 0.05) were inversely significant with BMD overall, but after stratification the significance was lost for resistin (−0.05 ± 0.04, p < 0.224) whereas adiponectin remained (−0.22 ± 0.07, p < 0.02) in low-BMD subjects. Adipsin, leptin and lipocalin-2 showed no significant associations. Findings of the present study revealed that only adiponectin showed a significantly strong inverse association with low BMD, suggesting that insulin sensitivity may influence bone health in Arab postmenopausal women.
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Affiliation(s)
- Mohammed Ghouse Ahmed Ansari
- Chair for Biomarkers of Chronic Diseases, Biochemistry Department, College of Science, King Saud University, Riyadh 11451, Saudi Arabia
| | - Syed Danish Hussain
- Chair for Biomarkers of Chronic Diseases, Biochemistry Department, College of Science, King Saud University, Riyadh 11451, Saudi Arabia
| | - Kaiser Ahmed Wani
- Chair for Biomarkers of Chronic Diseases, Biochemistry Department, College of Science, King Saud University, Riyadh 11451, Saudi Arabia
| | - Sobhy M Yakout
- Chair for Biomarkers of Chronic Diseases, Biochemistry Department, College of Science, King Saud University, Riyadh 11451, Saudi Arabia
| | - Dara Al-Disi
- Department of Community Health Sciences, College of Applied Medical Sciences, King Saud University, Riyadh 11451, Saudi Arabia
| | - Majed S Alokail
- Chair for Biomarkers of Chronic Diseases, Biochemistry Department, College of Science, King Saud University, Riyadh 11451, Saudi Arabia
| | - Jean-Yves Reginster
- Chair for Biomarkers of Chronic Diseases, Biochemistry Department, College of Science, King Saud University, Riyadh 11451, Saudi Arabia.,Department of Public Health, Epidemiology and Health Economics, University of Liège, Liège, Belgium
| | - Nasser M Al-Daghri
- Chair for Biomarkers of Chronic Diseases, Biochemistry Department, College of Science, King Saud University, Riyadh 11451, Saudi Arabia
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22
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Ham J, Lever L, Fox M, Reagan MR. In Vitro 3D Cultures to Reproduce the Bone Marrow Niche. JBMR Plus 2019; 3:e10228. [PMID: 31687654 PMCID: PMC6820578 DOI: 10.1002/jbm4.10228] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2019] [Revised: 07/23/2019] [Accepted: 07/29/2019] [Indexed: 12/30/2022] Open
Abstract
Over the past century, the study of biological processes in the human body has progressed from tissue culture on glass plates to complex 3D models of tissues, organs, and body systems. These dynamic 3D systems have allowed for more accurate recapitulation of human physiology and pathology, which has yielded a platform for disease study with a greater capacity to understand pathophysiology and to assess pharmaceutical treatments. Specifically, by increasing the accuracy with which the microenvironments of disease processes are modeled, the clinical manifestation of disease has been more accurately reproduced in vitro. The application of these models is crucial in all realms of medicine, but they find particular utility in diseases related to the complex bone marrow niche. Osteoblast, osteoclasts, bone marrow adipocytes, mesenchymal stem cells, and red and white blood cells represent some of cells that call the bone marrow microenvironment home. During states of malignant marrow disease, neoplastic cells migrate to and join this niche. These cancer cells both exploit and alter the niche to their benefit and to the patient's detriment. Malignant disease of the bone marrow, both primary and secondary, is a significant cause of morbidity and mortality today. Innovative study methods are necessary to improve patient outcomes. In this review, we discuss the evolution of 3D models and compare them to the preceding 2D models. With a specific focus on malignant bone marrow disease, we examine 3D models currently in use, their observed efficacy, and their potential in developing improved treatments and eventual cures. Finally, we comment on the aspects of 3D models that must be critically examined as systems continue to be optimized so that they can exert greater clinical impact in the future. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
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Affiliation(s)
- Justin Ham
- Center for Molecular MedicineMaine Medical Center Research InstituteScarboroughMEUSA,University of New EnglandBiddefordMEUSA
| | - Lauren Lever
- Center for Molecular MedicineMaine Medical Center Research InstituteScarboroughMEUSA,University of New EnglandBiddefordMEUSA
| | - Maura Fox
- University of New EnglandBiddefordMEUSA
| | - Michaela R Reagan
- Center for Molecular MedicineMaine Medical Center Research InstituteScarboroughMEUSA,University of Maine Graduate School of Biomedical Science and EngineeringOronoMEUSA,Sackler School of Graduate Biomedical SciencesTufts UniversityBostonMAUSA
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23
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Clinical Factors and Cellular Responses of In Situ Human Alveolar Bone–Derived Mesenchymal Stromal Cells Associated With Early Periimplant Marginal Bone Loss. IMPLANT DENT 2019; 28:421-429. [DOI: 10.1097/id.0000000000000904] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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24
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Knani L, Bartolini D, Kechiche S, Tortoioli C, Murdolo G, Moretti M, Messaoudi I, Reiter RJ, Galli F. Melatonin prevents cadmium-induced bone damage: First evidence on an improved osteogenic/adipogenic differentiation balance of mesenchymal stem cells as underlying mechanism. J Pineal Res 2019; 67:e12597. [PMID: 31340072 DOI: 10.1111/jpi.12597] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2019] [Revised: 06/25/2019] [Accepted: 06/28/2019] [Indexed: 12/13/2022]
Abstract
Melatonin (MLT) plays a role in preserving bone health, a function that may depend on homeostatic effects on both mature osteoblasts and mesenchymal stem cells (MSCs) of the bone tissue. In this study, these functions of MLT have been investigated in rat bone (femur) and in human adipose MSC (hMSC) during chronic exposure to low-grade cadmium (Cd) toxicity, a serious public health concern. The in vivo findings demonstrate that MLT protects against Cd-induced bone metabolism disruption and accumulation of bone marrow adipocytes, a cue of impaired osteogenic potential of skeletal MSC niches. This latter symptom was recapitulated in hMSCs in which Cd toxicity stimulated adipogenic differentiation. MLT was found to rescue, at least in part, the osteogenic differentiation properties of these cells. This study reports on a new bone cytoprotection function of MLT pertinent to Cd toxicity and its interfering effect on skeletal MSC differentiation properties that is worth investigating for its possible impact on human bone pathophysiology.
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Affiliation(s)
- Latifa Knani
- Laboratoire LR11ES41 Génétique Biodiversité et Valorisation des Bio-ressources, Institut Supérieur de Biotechnologie de Monastir, Université de Monastir, Monastir, Tunisie
| | - Desirée Bartolini
- Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy
| | - Safa Kechiche
- Laboratoire LR11ES41 Génétique Biodiversité et Valorisation des Bio-ressources, Institut Supérieur de Biotechnologie de Monastir, Université de Monastir, Monastir, Tunisie
| | - Cristina Tortoioli
- Section of Internal Medicine, Endocrine and Metabolic Sciences, University of Perugia, Perugia, Italy
| | - Giuseppe Murdolo
- Section of Internal Medicine, Endocrine and Metabolic Sciences, University of Perugia, Perugia, Italy
| | - Massimo Moretti
- Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy
| | - Imed Messaoudi
- Laboratoire LR11ES41 Génétique Biodiversité et Valorisation des Bio-ressources, Institut Supérieur de Biotechnologie de Monastir, Université de Monastir, Monastir, Tunisie
| | - Russel J Reiter
- Department of Cellular and Structural Biology, UT Health Science Center, San Antonio, TX, USA
| | - Francesco Galli
- Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy
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25
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Sebo ZL, Rendina-Ruedy E, Ables GP, Lindskog DM, Rodeheffer MS, Fazeli PK, Horowitz MC. Bone Marrow Adiposity: Basic and Clinical Implications. Endocr Rev 2019; 40:1187-1206. [PMID: 31127816 PMCID: PMC6686755 DOI: 10.1210/er.2018-00138] [Citation(s) in RCA: 68] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2018] [Accepted: 04/03/2019] [Indexed: 12/14/2022]
Abstract
The presence of adipocytes in mammalian bone marrow (BM) has been recognized histologically for decades, yet, until recently, these cells have received little attention from the research community. Advancements in mouse transgenics and imaging methods, particularly in the last 10 years, have permitted more detailed examinations of marrow adipocytes than ever before and yielded data that show these cells are critical regulators of the BM microenvironment and whole-body metabolism. Indeed, marrow adipocytes are anatomically and functionally separate from brown, beige, and classic white adipocytes. Thus, areas of BM space populated by adipocytes can be considered distinct fat depots and are collectively referred to as marrow adipose tissue (MAT) in this review. In the proceeding text, we focus on the developmental origin and physiologic functions of MAT. We also discuss the signals that cause the accumulation and loss of marrow adipocytes and the ability of these cells to regulate other cell lineages in the BM. Last, we consider roles for MAT in human physiology and disease.
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Affiliation(s)
- Zachary L Sebo
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut.,Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, Connecticut
| | | | - Gene P Ables
- Orentreich Foundation for the Advancement of Science, Cold Spring, New York
| | - Dieter M Lindskog
- Department of Orthopaedics and Rehabilitation, Yale University School of Medicine, New Haven, Connecticut
| | - Matthew S Rodeheffer
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut.,Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, Connecticut
| | - Pouneh K Fazeli
- Neuroendocrine Unit, Massachusetts General Hospital, Boston, Massachusetts
| | - Mark C Horowitz
- Department of Orthopaedics and Rehabilitation, Yale University School of Medicine, New Haven, Connecticut
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26
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Coutel X, Delattre J, Marchandise P, Falgayrac G, Béhal H, Kerckhofs G, Penel G, Olejnik C. Mandibular bone is protected against microarchitectural alterations and bone marrow adipose conversion in ovariectomized rats. Bone 2019; 127:343-352. [PMID: 31276849 DOI: 10.1016/j.bone.2019.06.031] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2019] [Revised: 06/02/2019] [Accepted: 06/29/2019] [Indexed: 02/05/2023]
Abstract
Osteoporosis is a disease that leads to a loss of bone mass and to alterations in the bone microarchitecture that occur in a site-specific manner; however it remains controversial in the jaw. The involvement of bone marrow adipose tissue (BMAT) in the bone metabolism has been suggested in several physiopathological contexts, such as in aging and osteoporosis. To test whether the BMAT content is related to mandibular bone loss, this study aimed to investigate the potential correlations between the trabecular bone microarchitecture on one hand and BMAT content and its spatial distribution in relation to bone surface on the other hand during aging and ovariectomy (OVX) during a long-term follow-up in a mature rat model. No age-related microarchitectural or BMAT changes were observed in the mandible. The OVX-induced bone loss was three-fold lower in the mandible than in the tibia and was observed only in the alveolar bone (not in the condyle). We also report a delayed increase in the mandibular BMAT content that remained 4-6-fold lower compared to tibia. This low BMAT content in the mandible was located at a distance from the trabecular bone surface (only 5% in contact with the bone surface versus 87% in the tibia). These findings highlight a specific mandibular response to OVX, in particular fewer microarchitectural alterations compared to that in the tibia. For the latter, the trabecular bone thickness and surface were correlated with the BMAT content. Oral functions may have a protective effect on the mandibular BMAT conversion in an OVX context.
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Affiliation(s)
- Xavier Coutel
- Univ. Lille, Univ. Littoral Côte d'Opale, CHU Lille, EA 4490 - PMOI, F-59000 Lille, France.
| | - Jérôme Delattre
- Univ. Lille, Univ. Littoral Côte d'Opale, CHU Lille, EA 4490 - PMOI, F-59000 Lille, France
| | - Pierre Marchandise
- Univ. Lille, Univ. Littoral Côte d'Opale, CHU Lille, EA 4490 - PMOI, F-59000 Lille, France
| | - Guillaume Falgayrac
- Univ. Lille, Univ. Littoral Côte d'Opale, CHU Lille, EA 4490 - PMOI, F-59000 Lille, France
| | - Hélène Béhal
- Univ. Lille, CHU Lille, EA 2694 - Santé publique: épidémiologie et qualité des soins, Unité de Méthodologie et Biostatistiques, F-59000 Lille, France
| | - Greet Kerckhofs
- Biomechanics Lab, Institute of Mechanics, Materials, and Civil Engineering, UCLouvain, Louvain-la-Neuve, Belgium; Institute of Experimental and Clinical Research, UCLouvain, Woluwe, Belgium; Department Materials Engineering, KU Leuven, Leuven, Belgium; Prometheus, Division of Skeletal Tissue Engineering, KU Leuven, Leuven, Belgium
| | - Guillaume Penel
- Univ. Lille, Univ. Littoral Côte d'Opale, CHU Lille, EA 4490 - PMOI, F-59000 Lille, France
| | - Cécile Olejnik
- Univ. Lille, Univ. Littoral Côte d'Opale, CHU Lille, EA 4490 - PMOI, F-59000 Lille, France
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27
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Li H, Yue B. Effects of various antimicrobial agents on multi-directional differentiation potential of bone marrow-derived mesenchymal stem cells. World J Stem Cells 2019; 11:322-336. [PMID: 31293715 PMCID: PMC6600849 DOI: 10.4252/wjsc.v11.i6.322] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2019] [Revised: 03/30/2019] [Accepted: 05/23/2019] [Indexed: 02/06/2023] Open
Abstract
Antimicrobial drugs of several classes play an important role in the treatment of bone and joint infections. In addition to fighting pathogenic microorganisms, the effects of drugs on local tissues and cells are also related to the course and prognosis of bone and joint infections. The multi-directional differentiation potential of bone marrow-derived mesenchymal stem cells (MSCs) is essential for tissue repair after local injury, which is directly related to the recovery of bone, cartilage, and medullary adipose tissue. Our previous studies and the literature indicate that certain antimicrobial agents can regulate the differentiation potential of bone marrow-derived MSCs. Here, in order to systematically analyze the effects of various antimicrobial drugs on local tissue regeneration, we comprehensively review the studies on the effects of these drugs on MSC differentiation, and classify them according to the three differentiation directions (osteogenesis, chondrogenesis, and adipogenesis). Our review demonstrates the specific effects of different antimicrobial agents on bone marrow-derived MSCs and the range of concentrations at which they work, and provides a basis for drug selection at different sites of infection.
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Affiliation(s)
- Hui Li
- Department of Bone and Joint Surgery, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200011, China
| | - Bing Yue
- Department of Bone and Joint Surgery, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200011, China.
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28
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Pagnotti GM, Styner M, Uzer G, Patel VS, Wright LE, Ness KK, Guise TA, Rubin J, Rubin CT. Combating osteoporosis and obesity with exercise: leveraging cell mechanosensitivity. Nat Rev Endocrinol 2019; 15:339-355. [PMID: 30814687 PMCID: PMC6520125 DOI: 10.1038/s41574-019-0170-1] [Citation(s) in RCA: 147] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Osteoporosis, a condition of skeletal decline that undermines quality of life, is treated with pharmacological interventions that are associated with poor adherence and adverse effects. Complicating efforts to improve clinical outcomes, the incidence of obesity is increasing, predisposing the population to a range of musculoskeletal complications and metabolic disorders. Pharmacological management of obesity has yet to deliver notable reductions in weight and debilitating complications are rarely avoided. By contrast, exercise shows promise as a non-invasive and non-pharmacological method of regulating both osteoporosis and obesity. The principal components of exercise - mechanical signals - promote bone and muscle anabolism while limiting formation and expansion of fat mass. Mechanical regulation of bone and marrow fat might be achieved by regulating functions of differentiated cells in the skeletal tissue while biasing lineage selection of their common progenitors - mesenchymal stem cells. An inverse relationship between adipocyte versus osteoblast fate selection from stem cells is implicated in clinical conditions such as childhood obesity and increased marrow adiposity in type 2 diabetes mellitus, as well as contributing to skeletal frailty. Understanding how exercise-induced mechanical signals can be used to improve bone quality while decreasing fat mass and metabolic dysfunction should lead to new strategies to treat chronic diseases such as osteoporosis and obesity.
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Affiliation(s)
- Gabriel M Pagnotti
- School of Medicine, Division of Endocrinology, Indiana University, Indianapolis, IN, USA
| | - Maya Styner
- Department of Medicine, Division of Endocrinology and Metabolism, University of North Carolina, Chapel Hill, NC, USA
| | - Gunes Uzer
- College of Mechanical and Biomedical Engineering, Boise State University, Boise, ID, USA
| | - Vihitaben S Patel
- Department of Biomedical Engineering, Stony Brook University, Stony Brook, NY, USA
| | - Laura E Wright
- School of Medicine, Division of Endocrinology, Indiana University, Indianapolis, IN, USA
| | - Kirsten K Ness
- Department of Epidemiology and Cancer Control, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Theresa A Guise
- School of Medicine, Division of Endocrinology, Indiana University, Indianapolis, IN, USA
| | - Janet Rubin
- Department of Medicine, Division of Endocrinology and Metabolism, University of North Carolina, Chapel Hill, NC, USA
| | - Clinton T Rubin
- Department of Biomedical Engineering, Stony Brook University, Stony Brook, NY, USA.
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29
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Liu H, He J, Koh SP, Zhong Y, Liu Z, Wang Z, Zhang Y, Li Z, Tam BT, Lin P, Xiao M, Young KH, Amini B, Starbuck MW, Lee HC, Navone NM, Davis RE, Tong Q, Bergsagel PL, Hou J, Yi Q, Orlowski RZ, Gagel RF, Yang J. Reprogrammed marrow adipocytes contribute to myeloma-induced bone disease. Sci Transl Med 2019; 11:eaau9087. [PMID: 31142679 PMCID: PMC6999853 DOI: 10.1126/scitranslmed.aau9087] [Citation(s) in RCA: 73] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2018] [Revised: 11/15/2018] [Accepted: 03/29/2019] [Indexed: 12/26/2022]
Abstract
Osteolytic lesions in multiple myeloma are caused by osteoclast-mediated bone resorption and reduced bone formation. A unique feature of myeloma is a failure of bone healing after successful treatment. We observed adipocytes on trabecular bone near the resorbed area in successfully treated patients. Normal marrow adipocytes, when cocultured with myeloma cells, were reprogrammed and produced adipokines that activate osteoclastogenesis and suppress osteoblastogenesis. These adipocytes have reduced expression of peroxisome proliferator-activated receptor γ (PPARγ) mediated by recruitment of polycomb repressive complex 2 (PRC2), which modifies PPARγ promoter methylation at trimethyl lysine-27 histone H3. We confirmed the importance of methylation in the PPARγ promoter by demonstrating that adipocyte-specific knockout of EZH2, a member of the PRC2, prevents adipocyte reprogramming and reverses bone changes in a mouse model. We validated the strong correlation between the frequency of bone lesions and the expression of EZH2 in marrow adipocytes from patients in remission. These results define a role for adipocytes in genesis of myeloma-associated bone disease and that reversal of adipocyte reprogramming has therapeutic implications.
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Affiliation(s)
- Huan Liu
- Department of Lymphoma and Myeloma, Center for Cancer Immunology Research, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Jin He
- Department of Lymphoma and Myeloma, Center for Cancer Immunology Research, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Su Pin Koh
- Department of Biochemistry and Molecular Biology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Yuping Zhong
- Department of Hematology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, People's Republic of China
| | - Zhiqiang Liu
- Department of Lymphoma and Myeloma, Center for Cancer Immunology Research, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Department of Pathophysiology, Tianjin Medical University, Tianjin, People's Republic of China
| | - Zhiqiang Wang
- Department of Lymphoma and Myeloma, Center for Cancer Immunology Research, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Yujin Zhang
- Department of Lymphoma and Myeloma, Center for Cancer Immunology Research, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Zongwei Li
- Department of Lymphoma and Myeloma, Center for Cancer Immunology Research, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Bjorn T Tam
- Department of Lymphoma and Myeloma, Center for Cancer Immunology Research, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Pei Lin
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Min Xiao
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Ken H Young
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Behrang Amini
- Department of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Michael W Starbuck
- Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Hans C Lee
- Department of Lymphoma and Myeloma, Center for Cancer Immunology Research, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Nora M Navone
- Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Richard E Davis
- Department of Lymphoma and Myeloma, Center for Cancer Immunology Research, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Qiang Tong
- USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
| | - P Leif Bergsagel
- Division of Hematology and Medical Oncology, Mayo Clinic, Scottsdale, AZ 85259, USA
| | - Jian Hou
- Department of Hematology, Renji Hospital, Shanghai Jiaotong University School of Medicine, 160 Pujian Rd, Shanghai, People's Republic of China
| | - Qing Yi
- Cancer Center for Hematological Malignancies, Houston Methodist Hospital, Houston, TX 77030, USA
| | - Robert Z Orlowski
- Department of Lymphoma and Myeloma, Center for Cancer Immunology Research, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Robert F Gagel
- Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Jing Yang
- Department of Lymphoma and Myeloma, Center for Cancer Immunology Research, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
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Song J, Li J, Yang F, Ning G, Zhen L, Wu L, Zheng Y, Zhang Q, Lin D, Xie C, Peng L. Nicotinamide mononucleotide promotes osteogenesis and reduces adipogenesis by regulating mesenchymal stromal cells via the SIRT1 pathway in aged bone marrow. Cell Death Dis 2019; 10:336. [PMID: 31000692 PMCID: PMC6472410 DOI: 10.1038/s41419-019-1569-2] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Revised: 03/28/2019] [Accepted: 04/03/2019] [Indexed: 12/17/2022]
Abstract
Mesenchymal stromal cells (MSCs) can differentiate to various cell types including osteoblasts, chondrocytes, and adipocytes. This cellular flexibility contributes to widespread clinical use of MSCs in tissue repair. However, challenges remain in efficient cellular expansion of MSCs for stem cell therapy. Current MSC culture methods have resulted in reduced self-renewal of MSCs and compromised therapeutic outcomes. This study identifies that nicotinamide mononucleotide (NMN), a key natural NAD+ intermediate, effectively encourages MSC expansion in vitro and in vivo. The in vitro expanded MSCs had heightened osteogenesis, but reduced adipogenesis. Furthermore, NMN supplementation stimulated osteogenesis of endogenous MSCs, and protected bone from aging and irradiation induced damage in mice. Mechanistically, we found that NMN treatment upregulated SIRT1. Genetically overexpressing SIRT1 in MSCs by using Prx1 cre; ColA1flox-stop-flox-SIRT1 mice promoted osteogenesis and reduced adipogenesis in aged mice. Overall, our data demonstrate that NMN promoted MSC self-renewal with strengthened osteogenesis and reduced adipogenesis via upregulating SIRT1 in aged mice.
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Affiliation(s)
- Jie Song
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Jing Li
- Guangdong-Hongkong-Macau Institute of CNS Regeneration, Ministry of Education CNS Regeneration Collaborative Joint Laboratory, Jinan University, Guangzhou, China
| | - Fangji Yang
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Gang Ning
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Limin Zhen
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Lina Wu
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Yongyuan Zheng
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Qi Zhang
- Cell-Gene Therapy Translational Medicine Research Center, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Dongjun Lin
- Department of Haematology, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, China.
| | - Chan Xie
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
| | - Liang Peng
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
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31
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Bae HK, Jung BD, Lee S, Park CK, Yang BK, Cheong HT. Correlation of spontaneous adipocyte generation with osteogenic differentiation of porcine skin-derived stem cells. J Vet Sci 2019; 20:16-26. [PMID: 30481989 PMCID: PMC6351758 DOI: 10.4142/jvs.2019.20.1.16] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2018] [Revised: 10/18/2018] [Accepted: 11/06/2018] [Indexed: 12/13/2022] Open
Abstract
The objective of this study was to examine effects of spontaneous adipocyte generation on osteogenic differentiation of porcine skin-derived stem cells (pSSCs). Correlation between osteogenic differentiation and adipocyte differentiation induced by osteocyte induction culture was determined using different cell lines. Osteogenic differentiation efficiency of pSSCs was then analyzed by controlling the expression of adipocyte-specific transcription factors during osteogenic induction culture. Among four cell lines, pSSCs-II had the lowest lipid droplet level but the highest calcium content (p < 0.05). It also expressed significantly low levels of peroxisome proliferator-activated receptor gamma 2 (PPARγ2) and adipocyte protein 2 (aP2) mRNAs but very high levels of runt-related transcription factor 2 (Runx2) and alkaline phosphatase (ALP) mRNAs as osteogenic makers (p < 0.05). Oil red O extraction was increased by 0.1 µM troglitazone (TGZ) treatment but decreased by 50 µM bisphenol A diglycidyl ether (BADGE) (p < 0.05). Calcium content was drastically increased after BADGE treatment compared to that in osteogenic induction control and TGZ-treated pSSCs (p < 0.05). Relative expression levels of PPARγ2 and aP2 mRNAs were increased by TGZ but decreased by BADGE. Expression levels of Rucx2 and ALP mRNAs, osteoblast-specific marker genes, were significantly increased by BADGE treatment (p < 0.05). The expression level of BCL2 like 1 was significantly higher in BADGE-treated pSSCs than that in TGZ-treated ones (p < 0.05). The results demonstrate that spontaneous adipocyte generation does not adversely affect osteogenic differentiation. However, reducing spontaneous adipocyte generation by inhibiting PPARγ2 mRNA expression can enhance in vitro osteogenic differentiation of pSSCs.
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Affiliation(s)
- Hyo-Kyung Bae
- College of Veterinaryy Medicine and Institute of Veterinary Science, Kangwon National University, Chuncheon 24341, Korea
| | - Bae-Dong Jung
- College of Veterinaryy Medicine and Institute of Veterinary Science, Kangwon National University, Chuncheon 24341, Korea
| | - Seunghyung Lee
- College of Animal Life Sciences, Kangwon National University, Chuncheon 24341, Korea
| | - Choon-Keun Park
- College of Animal Life Sciences, Kangwon National University, Chuncheon 24341, Korea
| | - Boo-Keun Yang
- College of Animal Life Sciences, Kangwon National University, Chuncheon 24341, Korea
| | - Hee-Tae Cheong
- College of Veterinaryy Medicine and Institute of Veterinary Science, Kangwon National University, Chuncheon 24341, Korea
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Chen X, Hua W, Huang X, Chen Y, Zhang J, Li G. Regulatory Role of RNA N 6-Methyladenosine Modification in Bone Biology and Osteoporosis. Front Endocrinol (Lausanne) 2019; 10:911. [PMID: 31998240 PMCID: PMC6965011 DOI: 10.3389/fendo.2019.00911] [Citation(s) in RCA: 69] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Accepted: 12/13/2019] [Indexed: 12/26/2022] Open
Abstract
Osteoporosis is a metabolic skeletal disorder in which bone mass is depleted and bone structure is destroyed to the degree that bone becomes fragile and prone to fractures. Emerging evidence suggests that N6-methyladenosine (m6A) modification, a novel epitranscriptomic marker, has a significant role in bone development and metabolism. M6A modification not only participates in bone development, but also plays important roles as writers and erasers in the osteoporosis. M6A methyltransferase METTL3 and demethyltransferase FTO involves in the delicate process between adipogenesis differentiation and osteogenic differentiation, which is important for the pathological development of osteoporosis. Conditional knockdown of the METTL3 in bone marrow stem cells (BMSCs) could suppress PI3K-Akt signaling, limit the expression of bone formation-related genes (such as Runx2 and Osterix), restrain the expression of vascular endothelial growth factor (VEGF) and down-regulate the decreased translation efficiency of parathyroid hormone receptor-1 mRNA. Meanwhile, knockdown of the METTL3 significantly promoted the adipogenesis process and janus kinase 1 (JAK1) protein expression via an m6A-dependent way. Specifically, there was a negative correlation between METTL3 expression and porcine BMSCs adipogenesis. The evidence above suggested that the relationship between METTL3 expression and adipogenesis was inverse, and osteogenesis was positive, respectively. Similarly, FTO regulated for BMSCs fate determination during osteoporosis through the GDF11-FTO-PPARγ axis, prompting the shift of MSC lineage commitment to adipocyte and inhibiting bone formation during osteoporosis. In this systematic review, we summarize the most up-to-date evidence of m6A RNA modification in osteoporosis and highlight the potential role of m6A in prevention, treatment, and management of osteoporosis.
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Affiliation(s)
- Xuejiao Chen
- Center for Clinical Epidemiology and Methodology (CCEM), Guangdong Second Provincial General Hospital, Guangzhou, China
| | - Wenfeng Hua
- Department of Laboratory Medicine and Central Laboratories, Guangdong Second Provincial General Hospital, Guangzhou, China
| | - Xin Huang
- Center for Clinical Epidemiology and Methodology (CCEM), Guangdong Second Provincial General Hospital, Guangzhou, China
| | - Yuming Chen
- Department of Medical Statistics and Epidemiology, School of Public Health, Sun Yat-sen University, Guangzhou, China
| | - Junguo Zhang
- Center for Clinical Epidemiology and Methodology (CCEM), Guangdong Second Provincial General Hospital, Guangzhou, China
| | - Guowei Li
- Center for Clinical Epidemiology and Methodology (CCEM), Guangdong Second Provincial General Hospital, Guangzhou, China
- Department of Health Research Methods, Evidence, and Impact (HEI), McMaster University, Hamilton, ON, Canada
- *Correspondence: Guowei Li
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33
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Wilson A, Fu H, Schiffrin M, Winkler C, Koufany M, Jouzeau JY, Bonnet N, Gilardi F, Renevey F, Luther SA, Moulin D, Desvergne B. Lack of Adipocytes Alters Hematopoiesis in Lipodystrophic Mice. Front Immunol 2018; 9:2573. [PMID: 30483254 PMCID: PMC6244608 DOI: 10.3389/fimmu.2018.02573] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2018] [Accepted: 10/18/2018] [Indexed: 12/14/2022] Open
Abstract
Adult hematopoiesis takes place in the perivascular zone of the bone cavity, where endothelial cells, mesenchymal stromal/stem cells and their derivatives such as osteoblasts are key components of bone marrow (BM) niches. Defining the contribution of BM adipocytes to the hematopoietic stem cell niche remains controversial. While an excess of medullar adiposity is generally considered deleterious for hematopoiesis, an active role for adipocytes in shaping the niche has also been proposed. We thus investigated the consequences of total adipocyte deletion, including in the BM niche, on adult hematopoiesis using mice carrying a constitutive deletion of the gene coding for the nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ). We show that Pparg Δ/Δ lipodystrophic mice exhibit severe extramedullary hematopoiesis (EMH), which we found to be non-cell autonomous, as it is reproduced when wild-type donor BM cells are transferred into Pparg Δ/Δ recipients. This phenotype is not due to a specific alteration linked to Pparg deletion, such as chronic inflammation, since it is also found in AZIPtg/+ mice, another lipodystrophic mouse model with normal PPARγ expression, that display only very moderate levels of inflammation. In both models, the lack of adipocytes alters subpopulations of both myeloid and lymphoid cells. The CXCL12/CXCR4 axis in the BM is also dysregulated in an adipocyte deprived environment supporting the hypothesis that adipocytes are required for normal hematopoietic stem cell mobilization or retention. Altogether, these data suggest an important role for adipocytes, and possibly for the molecular interactions they provide within the BM, in maintaining the appropriate microenvironment for hematopoietic homeostasis.
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Affiliation(s)
- Anne Wilson
- Department of Oncology, University of Lausanne, Epalinges, Switzerland
| | - He Fu
- Faculty of Biology and Medicine, Center for Integrative Genomics, Genopode, University of Lausanne, Lausanne, Switzerland
| | - Mariano Schiffrin
- Faculty of Biology and Medicine, Center for Integrative Genomics, Genopode, University of Lausanne, Lausanne, Switzerland
| | - Carine Winkler
- Faculty of Biology and Medicine, Center for Integrative Genomics, Genopode, University of Lausanne, Lausanne, Switzerland
| | - Meriem Koufany
- IMoPA, UMR7365 CNRS-Université de Lorraine, Vandœuvre-lès-Nancy, France
| | - Jean-Yves Jouzeau
- IMoPA, UMR7365 CNRS-Université de Lorraine, Vandœuvre-lès-Nancy, France
| | - Nicolas Bonnet
- Division of Bone Diseases, Department of Internal Medicine Specialties, Faculty of Medicine, Geneva University Hospital, Geneva, Switzerland
| | - Federica Gilardi
- Faculty of Biology and Medicine, Center for Integrative Genomics, Genopode, University of Lausanne, Lausanne, Switzerland
| | - François Renevey
- Department of Biochemistry, Center for Immunity and Infection, University of Lausanne, Epalinges, Switzerland
| | - Sanjiv A Luther
- Department of Biochemistry, Center for Immunity and Infection, University of Lausanne, Epalinges, Switzerland
| | - David Moulin
- IMoPA, UMR7365 CNRS-Université de Lorraine, Vandœuvre-lès-Nancy, France.,CHRU de Nancy, Contrat d'interface, Vandœuvre-lès-Nancy, France
| | - Béatrice Desvergne
- Faculty of Biology and Medicine, Center for Integrative Genomics, Genopode, University of Lausanne, Lausanne, Switzerland
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34
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Piuzzi NS, Mantripragada VP, Sumski A, Selvam S, Boehm C, Muschler GF. Bone Marrow-Derived Cellular Therapies in Orthopaedics. JBJS Rev 2018; 6:e4. [PMID: 30461435 DOI: 10.2106/jbjs.rvw.18.00007] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
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35
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Park S, Na W, Sohn C. Relationship between osteosarcopenic obesity and dietary inflammatory index in postmenopausal Korean women: 2009 to 2011 Korea National Health and Nutrition Examination Surveys. J Clin Biochem Nutr 2018; 63:211-216. [PMID: 30487671 PMCID: PMC6252300 DOI: 10.3164/jcbn.18-10] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2018] [Accepted: 02/21/2018] [Indexed: 12/31/2022] Open
Abstract
Osteosarcopenic obesity syndrome is a condition including osteopenia, sarcopenia and obesity. A pro-inflammatory dietary pattern has been reported to be associated with obesity and osteoporosis. However, studies on the association of dietary inflammatory index with osteosarcopenic obesity syndrome in the Korean population are lacking. The aim of this study was to analyze the relationship between dietary inflammatory index and osteosarcopenic obesity syndrome among Korean postmenopausal women. We analyzed the 2009-2011 Korea National Health and Nutrition Examination Survey, consisting of 1,344 postmenopausal women aged 50 years or older. Body composition was evaluated by dual-energy X-ray absorptiometry. Dietary inflammatory index was estimated after analyzing 36 nutrients and 9 foods using a 24-h dietary recall data. The association between dietary inflammatory index levels and the body composition was analyzed by logistic regression models with dietary inflammatory index fit as a dichotomous variable. The dietary inflammatory index was -0.96 ± 0.22 in the normal group, 0.12 ± 0.16 in the osteopenic obesity group, 0.00 ± 0.18 in the osteosarcopenia group, 0.12 ± 0.33 in the sarcopenic obesity group, and -0.02 ± 0.14 in the osteosarcopenic obesity group (p<0.001). After adjusting for potential covariates, women with higher dietary inflammatory index scores were more likely to have risk of osteopenic obesity (OR = 2.757, 95% CI: 1.398-5.438, p<0.01) and that of osteosarcopenic obesity (OR = 2.186, 95% CI: 1.182-4.044, p<0.05). The results indicate that pro-inflammatory diet was associate with increased odds of the osteosarcopenic obesity in postmenopausal Korean women. Therefore, studies are needed to identify the effects of anti-inflammatory diets, which can reduce the degree of inflammation through dietary intake.
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Affiliation(s)
- Susan Park
- Department of Food and Nutrition, Wonkwang University, Iksan-daero, 460, Iksan, Jeonbuk 54538, Korea
| | - Woori Na
- Department of Food and Nutrition, Wonkwang University, Iksan-daero, 460, Iksan, Jeonbuk 54538, Korea
| | - Cheongmin Sohn
- Department of Food and Nutrition, Wonkwang University, Iksan-daero, 460, Iksan, Jeonbuk 54538, Korea
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Abstract
The emergence of bone as an endocrine organ able to influence whole body metabolism, together with comorbid epidemics of obesity, diabetes, and osteoporosis, have prompted a renewed interest in the intermediary metabolism of the osteoblast. To date, most studies have focused on the utilization of glucose by this specialized cell, but the oxidation of fatty acids results in a larger energy yield. Osteoblasts express the requisite receptors and catabolic enzymes to take up and then metabolize fatty acids, which appears to be required during later stages of differentiation when the osteoblast is dedicated to matrix production and mineralization. In this article, we provide an overview of fatty acid β-oxidation and highlight studies demonstrating that the skeleton plays a significant role in the clearance of circulating lipoproteins and non-esterified fatty acids. Additionally, we review the requirement for long-chain fatty acid metabolism during post-natal bone development and the effects of anabolic stimuli on fatty acid utilization by osteoblasts. These recent findings may help to explain the skeletal manifestations of human diseases associated with impaired lipid metabolism while also providing additional insights into the metabolic requirements of skeletal homeostasis.
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Affiliation(s)
- Priyanka Kushwaha
- Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Michael J Wolfgang
- Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Ryan C Riddle
- Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Baltimore Veterans Administration Medical Center, Baltimore, MD, USA.
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37
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Correa-Rodríguez M, Schmidt-RioValle J, Rueda-Medina B. SOX6 rs7117858 polymorphism is associated with osteoporosis and obesity-related phenotypes. Eur J Clin Invest 2018; 48:e13011. [PMID: 30062780 DOI: 10.1111/eci.13011] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2018] [Accepted: 07/29/2018] [Indexed: 12/16/2022]
Abstract
BACKGROUND SOX6 has been recently proposed as a pleiotropic gene for obesity and osteoporosis. The aim of this study was to investigate whether the rs7117858 genetic variant in SOX6 was associated with bone mass assessed by quantitative ultrasound (QUS) and obesity-related measures in a population of young adults. METHODS A cross-sectional study was conducted in 550 unrelated healthy individuals of Caucasian ancestry (381 (69.3%) female and 169 (30.7%) male; mean age 20.46 ± 2.69). Bone mass was assessed through calcaneal QUS) parameter (BUA, dB/MHz). Obesity-related traits including weight, body mass index (BMI), fat mass (FM) and fat-free mass (FFM) were analysed. RESULTS The linear regression analysis revealed that the rs7117858 SNP was significantly associated with FFM after adjustments for covariables in the whole sample (P = 0.027, β (95% CI) = 0.053 (0.092, 1.516). In addition, a significant association with QUS measurement adjusted for confounding factors was found in females (P = 0.043, β (95% CI) = 0.104 (0.138. 8.384). CONCLUSIONS We demonstrate for the first time that SOX6 influence FFM and QUS trait in a population of young adults, suggesting the implication of this gene in obesity and osteoporosis-related phenotypes during early adulthood.
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Affiliation(s)
- María Correa-Rodríguez
- Department of Nursing, Faculty of Health Sciences, University of Granada, Granada, Spain.,Instituto Investigación Biosanitaria, IBS, Granada, Spain
| | - Jacqueline Schmidt-RioValle
- Department of Nursing, Faculty of Health Sciences, University of Granada, Granada, Spain.,Centro de Investigación Mente, Cerebro y Comportamiento (CIMCYC), University of Granada, Granada, Spain
| | - Blanca Rueda-Medina
- Department of Nursing, Faculty of Health Sciences, University of Granada, Granada, Spain.,Instituto Investigación Biosanitaria, IBS, Granada, Spain
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38
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Hassanshahi M, Su Y, Fan C, Khabbazi S, Hassanshahi A, Xian CJ. Methotrexate chemotherapy–induced damages in bone marrow sinusoids: An in vivo and in vitro study. J Cell Biochem 2018. [DOI: 10.1002/jcb.27589] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Affiliation(s)
- Mohammadhossein Hassanshahi
- School of Pharmacy and Medical Sciences, UniSA Cancer Research Institute, University of South Australia Adelaide Australia
| | - Yu‐Wen Su
- School of Pharmacy and Medical Sciences, UniSA Cancer Research Institute, University of South Australia Adelaide Australia
| | - Chia‐Ming Fan
- School of Pharmacy and Medical Sciences, UniSA Cancer Research Institute, University of South Australia Adelaide Australia
| | - Samira Khabbazi
- School of Pharmacy and Medical Sciences, UniSA Cancer Research Institute, University of South Australia Adelaide Australia
| | - Alireza Hassanshahi
- Department of Biology Shahrekord Branch, Islamic Azad University Shahrekord Iran
| | - Cory J. Xian
- School of Pharmacy and Medical Sciences, UniSA Cancer Research Institute, University of South Australia Adelaide Australia
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40
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Dubey NK, Mishra VK, Dubey R, Deng YH, Tsai FC, Deng WP. Revisiting the Advances in Isolation, Characterization and Secretome of Adipose-Derived Stromal/Stem Cells. Int J Mol Sci 2018; 19:ijms19082200. [PMID: 30060511 PMCID: PMC6121360 DOI: 10.3390/ijms19082200] [Citation(s) in RCA: 80] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Revised: 07/08/2018] [Accepted: 07/24/2018] [Indexed: 12/13/2022] Open
Abstract
Adipose-derived stromal/stem cells (ASCs) seems to be a promising regenerative therapeutic agent due to the minimally invasive approach of their harvest and multi-lineage differentiation potential. The harvested adipose tissues are further digested to extract stromal vascular fraction (SVF), which is cultured, and the anchorage-dependent cells are isolated in order to characterize their stemness, surface markers, and multi-differentiation potential. The differentiation potential of ASCs is directed through manipulating culture medium composition with an introduction of growth factors to obtain the desired cell type. ASCs have been widely studied for its regenerative therapeutic solution to neurologic, skin, wound, muscle, bone, and other disorders. These therapeutic outcomes of ASCs are achieved possibly via autocrine and paracrine effects of their secretome comprising of cytokines, extracellular proteins and RNAs. Therefore, secretome-derivatives might offer huge advantages over cells through their synthesis and storage for long-term use. When considering the therapeutic significance and future prospects of ASCs, this review summarizes the recent developments made in harvesting, isolation, and characterization. Furthermore, this article also provides a deeper insight into secretome of ASCs mediating regenerative efficacy.
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Affiliation(s)
- Navneet Kumar Dubey
- Ceramics and Biomaterials Research Group, Advanced Institute of Materials Science, Ton Duc Thang University, Ho Chi Minh City 700000, Vietnam.
- Faculty of Applied Sciences, Ton Duc Thang University, Ho Chi Minh City 700000, Vietnam.
| | - Viraj Krishna Mishra
- Applied Biotech Engineering Centre (ABEC), Department of Biotechnology, Ambala College of Engineering and Applied Research, Ambala 133101, India.
| | - Rajni Dubey
- Graduate Institute Food Science and Technology, National Taiwan University, Taipei 10617, Taiwan.
| | - Yue-Hua Deng
- Stem Cell Research Center, Taipei Medical University, Taipei 11031, Taiwan.
- Department of Life Science, Fu Jen Catholic University, New Taipei City 24205, Taiwan.
| | - Feng-Chou Tsai
- School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei 11031, Taiwan.
| | - Win-Ping Deng
- Stem Cell Research Center, Taipei Medical University, Taipei 11031, Taiwan.
- School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei 11031, Taiwan.
- Department of Basic medicine, Fu-Jen Catholic University, New Taipei City 24205, Taiwan.
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41
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Tencerova M, Figeac F, Ditzel N, Taipaleenmäki H, Nielsen TK, Kassem M. High-Fat Diet-Induced Obesity Promotes Expansion of Bone Marrow Adipose Tissue and Impairs Skeletal Stem Cell Functions in Mice. J Bone Miner Res 2018; 33:1154-1165. [PMID: 29444341 DOI: 10.1002/jbmr.3408] [Citation(s) in RCA: 169] [Impact Index Per Article: 24.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2017] [Revised: 02/08/2018] [Accepted: 02/09/2018] [Indexed: 12/11/2022]
Abstract
Obesity represents a risk factor for development of insulin resistance and type 2 diabetes. In addition, it has been associated with increased adipocyte formation in the bone marrow (BM) along with increased risk for bone fragility fractures. However, little is known on the cellular mechanisms that link obesity, BM adiposity, and bone fragility. Thus, in an obesity intervention study in C57BL/6J mice fed with a high-fat diet (HFD) for 12 weeks, we investigated the molecular and cellular phenotype of bone marrow adipose tissue (BMAT), BM progenitor cells, and BM microenvironment in comparison to peripheral adipose tissue (AT). HFD decreased trabecular bone mass by 29%, cortical thickness by 5%, and increased BM adiposity by 184%. In contrast to peripheral AT, BMAT did not exhibit pro-inflammatory phenotype. BM progenitor cells isolated from HFD mice exhibited decreased mRNA levels of inflammatory genes (Tnfα, IL1β, Lcn2) and did not manifest an insulin resistant phenotype evidenced by normal levels of pAKT after insulin stimulation as well as normal levels of insulin signaling genes. In addition, BM progenitor cells manifested enhanced adipocyte differentiation in HFD condition. Thus, our data demonstrate that BMAT expansion in response to HFD exerts a deleterious effect on the skeleton. Continuous recruitment of progenitor cells to adipogenesis leads to progenitor cell exhaustion, decreased recruitment to osteoblastic cells, and decreased bone formation. In addition, the absence of insulin resistance and inflammation in the BM suggest that BMAT buffers extra energy in the form of triglycerides and thus plays a role in whole-body energy homeostasis. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc.
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Affiliation(s)
- Michaela Tencerova
- Department of Molecular Endocrinology, KMEB, University of Southern Denmark and Odense University Hospital, Odense C, Denmark.,Danish Diabetes Academy, Odense C, Denmark
| | - Florence Figeac
- Department of Molecular Endocrinology, KMEB, University of Southern Denmark and Odense University Hospital, Odense C, Denmark
| | - Nicholas Ditzel
- Department of Molecular Endocrinology, KMEB, University of Southern Denmark and Odense University Hospital, Odense C, Denmark
| | - Hanna Taipaleenmäki
- Molecular Skeletal Biology Laboratory, Department of Trauma, Hand, and Reconstructive Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Tina Kamilla Nielsen
- Department of Molecular Endocrinology, KMEB, University of Southern Denmark and Odense University Hospital, Odense C, Denmark
| | - Moustapha Kassem
- Department of Molecular Endocrinology, KMEB, University of Southern Denmark and Odense University Hospital, Odense C, Denmark.,Department of Cellular and Molecular Medicine, Danish Stem Cell Center (DanStem), University of Copenhagen, Copenhagen, Denmark.,Stem Cell Unit, Department of Anatomy, Faculty of Medicine, King Saud University, Kingdom of Saudi Arabia
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42
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Association between circulatory levels of adipokines and bone mineral density in postmenopausal women. Menopause 2018; 23:984-92. [PMID: 27433863 DOI: 10.1097/gme.0000000000000655] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVE Epidemiological evidence indicates that excess fat may be beneficial for bone health, offering protective effects against the onset of postmenopausal osteoporosis. Experimental data suggest that this link might be due to the direct effect of adipokines on bone tissue. Confirmatory evidence of this association, however, remains limited. METHODS The levels of a panel of selected adipokines including interleukin (IL)-6, -8, -1β, adipsin, lipocalin-2/neutrophil gelatinase-associated ipocalin, tumor necrosis factor alpha, monocyte chemoattractant protein-1, plasminogen activator inhibitor-1, hepatocyte growth factor, resistin, leptin, and adiponectin in a group of osteopenic and osteoporotic postmenopausal women were compared with those of unaffected women (n = 127). RESULTS Univariate analysis revealed that leptin and adiponectin were significantly correlated with bone mineral density (BMD). In particular, leptin was positively associated with BMD of the spine (r = 0.22, P < 0.05), femoral neck (r = 0.23, P < 0.05), trochanter (r = 0.20, P < 0.05), and total hip (r = 0.27, P < 0.01), whereas adiponectin was inversely correlated with BMD at the trochanter (r = -0.21, P < 0.05). No correlations were, however, significant after adjusting for body fat variables. Stratification of the sample according to IL-6 levels revealed that adiponectin remained significantly inversely associated with BMD, regardless of fat levels and age (β=-0.29, P < 0.05; r = 0.198) in the subgroup of participants with low levels of IL-6. CONCLUSIONS Our data suggest that circulating adiponectin is inversely associated with markers of bone health in postmenopausal women, and that the interaction is influenced by IL-6 levels.
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43
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Mattiucci D, Maurizi G, Izzi V, Cenci L, Ciarlantini M, Mancini S, Mensà E, Pascarella R, Vivarelli M, Olivieri A, Leoni P, Poloni A. Bone marrow adipocytes support hematopoietic stem cell survival. J Cell Physiol 2018; 233:1500-1511. [PMID: 28574591 DOI: 10.1002/jcp.26037] [Citation(s) in RCA: 74] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2017] [Accepted: 06/01/2017] [Indexed: 12/23/2022]
Abstract
In bone marrow (BM), hematopoietic elements are mingled with adipocytes (BM-A), which are the most abundant stromal component in the niche. BM-A progressively increase with aging, eventually occupying up to 50% of BM cavities. In this work, the role played by BM-A was explored by studying primary human BM-A isolated from hip surgery patients at the molecular level, through microarray analysis, and at the functional level, by assessing their relationship with primary human hematopoietic stem cells (HSC) by the long-term culture initiating cell (LTC-IC) assay. Findings demonstrated that BM-A are capable of supporting HSC survival in the LTC-IC assay, since after 5 weeks of co-culture, HSC were still able to proliferate and differentiate. Furthermore, critical molecules such as C-X-C motif chemokine 12 (CXCL12), interleukin (IL)-8, colony-stimulating factor 3 (CSF3), and leukaemia inhibitory factor (LIF), were expressed at similar levels in BM-A and in primary human BM mesenchymal stromal cells (BM-MSC), whereas IL-3 was higher in BM-A. Interestingly, BM-A displayed a different gene expression profile compared with subcutaneous adipose tissue adipocytes (AT-A) collected from abdominal surgery patients, especially in terms of regulation of lipid metabolism, stemness genes, and white-to-brown differentiation pathways. Accordingly, analysis of the gene pathways involved in hematopoiesis regulation showed that BM-A are more closely related to BM-MSC than to AT-A. The present data suggest that BM-A play a supporting role in the hematopoietic niche and directly sustain HSC survival.
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Affiliation(s)
- Domenico Mattiucci
- Dipartimento Scienze Cliniche e Molecolari, Clinica di Ematologia, Università Politecnica delle Marche, Ancona, Italy
| | - Giulia Maurizi
- Dipartimento Scienze Cliniche e Molecolari, Clinica di Ematologia, Università Politecnica delle Marche, Ancona, Italy
| | - Valerio Izzi
- Faculty of Biochemistry and Molecular Medicine, Center for Cell-Matrix Research and Biocenter Oulu, University of Oulu, Oulu, Finland
| | - Lorenzo Cenci
- Dipartimento Scienze Cliniche e Molecolari, Clinica di Ematologia, Università Politecnica delle Marche, Ancona, Italy
| | - Marco Ciarlantini
- Dipartimento Scienze Cliniche e Molecolari, Clinica di Ematologia, Università Politecnica delle Marche, Ancona, Italy
| | - Stefania Mancini
- Dipartimento Scienze Cliniche e Molecolari, Clinica di Ematologia, Università Politecnica delle Marche, Ancona, Italy
| | - Emanuela Mensà
- Cardiology Unit, Italian National Research Center on Aging (INRCA-IRCCS), Experimental Models in Clinical Pathology, INRCA-IRCCS National Institute, Ancona, Italy
| | | | - Marco Vivarelli
- Hepatobiliary and Abdominal Transplantation Surgery, Department of Experimental and Clinical Medicine, Università Politecnica delle Marche, Ancona, Italy
| | - Attilio Olivieri
- Dipartimento Scienze Cliniche e Molecolari, Clinica di Ematologia, Università Politecnica delle Marche, Ancona, Italy
| | - Pietro Leoni
- Dipartimento Scienze Cliniche e Molecolari, Clinica di Ematologia, Università Politecnica delle Marche, Ancona, Italy
| | - Antonella Poloni
- Dipartimento Scienze Cliniche e Molecolari, Clinica di Ematologia, Università Politecnica delle Marche, Ancona, Italy
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44
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Yang Y, Fang S. Small non-coding RNAs-based bone regulation and targeting therapeutic strategies. Mol Cell Endocrinol 2017; 456:16-35. [PMID: 27888003 PMCID: PMC7116989 DOI: 10.1016/j.mce.2016.11.018] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2016] [Revised: 11/06/2016] [Accepted: 11/21/2016] [Indexed: 01/08/2023]
Abstract
Small non-coding RNAs, which are 20-25 nucleotide ribonucleic acids, have emerged as an important transformation in the biological evolution over almost three decades. microRNAs (miRNAs) and short interfering RNAs (siRNAs) are two significant categories of the small RNAs that exert important effects on bone endocrinology and skeletology. Therefore, clarifying the expression and function of these important molecules in bone endocrine physiology and pathology is of great significance for improving their potential therapeutic value for metabolism-associated bone diseases. In the present review, we highlight the recent advances made in understanding the function and molecular mechanism of these small non-coding RNAs in bone metabolism, especially their potentially therapeutic values in bone-related diseases.
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Affiliation(s)
- Ying Yang
- Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai JiaoTong University, School of Medicine, Shanghai, China
| | - Sijie Fang
- Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai JiaoTong University, School of Medicine, Shanghai, China.
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45
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Abdalrahaman N, McComb C, Foster JE, Lindsay RS, Drummond R, McKay GA, Perry CG, Ahmed SF. The relationship between adiposity, bone density and microarchitecture is maintained in young women irrespective of diabetes status. Clin Endocrinol (Oxf) 2017; 87:327-335. [PMID: 28656591 DOI: 10.1111/cen.13410] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2017] [Revised: 05/31/2017] [Accepted: 06/24/2017] [Indexed: 12/26/2022]
Abstract
BACKGROUND The relationship between bone health and adiposity and how it may be affected in people with chronic metabolic conditions is complex. METHODS Seventeen women with type 1 diabetes mellitus (T1DM) and nine age-matched healthy women with a median age of 22.6 years (range, 17.4, 23.8) were studied by 3T MRI and MR spectroscopy to assess abdominal adiposity, tibial bone microarchitecture and vertebral bone marrow adiposity (BMA). Additional measures included DXA-based assessments of total body (TB), femoral neck (FN) and lumbar spine (LS) bone mineral density (BMD) and fat mass (FM). RESULTS Although women with T1DM had similar BMI and BMA to the controls, they had higher visceral and subcutaneous adiposity on MRI (P<.05) and total body FM by DXA (P=.03). Overall, in the whole cohort, a clear inverse association was evident between BMA and BMD at all sites (P<.05). These associations remained significant after adjusting for age, BMI, FM and abdominal adiposity. In addition, visceral adiposity, but not subcutaneous adiposity, showed a positive association with BMA (r, .4, P=.03), and a negative association with total body BMD (r, .5, P=.02). Apparent trabecular separation as assessed by MRI showed an inverse association to total body BMD by DXA (r, -.4, P=.04). CONCLUSION Irrespective of the presence of an underlying metabolic condition, young women display a negative relationship between MRI-measured BMA and DXA-based assessment of BMD. Furthermore, an association between BMA and visceral adiposity supports the notion of a common origin of these two fat depots.
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Affiliation(s)
- N Abdalrahaman
- Developmental Endocrinology Research Group, School of Medicine, University of Glasgow, Glasgow, UK
| | - C McComb
- Clinical Physics, NHS Greater Glasgow & Clyde, Glasgow, UK
- BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK
| | - J E Foster
- Clinical Physics, NHS Greater Glasgow & Clyde, Glasgow, UK
- BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK
| | - R S Lindsay
- BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK
- Stobhill Diabetes Centre, Stobhill Hospital, Glasgow, UK
| | - R Drummond
- Stobhill Diabetes Centre, Stobhill Hospital, Glasgow, UK
| | - G A McKay
- Stobhill Diabetes Centre, Stobhill Hospital, Glasgow, UK
| | - C G Perry
- Stobhill Diabetes Centre, Stobhill Hospital, Glasgow, UK
| | - S F Ahmed
- Developmental Endocrinology Research Group, School of Medicine, University of Glasgow, Glasgow, UK
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46
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Ho L, Wang L, Roth TM, Pan Y, Verdin EM, Hsiao EC, Nissenson RA. Sirtuin-3 Promotes Adipogenesis, Osteoclastogenesis, and Bone Loss in Aging Male Mice. Endocrinology 2017; 158:2741-2753. [PMID: 28911171 PMCID: PMC5659662 DOI: 10.1210/en.2016-1739] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2016] [Accepted: 07/05/2017] [Indexed: 12/22/2022]
Abstract
Sirtuin-3 (Sirt3) is an essential metabolic regulatory enzyme that plays an important role in mitochondrial metabolism, but its role in bone marrow and skeletal homeostasis remains largely unknown. In this study, we hypothesize that increased expression of Sirt3 plays a role in skeletal aging. Using mice that overexpress Sirt3 [i.e., Sirt3 transgenic (Sirt3Tg)], we show that Sirt3 is a positive regulator of adipogenesis and osteoclastogenesis and a negative regulator of skeletal homeostasis. Sirt3Tg mice exhibited more adipocytes in the tibia compared with control mice. Bone marrow stromal cells (BMSCs) from Sirt3Tg mice displayed an enhanced ability to differentiate into adipocytes compared with control BMSCs. We found a 2.5-fold increase in the number of osteoclasts on the bone surface in Sirt3Tg mice compared with control mice (P < 0.03), and increased osteoclastogenesis in vitro. Importantly, Sirt3 activates the mechanistic target of rapamycin (mTOR) pathway to regulate osteoclastogenesis. Sirt3Tg male mice exhibited a significant reduction in cortical thickness at the tibiofibular junction (P < 0.05). In summary, Sirt3 activity in bone marrow cells is associated with increased adipogenesis, increased osteoclastogenesis through activation of mTOR signaling, and reduced bone mass. Interestingly, Sirt3 expression in bone marrow cells increases during aging, suggesting that Sirt3 promotes age-related adipogenesis and osteoclastogenesis associated with bone loss. These findings identify Sirt3 as an important regulator of adipogenesis and skeletal homeostasis in vivo and identify Sirt3 as a potential target for the treatment of osteoporosis.
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Affiliation(s)
- Linh Ho
- Endocrine Research Unit, VA Medical Center and Departments of Medicine and Physiology, University of California, San Francisco, San Francisco, California 94158
| | - Liping Wang
- Endocrine Research Unit, VA Medical Center and Departments of Medicine and Physiology, University of California, San Francisco, San Francisco, California 94158
| | - Theresa M. Roth
- Endocrine Research Unit, VA Medical Center and Departments of Medicine and Physiology, University of California, San Francisco, San Francisco, California 94158
| | - Yong Pan
- Gladstone Institutes, University of California, San Francisco, San Francisco, California 94941
| | - Eric M. Verdin
- Gladstone Institutes, University of California, San Francisco, San Francisco, California 94941
| | - Edward C. Hsiao
- Division of Endocrinology and Metabolism, Institute for Human Genetics, University of California, San Francisco, San Francisco, California 94143
| | - Robert A. Nissenson
- Endocrine Research Unit, VA Medical Center and Departments of Medicine and Physiology, University of California, San Francisco, San Francisco, California 94158
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47
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Bani-Ahmad MA, Khabour OF, Gharibeh MY, Alshlool KN. The impact of multiple blood donations on the risk of cardiovascular diseases: Insight of lipid profile. Transfus Clin Biol 2017; 24:410-416. [PMID: 28797569 DOI: 10.1016/j.tracli.2017.07.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2016] [Accepted: 07/04/2017] [Indexed: 12/29/2022]
Abstract
OBJECTIVES The reduction in blood viscosity and iron store were proposed to be connected to the reduction in the risk of cardiovascular disease (CVD) among multiple blood donors. Herein, we evaluated the modulation of serum lipids levels in accordance with donation events. Furthermore, atherogenic impacts on the risk of CVD were investigated. MATERIALS AND METHODS A total of 100 voluntarily male donors were included in the study. Fifty donors were multiple time donors (MTD) and 50 were single time donors (STD). Levels of serum lipids were determined and atherogenic indices including TG/HDL and CHO/HDL ratios were calculated. QRISK2 parameters were determined to evaluate the 10-years risk of developing CVD. RESULTS Among MTD, there were significantly higher serum levels of triglycerides (TG) and very low-density lipoproteins (VLDL) combined with significantly lower HDL level. These modulations were significantly correlated to the extent of donation. Both CHO/HDL and TG/HDL ratios were also significantly higher among MTD. However, only TG/HDL ratio was strongly correlated to the donation extent even when controlled for age, BMI and smoking status. Despite the significant difference in QRISK2 parameters between study groups, none of these parameters was correlated to the extent of donation when controlling for age, BMI and smoking status. CONCLUSION We demonstrate that multiple blood donation is associated with an unfavorable modulation of serum levels of lipids that is influenced by donation extent. This modulation is not associated with an increased risk of CVD but may weakly contribute in a higher risk for coronary heart disease (CHD).
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Affiliation(s)
- M A Bani-Ahmad
- Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, Jordan University of Science and Technology, P.O. Box 3030, 22110 Irbid, Jordan.
| | - O F Khabour
- Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, Jordan University of Science and Technology, P.O. Box 3030, 22110 Irbid, Jordan
| | - M Y Gharibeh
- Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, Jordan University of Science and Technology, P.O. Box 3030, 22110 Irbid, Jordan
| | - K N Alshlool
- Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, Jordan University of Science and Technology, P.O. Box 3030, 22110 Irbid, Jordan
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48
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Bone marrow adipocytes promote the regeneration of stem cells and haematopoiesis by secreting SCF. Nat Cell Biol 2017; 19:891-903. [PMID: 28714970 PMCID: PMC5536858 DOI: 10.1038/ncb3570] [Citation(s) in RCA: 371] [Impact Index Per Article: 46.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2016] [Accepted: 06/12/2017] [Indexed: 12/14/2022]
Abstract
Endothelial cells and Leptin Receptor+ (LepR+) stromal cells are critical sources of haematopoietic stem cell (HSC) niche factors, including Stem Cell Factor (SCF), in bone marrow. After irradiation or chemotherapy, these cells are depleted while adipocytes become abundant. We discovered that bone marrow adipocytes synthesize SCF. They arise from Adipoq-Cre/ER+ progenitors, which represent ~5% of LepR+ cells, and proliferate after irradiation. Scf deletion using Adipoq-Cre/ER inhibited hematopoietic regeneration after irradiation or 5-fluorouracil treatment, depleting HSCs and reducing mouse survival. Scf from LepR+ cells, but not endothelial, hematopoietic, or osteoblastic cells, also promoted regeneration. In non-irradiated mice, Scf deletion using Adipoq-Cre/ER did not affect HSC frequency in long bones, which have few adipocytes, but depleted HSCs in tail vertebrae, which have abundant adipocytes. A-ZIP/F1 ‘fatless” mice exhibited delayed hematopoietic regeneration in long bones but not in tail vertebrae, where adipocytes inhibited vascularization. Adipocytes are a niche component that promotes hematopoietic regeneration.
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49
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Horowitz MC, Berry R, Holtrup B, Sebo Z, Nelson T, Fretz JA, Lindskog D, Kaplan JL, Ables G, Rodeheffer MS, Rosen CJ. Bone marrow adipocytes. Adipocyte 2017; 6:193-204. [PMID: 28872979 DOI: 10.1080/21623945.2017.1367881] [Citation(s) in RCA: 133] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Adipocytes were identified in human bone marrow more than a century ago, yet until recently little has been known about their origin, development, function or interactions with other cells in the bone marrow. Little functional significance has been attributed to these cells, a paradigm that still persists today. However, we now know that marrow adipose tissue increases with age and in response to a variety of physiologic induction signals. Bone marrow adipocytes have recently been shown to influence other cell populations within the marrow and can affect whole body metabolism by the secretion of a defined set of adipokines. Recent research shows that marrow adipocytes are distinct from white, brown and beige adipocytes, indicating that the bone marrow is a distinct adipose depot. This review will highlight recent data regarding these areas and the interactions of marrow adipose tissue (MAT) with cells within and outside of the bone marrow.
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Affiliation(s)
- Mark C. Horowitz
- Department of Orthopaedics and Rehabilitation, Yale University School of Medicine, New Haven, CT, USA
| | - Ryan Berry
- Department of Orthopaedics and Rehabilitation, Yale University School of Medicine, New Haven, CT, USA
| | - Brandon Holtrup
- Department of Molecular, Cell, and Developmental Biology, Yale University, New Haven, CT, USA
| | - Zachary Sebo
- Department of Molecular, Cell, and Developmental Biology, Yale University, New Haven, CT, USA
| | - Tracy Nelson
- Department of Orthopaedics and Rehabilitation, Yale University School of Medicine, New Haven, CT, USA
| | - Jackie A. Fretz
- Department of Orthopaedics and Rehabilitation, Yale University School of Medicine, New Haven, CT, USA
| | - Dieter Lindskog
- Department of Orthopaedics and Rehabilitation, Yale University School of Medicine, New Haven, CT, USA
| | - Jennifer L. Kaplan
- Department of Comparative Medicine and Molecular, Cellular, and Developmental Biology, Yale University School of Medicine, New Haven, CT, USA
| | - Gene Ables
- Orentreich Foundation for the Advancement of Science, Cold Spring, NY, USA
| | - Matthew S. Rodeheffer
- Department of Comparative Medicine and Molecular, Cellular, and Developmental Biology, Yale University School of Medicine, New Haven, CT, USA
| | - Clifford J. Rosen
- The Center for Clinical and Translational Research, Maine Medical Center Research Institute, Scarborough, ME, USA
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50
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Yu NY, Wolfson T, Middleton MS, Hamilton G, Gamst A, Angeles JE, Schwimmer JB, Sirlin CB. Bone marrow fat content is correlated with hepatic fat content in paediatric non-alcoholic fatty liver disease. Clin Radiol 2017; 72:425.e9-425.e14. [PMID: 28063601 PMCID: PMC5376517 DOI: 10.1016/j.crad.2016.11.017] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2016] [Revised: 10/03/2016] [Accepted: 11/21/2016] [Indexed: 10/20/2022]
Abstract
AIM To investigate the relationship between bone marrow fat content and hepatic fat content in children with known or suspected non-alcoholic fatty liver disease (NAFLD). MATERIALS AND METHODS This was an institutional review board-approved, Health Insurance Portability and Accountability Act (HIPAA)-compliant, cross-sectional, prospective analysis of data collected between October 2010 to March 2013 in 125 children with known or suspected NAFLD. Written informed consent was obtained for same-day research magnetic resonance imaging (MRI) of the lumbar spine, liver, and abdominal adiposity. Lumbar spine bone marrow proton density fat fraction (PDFF) and hepatic PDFF were estimated using complex-based MRI (C-MRI) techniques and magnitude-based MRI (M-MRI), respectively. Visceral adipose tissue (VAT) and subcutaneous adipose tissue (SCAT) were quantified using high-resolution MRI. All images were acquired by two MRI technologists. Hepatic M-MRI images were analysed by an image analyst; all other images were analysed by a single investigator. The relationship between lumbar spine bone marrow PDFF and hepatic PDFF was assessed with and without adjusting for the presence of covariates using correlation and regression analysis. RESULTS Lumbar spine bone marrow PDFF was positively associated with hepatic PDFF in children with known or suspected NAFLD prior to adjusting for covariates (r=0.33, p=0.0002). Lumbar spine bone marrow PDFF was positively associated with hepatic PDFF in children with known or suspected NAFLD (r=0.24, p=0.0079) after adjusting for age, sex, body mass index z-score, VAT, and SCAT in a multivariable regression analysis. CONCLUSION Bone marrow fat content is positively associated with hepatic fat content in children with known or suspected NAFLD. Further research is needed to confirm these results and understand their clinical and biological implications.
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Affiliation(s)
- N Y Yu
- Liver Imaging Group, Department of Radiology, University of California, San Diego School of Medicine, San Diego, CA, USA
| | - T Wolfson
- Computational and Applied Statistics Laboratory, San Diego Supercomputer Center, University of California, San Diego, La Jolla, CA, USA
| | - M S Middleton
- Liver Imaging Group, Department of Radiology, University of California, San Diego School of Medicine, San Diego, CA, USA
| | - G Hamilton
- Liver Imaging Group, Department of Radiology, University of California, San Diego School of Medicine, San Diego, CA, USA
| | - A Gamst
- Computational and Applied Statistics Laboratory, San Diego Supercomputer Center, University of California, San Diego, La Jolla, CA, USA
| | - J E Angeles
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of California, San Diego School of Medicine, San Diego, CA, USA
| | - J B Schwimmer
- Liver Imaging Group, Department of Radiology, University of California, San Diego School of Medicine, San Diego, CA, USA; Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of California, San Diego School of Medicine, San Diego, CA, USA; Department of Gastroenterology, Rady Children's Hospital San Diego, San Diego, CA, USA
| | - C B Sirlin
- Liver Imaging Group, Department of Radiology, University of California, San Diego School of Medicine, San Diego, CA, USA.
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