|
1
|
Ponsuksili S, Li S, Siengdee P, Hadlich F, Trakooljul N, Oster M, Reyer H, Wimmers K. DNA methylation in adipocyte differentiation of porcine mesenchymal stem cells and the impact of the donor metabolic type. Genomics 2025; 117:111050. [PMID: 40306557 DOI: 10.1016/j.ygeno.2025.111050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2024] [Revised: 07/26/2024] [Accepted: 04/22/2025] [Indexed: 05/02/2025]
Abstract
The impact of metabolic donor mesenchymal stem cells (MSCs) on DNA methylation, a critical epigenetic mechanism, significantly regulates adipogenesis. In this study, we investigated epigenetic changes during differentiation of synovial MSCs (SMSCs) from two pig breeds differing in metabolic performance (German Landrace (DL) and Angeln Saddleback (AS)). Stimulation of SMSCs to differentiate into adipocytes in vitro revealed several differentially methylated loci and regions, particularly on gene promoter regions, at day 7 and 14. AS breeds, known for higher fat deposition, exhibited more hypermethylation compared to DL. Furthermore, we utilized differentially methylated regions associated with the adipogenic process and breed, especially those in promoter regions, for predicting transcription factor motifs. This study provides insights into the DNA methylation landscape during adipogenesis in pigs of different metabolic types, revealing its role in regulating cell fate and donor memory retention in culture.
Collapse
Affiliation(s)
- Siriluck Ponsuksili
- Research Institute for Farm Animal Biology (FBN), Wilhelm-Stahl-Allee 2, 18196, Dummerstorf, Germany.
| | - Shuaichen Li
- Research Institute for Farm Animal Biology (FBN), Wilhelm-Stahl-Allee 2, 18196, Dummerstorf, Germany
| | - Puntita Siengdee
- Research Institute for Farm Animal Biology (FBN), Wilhelm-Stahl-Allee 2, 18196, Dummerstorf, Germany; Chulabhorn Graduate Institute, Program in Applied Biological Sciences, Chulabhorn Royal Academy, Kamphaeng Phet 6 Road, Laksi, Bangkok 10210, Thailand
| | - Frieder Hadlich
- Research Institute for Farm Animal Biology (FBN), Wilhelm-Stahl-Allee 2, 18196, Dummerstorf, Germany
| | - Nares Trakooljul
- Research Institute for Farm Animal Biology (FBN), Wilhelm-Stahl-Allee 2, 18196, Dummerstorf, Germany
| | - Michael Oster
- Research Institute for Farm Animal Biology (FBN), Wilhelm-Stahl-Allee 2, 18196, Dummerstorf, Germany
| | - Henry Reyer
- Research Institute for Farm Animal Biology (FBN), Wilhelm-Stahl-Allee 2, 18196, Dummerstorf, Germany
| | - Klaus Wimmers
- Research Institute for Farm Animal Biology (FBN), Wilhelm-Stahl-Allee 2, 18196, Dummerstorf, Germany; Faculty of Agricultural and Environmental Sciences, University of Rostock, Justus-von-Liebig-Weg 6b, 18059 Rostock, Germany
| |
Collapse
|
|
2
|
Ismail UN, Azlan CA, Khairullah S, Azman RR, Omar NF, Md Shah MN, Jackson N, Ng KH. Marrow Fat-Cortical Bone Relationship in β-Thalassemia: A Study Using MRI. J Magn Reson Imaging 2024; 60:2447-2456. [PMID: 38556790 DOI: 10.1002/jmri.29366] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Revised: 03/13/2024] [Accepted: 03/14/2024] [Indexed: 04/02/2024] Open
Abstract
BACKGROUND Growing evidence suggests that marrow adipocytes play an active role in the regulation of bone metabolism and hematopoiesis. However, research on the relationship between bone and fat in the context of hematological diseases, particularly β-thalassemia, remains limited. PURPOSE To investigate the relationship between marrow fat and cortical bone thickness in β-thalassemia and to identify key determinants influencing these variables. STUDY TYPE Prospective. SUBJECTS Thirty-five subjects in four subject groups of increasing disease severity: 6 healthy control (25.0 ± 5.3 years, 2 male), 4 β-thalassemia minor, 13 intermedia, and 12 major (29.1 ± 6.4 years, 15 male). FIELD STRENGTH/SEQUENCE 3.0 T, 3D fast low angle shot sequence and T1-weighted turbo spin echo. ASSESSMENT Analyses on proton density fat fraction (PDFF) and R2* values in femur subregions (femoral head, greater trochanter, intertrochanteric, diaphysis, distal) and cortical thickness (CBI) of the subjects' left femur. Clinical data such as age, sex, body mass index (BMI), and disease severity were also included. STATISTICAL TESTS One-way analysis of variance (ANOVA), mixed ANOVA, Pearson correlation and multiple regression. P-values <0.05 were considered significant. RESULTS Bone marrow PDFF significantly varied between the femur subregions, F(2.89,89.63) = 44.185 and disease severity, F(1,3) = 12.357. A significant interaction between subject groups and femur subregions on bone marrow PDFF was observed, F(8.67,89.63) = 3.723. Notably, a moderate positive correlation was observed between PDFF and CBI (r = 0.33-0.45). Multiple regression models for both PDFF (R2 = 0.476, F(13,151) = 10.547) and CBI (R2 = 0.477, F(13,151) = 10.580) were significant. Significant predictors for PDFF were disease severity (βTMi = 0.36, βTMa = 0.17), CBI (β = 0.24), R2* (β = -0.32), and height (β = -0.29) while for CBI, the significant determinants were sex (β = -0.27), BMI (β = 0.55), disease severity (βTMi = 2.15), and PDFF (β = 0.25). DATA CONCLUSION This study revealed a positive correlation between bone marrow fat fraction and cortical bone thickness in β-thalassemia with varying disease severity, potentially indicating a complex interplay between bone health and marrow composition. EVIDENCE LEVEL 2 TECHNICAL EFFICACY: Stage 3.
Collapse
Affiliation(s)
- Umi Nabilah Ismail
- Makmal Pemprosesan Imej Kefungsian (Functional Image Processing Laboratory), Department of Radiology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Bangi, Malaysia
| | - Che Ahmad Azlan
- Department of Biomedical Imaging, Faculty of Medicine, Universiti Malaya, Kuala Lumpur, Malaysia
| | - Shasha Khairullah
- Haematology Unit, Department of Medicine, Faculty of Medicine, Universiti Malaya, Kuala Lumpur, Malaysia
| | - Raja Rizal Azman
- Department of Biomedical Imaging, Faculty of Medicine, Universiti Malaya, Kuala Lumpur, Malaysia
| | - Nur Farhayu Omar
- Department of Radiology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Malaysia
| | - Mohammad Nazri Md Shah
- Department of Biomedical Imaging, Faculty of Medicine, Universiti Malaya, Kuala Lumpur, Malaysia
| | - Nicholas Jackson
- Red Cell Unit, Department of Haematology, University College London Hospital, London, UK
| | - Kwan Hoong Ng
- Department of Biomedical Imaging, Faculty of Medicine, Universiti Malaya, Kuala Lumpur, Malaysia
| |
Collapse
|
|
3
|
Clarke SA, Eng PC, Comninos AN, Lazarus K, Choudhury S, Tsang C, Meeran K, Tan TM, Dhillo WS, Abbara A. Current Challenges and Future Directions in the Assessment of Glucocorticoid Status. Endocr Rev 2024; 45:795-817. [PMID: 38795365 PMCID: PMC11581704 DOI: 10.1210/endrev/bnae016] [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] [Received: 08/04/2023] [Revised: 05/07/2024] [Accepted: 05/23/2024] [Indexed: 05/27/2024]
Abstract
Glucocorticoid (GC) hormones are secreted in a circadian and ultradian rhythm and play a critical role in maintaining physiological homeostasis, with both excess and insufficient GC associated with adverse effects on health. Current assessment of GC status is primarily clinical, often in conjunction with serum cortisol values, which may be stimulated or suppressed depending on the GC disturbance being assessed. In the setting of extreme perturbations in cortisol levels ie, markedly low or high levels, symptoms and signs of GC dysfunction may be overt. However, when disturbances in cortisol GC status values are less extreme, such as when assessing optimization of a GC replacement regimen, signs and symptoms can be more subtle or nonspecific. Current tools for assessing GC status are best suited to identifying profound disturbances but may lack sensitivity for confirming optimal GC status. Moreover, single cortisol values do not necessarily reflect an individual's GC status, as they are subject to inter- and intraindividual variation and do not take into account the pulsatile nature of cortisol secretion, variation in binding proteins, or local tissue concentrations as dictated by 11beta-hydroxysteroid dehydrogenase activity, as well as GC receptor sensitivity. In the present review, we evaluate possible alternative methods for the assessment of GC status that do not solely rely on the measurement of circulating cortisol levels. We discuss the potential of changes in metabolomic profiles, micro RNA, gene expression, and epigenetic and other novel biomarkers such as growth differentiating factor 15 and osteocalcin, which could in the future aid in the objective classification of GC status.
Collapse
Affiliation(s)
- Sophie A Clarke
- Section of Investigative Medicine, Imperial College London, London W12 ONN, UK
- Department of Endocrinology, Imperial College Healthcare NHS Trust, London W6 8RF, UK
| | - Pei Chia Eng
- Section of Investigative Medicine, Imperial College London, London W12 ONN, UK
- Department of Endocrinology, Imperial College Healthcare NHS Trust, London W6 8RF, UK
- Department of Endocrinology, National University of Singapore, Singapore
| | - Alexander N Comninos
- Section of Investigative Medicine, Imperial College London, London W12 ONN, UK
- Department of Endocrinology, Imperial College Healthcare NHS Trust, London W6 8RF, UK
| | - Katharine Lazarus
- Section of Investigative Medicine, Imperial College London, London W12 ONN, UK
- Department of Endocrinology, Imperial College Healthcare NHS Trust, London W6 8RF, UK
| | - Sirazum Choudhury
- Section of Investigative Medicine, Imperial College London, London W12 ONN, UK
- Department of Endocrinology, Imperial College Healthcare NHS Trust, London W6 8RF, UK
| | - Christie Tsang
- Section of Investigative Medicine, Imperial College London, London W12 ONN, UK
| | - Karim Meeran
- Section of Investigative Medicine, Imperial College London, London W12 ONN, UK
- Department of Endocrinology, Imperial College Healthcare NHS Trust, London W6 8RF, UK
| | - Tricia M Tan
- Section of Investigative Medicine, Imperial College London, London W12 ONN, UK
- Department of Endocrinology, Imperial College Healthcare NHS Trust, London W6 8RF, UK
| | - Waljit S Dhillo
- Section of Investigative Medicine, Imperial College London, London W12 ONN, UK
- Department of Endocrinology, Imperial College Healthcare NHS Trust, London W6 8RF, UK
| | - Ali Abbara
- Section of Investigative Medicine, Imperial College London, London W12 ONN, UK
- Department of Endocrinology, Imperial College Healthcare NHS Trust, London W6 8RF, UK
| |
Collapse
|
|
4
|
Behler-Janbeck F, Baranowsky A, Yorgan TA, Jaeckstein MY, Worthmann A, Fuh MM, Gunasekaran K, Tiegs G, Amling M, Schinke T, Heeren J. The short-chain fatty acid receptors Gpr41/43 regulate bone mass by promoting adipogenic differentiation of mesenchymal stem cells. Front Endocrinol (Lausanne) 2024; 15:1392418. [PMID: 39363899 PMCID: PMC11446854 DOI: 10.3389/fendo.2024.1392418] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Accepted: 07/24/2024] [Indexed: 10/05/2024] Open
Abstract
Bone is a dynamic tissue that is constantly remodeled throughout adult life. Recently, it has been shown that bone turnover decreases shortly after food consumption. This process has been linked to the fermentation of non-digestible food ingredients such as inulin by gut microbes, which results in the production of the short-chain fatty acids (SCFAs) acetate, propionate and butyrate. SCFAs exert various metabolic functions, which in part can be explained by activation of G protein-coupled receptors (Gpr) 41 and 43. However, the potential relevance of a SCFA-Gpr41/43 signaling axis for bone metabolism has not been established. The aim of our study is to investigate the role of Gpr41/43 in bone metabolism and osteogenic differentiation of mesenchymal stem cells. For this purpose, we analyzed the skeletal phenotype of wild type controls (WT) and Gpr41/43 double knockout (Gpr41/43 dKO) mice fed either a chow or an inulin-enriched diet. In addition, we isolated bone marrow derived mesenchymal stem cells from WT and Gpr41/43 dKO mice and differentiated them into osteoblasts in the absence or presence of acetate. MicroCT scanning of femoral bones of Gpr41/43 dKO mice revealed a significant increase of trabecular bone volume and trabecular compared to WT controls. Treatment of WT bone marrow-derived osteoblasts with acetate resulted in decreased mineralization and substantial downregulation of bone formation markers such as Phex, Ptgs2 and Col1a1. Notably, this effect was strongly attenuated in differentiated osteoblasts lacking Gpr41/43. Inversely, acetate supplementation resulted in higher levels of adipocyte marker genes including Pparg, Lpl and Adipoq in bone marrow-derived cells from WT mice, an effect blunted in differentiated cells isolated from Gpr41/43 dKO mice. Overall, these data indicate that acetate regulates bone architecture via SCFA-Gpr41/43 signaling by modulating the osteogenic versus adipogenic differentiation of mesenchymal stem cells.
Collapse
Affiliation(s)
- Friederike Behler-Janbeck
- Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Anke Baranowsky
- Department of Trauma and Orthopaedic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Timur A. Yorgan
- Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Michelle Y. Jaeckstein
- Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Anna Worthmann
- Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Marceline M. Fuh
- Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Karthikeyan Gunasekaran
- Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Gisa Tiegs
- Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Michael Amling
- Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Thorsten Schinke
- Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Joerg Heeren
- Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| |
Collapse
|
|
5
|
Sun Y, Chen P, Zhao B. Role of extracellular vesicles associated with microRNAs and their interplay with cuproptosis in osteoporosis. Noncoding RNA Res 2024; 9:715-719. [PMID: 38577024 PMCID: PMC10990744 DOI: 10.1016/j.ncrna.2024.03.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2023] [Revised: 03/02/2024] [Accepted: 03/05/2024] [Indexed: 04/06/2024] Open
Abstract
Osteoporosis (OP)-associated fractures can result in severe morbidity and disability, reduced quality of life, and death. Previous studies have suggested that small noncoding RNAs, for example, small regulatory microRNAs (miRNAs), play a key role in OP by inhibiting target gene expression. Cuproptosis, a recently proposed copper-induced cell death pathway, is linked with OP. Here, we describe the contribution of exosomal miRNAs and cuproptosis to OP. First, we highlight the characteristics of exosomes and roles of exosome-related miRNAs. Next, we discuss the relationship between cuproptosis and OP. Subsequently, we analyze the crosstalk of exosomal miRNAs with cuproptosis in the development of OP. This review aims to investigate a new clinical treatment method for OP.
Collapse
Affiliation(s)
- Yong Sun
- Department of Sports Medicine, Fourth Medical Center of Chinese PLA General Hospital, Beijing, 100853, China
| | - Peng Chen
- Department of Orthopedics, The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, 510405, Guangdong Province, China
| | - Bin Zhao
- Department of Sports Medicine, Fourth Medical Center of Chinese PLA General Hospital, Beijing, 100853, China
| |
Collapse
|
|
6
|
Iacobini C, Vitale M, Haxhi J, Menini S, Pugliese G. Impaired Remodeling of White Adipose Tissue in Obesity and Aging: From Defective Adipogenesis to Adipose Organ Dysfunction. Cells 2024; 13:763. [PMID: 38727299 PMCID: PMC11083890 DOI: 10.3390/cells13090763] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Revised: 04/22/2024] [Accepted: 04/25/2024] [Indexed: 05/13/2024] Open
Abstract
The adipose organ adapts and responds to internal and environmental stimuli by remodeling both its cellular and extracellular components. Under conditions of energy surplus, the subcutaneous white adipose tissue (WAT) is capable of expanding through the enlargement of existing adipocytes (hypertrophy), followed by de novo adipogenesis (hyperplasia), which is impaired in hypertrophic obesity. However, an impaired hyperplastic response may result from various defects in adipogenesis, leading to different WAT features and metabolic consequences, as discussed here by reviewing the results of the studies in animal models with either overexpression or knockdown of the main molecular regulators of the two steps of the adipogenesis process. Moreover, impaired WAT remodeling with aging has been associated with various age-related conditions and reduced lifespan expectancy. Here, we delve into the latest advancements in comprehending the molecular and cellular processes underlying age-related changes in WAT function, their involvement in common aging pathologies, and their potential as therapeutic targets to influence both the health of elderly people and longevity. Overall, this review aims to encourage research on the mechanisms of WAT maladaptation common to conditions of both excessive and insufficient fat tissue. The goal is to devise adipocyte-targeted therapies that are effective against both obesity- and age-related disorders.
Collapse
|
|
7
|
Moscatelli F, Monda A, Messina G, Picciocchi E, Monda M, Di Padova M, Monda V, Mezzogiorno A, Dipace A, Limone P, Messina A, Polito R. Exploring the Interplay between Bone Marrow Stem Cells and Obesity. Int J Mol Sci 2024; 25:2715. [PMID: 38473961 DOI: 10.3390/ijms25052715] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2024] [Revised: 02/13/2024] [Accepted: 02/19/2024] [Indexed: 03/14/2024] Open
Abstract
Obesity, a complex disorder with rising global prevalence, is a chronic, inflammatory, and multifactorial disease and it is characterized by excessive adipose tissue accumulation and associated comorbidities. Adipose tissue (AT) is an extremely diverse organ. The composition, structure, and functionality of AT are significantly influenced by characteristics specific to everyone, in addition to the variability connected to various tissue types and its location-related heterogeneity. Recent investigation has shed light on the intricate relationship between bone marrow stem cells and obesity, revealing potential mechanisms that contribute to the development and consequences of this condition. Mesenchymal stem cells within the bone marrow, known for their multipotent differentiation capabilities, play a pivotal role in adipogenesis, the process of fat cell formation. In the context of obesity, alterations in the bone marrow microenvironment may influence the differentiation of mesenchymal stem cells towards adipocytes, impacting overall fat storage and metabolic balance. Moreover, bone marrow's role as a crucial component of the immune system adds another layer of complexity to the obesity-bone marrow interplay. This narrative review summarizes the current research findings on the connection between bone marrow stem cells and obesity, highlighting the multifaceted roles of bone marrow in adipogenesis and inflammation.
Collapse
Affiliation(s)
- Fiorenzo Moscatelli
- Department of Wellbeing, Nutrition and Sport, Pegaso Telematic University, 80143 Naples, Italy
| | - Antonietta Monda
- Department of Experimental Medicine, Section of Human Physiology and Unit of Dietetics and Sports Medicine, University of Campania "Luigi Vanvitelli", 80138 Naples, Italy
| | - Giovanni Messina
- Department of Experimental Medicine, Section of Human Physiology and Unit of Dietetics and Sports Medicine, University of Campania "Luigi Vanvitelli", 80138 Naples, Italy
| | - Elisabetta Picciocchi
- Department of Experimental Medicine, Section of Human Physiology and Unit of Dietetics and Sports Medicine, University of Campania "Luigi Vanvitelli", 80138 Naples, Italy
| | - Marcellino Monda
- Department of Experimental Medicine, Section of Human Physiology and Unit of Dietetics and Sports Medicine, University of Campania "Luigi Vanvitelli", 80138 Naples, Italy
| | - Marilena Di Padova
- Department of Humanistic Studies, University of Foggia, 71100 Foggia, Italy
| | - Vincenzo Monda
- Department of Exercise Sciences and Well-Being, University of Naples "Parthenope", 80138 Naples, Italy
| | - Antonio Mezzogiorno
- Department of Mental Health, Fisics and Preventive Medicine, University of Campania "Luigi Vanvitelli", 80138 Naples, Italy
| | - Anna Dipace
- Department of Wellbeing, Nutrition and Sport, Pegaso Telematic University, 80143 Naples, Italy
| | - Pierpaolo Limone
- Department of Wellbeing, Nutrition and Sport, Pegaso Telematic University, 80143 Naples, Italy
| | - Antonietta Messina
- Department of Experimental Medicine, Section of Human Physiology and Unit of Dietetics and Sports Medicine, University of Campania "Luigi Vanvitelli", 80138 Naples, Italy
| | - Rita Polito
- Department of Clinical and Experimental Medicine, University of Foggia, 71122 Foggia, Italy
| |
Collapse
|
|
8
|
Boregowda SV, Haga CL, Supper VM, Booker CN, Phinney DG. Novel role for alpha-2-macroglobulin (A2M) as a disease modifying protein in senile osteoporosis. Front Cell Dev Biol 2023; 11:1294438. [PMID: 37965574 PMCID: PMC10642388 DOI: 10.3389/fcell.2023.1294438] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Accepted: 10/17/2023] [Indexed: 11/16/2023] Open
Abstract
Introduction: In the rapidly aging U.S. population, age-induced bone loss (senile osteoporosis) represents a major public health concern that is associated with a significant increased risk for low trauma fragility fractures, which are debilitating to patients, cause significant morbidity and mortality, and are costly to treat and manage. While various treatments exist to slow bone loss in osteoporosis patients, these suffer from poor tolerability and label restrictions that limit their overall effectiveness. Over the past decade, skeletal stem/progenitor cells (SSPCs), which are the main precursor of osteoblasts and adipocytes in adult bone marrow (BM), have emerged as important players in osteoporosis. Methods: Age-induced skeletal pathology was quantified in elderly (24-month-old) vs. mature (3-month-old) mice by micro-CT and changes in SSPC abundance in the BM of these mice was quantified by fluorescence-activated cell sorting (FACS). SSPCs from elderly vs. mature mice were also analyzed by RNA-Seq to identify differentially expressed genes (DEGs), and gain and loss-of-function studies were performed in human BM-derived mesenchymal stromal cells (BM-MSCs) to assess A2M function. Results: Elderly mice were shown to exhibit significant age-induced skeletal pathology, which correlated with a significant increase in SSPC abundance in BM. RNA-seq analysis identified alpha-2-macroglobulin (A2M), a pan-protease inhibitor that also binds inflammatory cytokines, as one of the most downregulated transcripts in SSPCs isolated from the BM of elderly vs. mature mice, and silencing of A2M expression in human BM-MSCs induced their proliferation and skewed their lineage bifurcation toward adipogenesis at the expense of osteogenesis thereby recapitulating critical aspects of age-induced stem cell dysfunction. Conclusion: These findings identify A2M as a novel disease modifying protein in osteoporosis, downregulation of which in bone marrow promotes SSPC dysfunction and imbalances in skeletal homeostasis.
Collapse
Affiliation(s)
| | | | | | | | - Donald G. Phinney
- Department of Molecular Medicine, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation and Technology, Jupiter, FL, United States
| |
Collapse
|
|
9
|
Cathey A, Tamayo-Ortiz M, Tamayo-Orozco J, Meeker JD, Peterson KE, Trejo-Valdivia B, Téllez-Rojo MM, Watkins DJ. Calcium supplementation and body mass index modify associations between prenatal phthalate exposure and perinatal bone ultrasound measures among pregnant women. ENVIRONMENTAL RESEARCH 2023; 233:116513. [PMID: 37385416 PMCID: PMC10529894 DOI: 10.1016/j.envres.2023.116513] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Revised: 06/09/2023] [Accepted: 06/24/2023] [Indexed: 07/01/2023]
Abstract
Phthalates have endocrine activity that may interfere with bone health, particularly during pregnancy and the early postpartum period, when bone resorption increases. We evaluated associations between prenatal phthalate exposure and perinatal bone health among 289 mothers in the ELEMENT birth cohort in Mexico City who were randomized upon recruitment to receive 1,200 mg daily calcium supplementation or placebo throughout pregnancy. Spot urine samples at up to three timepoints during pregnancy were assayed for 9 phthalate metabolites. Bone integrity was assessed by quantitative ultrasound speed of sound (SOS) measurements of the phalange and distal radius at 3, 6, and 8 months of pregnancy and 1, 3, 7, and 12 months postpartum. Geometric means of specific gravity-corrected phthalate concentrations were used as overall measures of prenatal exposure. Linear mixed effect models estimated associations between phthalate exposure and repeated perinatal bone SOS measures, adjusting for age, pre-pregnancy body mass index (BMI), education, parity, calcium supplementation, and month of pregnancy/postpartum. Effect modification by calcium supplementation and BMI were assessed in sensitivity analyses. An interquartile range increase in MEP and MiBP increased pregnancy phalange z-scores (β: 0.11; 95%CI: 0.003, 0.31 and β: 0.15; 95%CI: 0.00,0.42, respectively). Higher concentrations of several phthalate metabolites resulted in lower SOS measures among women who received calcium supplements (compared to placebo group) but higher SOS measures among women with a BMI≥25 (compared to BMI<25). These results suggest that phthalate exposure may interfere with bone remodeling during pregnancy, and that consideration of effect modifiers is paramount to fully understand the effects of environmental exposures on bone health.
Collapse
Affiliation(s)
- Amber Cathey
- Department of Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, MI, 48109, USA
| | - Marcela Tamayo-Ortiz
- Occupational Health Research Unit, Mexican Social Security Institute, Mexico City, Mexico.
| | - Juan Tamayo-Orozco
- Mexican Committee for the Prevention of Osteoporosis, Mexico City, Mexico
| | - John D Meeker
- Department of Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, MI, 48109, USA
| | - Karen E Peterson
- Department of Nutritional Sciences, University of Michigan School of Public Health, Ann Arbor, MI, 48109, USA
| | - Belem Trejo-Valdivia
- Center for Nutrition and Health Research, National Institute of Public Health, Cuernavaca, Mexico
| | - Martha Maria Téllez-Rojo
- Center for Nutrition and Health Research, National Institute of Public Health, Cuernavaca, Mexico
| | - Deborah J Watkins
- Department of Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, MI, 48109, USA
| |
Collapse
|
|
10
|
Gu H, Wei J. Peiminine regulates bone-fat balance by canonical Wnt/β-catenin pathway in an ovariectomized rat model. Phytother Res 2023. [PMID: 36799485 DOI: 10.1002/ptr.7780] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Revised: 11/19/2022] [Accepted: 01/29/2023] [Indexed: 02/18/2023]
Abstract
Peiminine is a major biologically active component of Fritillaria thunbergii Miq that exhibits good anticancer, antiinflammatory, and anti-osteoclast effects. However, its effects on osteoporosis (OP) remain unknown. This study aimed to explore whether Peiminine was able to regulate osteogenesis and adipogenesis in ovariectomized (OVX) rat. The effects on the differentiation of bone marrow stem cells (BMSCs), function of Wnt/β-catenin pathway, ALP activity, calcium nodule deposition, as well as adipocyte formation in vitro by Peiminine at different concentrations, were detected. The curative effects of Peiminine on the ovariectomy-induced osteoporosis model by micro-CT and bone histomorphology assays were analyzed. The promotion of osteogenic differentiation and inhibition of adipogenic differentiation by Peiminine (5-40 μg/mL) was detected and the optimum concentration was 20 μg/mL. Mechanistically, Peiminine regulated the fate of BMSCs in vitro, and activated Wnt/β-catenin signaling pathway by restraining phosphorylation of β-catenin and promoting the nuclear translocation of β-catenin. Moreover, Peiminine prevented ovariectomy-induced osteoporosis by alleviating trabecular bone loss and inhibiting adipose formation. Our data suggested that Peiminine could attenuate ovariectomy-induced osteoporosis by alleviating trabecular bone loss and inhibiting adipose formation. These encouraging discoveries could lay the foundation for Peiminine to be a promising preventive treatment strategy for skeletal diseases, such as osteoporosis.
Collapse
Affiliation(s)
- Hanwen Gu
- Department of Joint Orthopedics, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Jian Wei
- Department of Joint Orthopedics, Liuzhou People's Hospital affiliated to Guangxi Medical University, Liuzhou, China
| |
Collapse
|
|
11
|
Beekman KM, Duque G, Corsi A, Tencerova M, Bisschop PH, Paccou J. Osteoporosis and Bone Marrow Adipose Tissue. Curr Osteoporos Rep 2023; 21:45-55. [PMID: 36534306 DOI: 10.1007/s11914-022-00768-1] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/17/2022] [Indexed: 12/23/2022]
Abstract
PURPOSE OF REVIEW This review focuses on the recent findings regarding bone marrow adipose tissue (BMAT) concerning bone health. We summarize the variations in BMAT in relation to age, sex, and skeletal sites, and provide an update on noninvasive imaging techniques to quantify human BMAT. Next, we discuss the role of BMAT in patients with osteoporosis and interventions that affect BMAT. RECENT FINDINGS There are wide individual variations with region-specific fluctuation and age- and gender-specific differences in BMAT content and composition. The Bone Marrow Adiposity Society (BMAS) recommendations aim to standardize imaging protocols to increase comparability across studies and sites. Water-fat imaging (WFI) seems an accurate and efficient alternative for spectroscopy (1H-MRS). Most studies indicate that greater BMAT is associated with lower bone mineral density (BMD) and a higher prevalence of vertebral fractures. The proton density fat fraction (PDFF) and changes in lipid composition have been associated with an increased risk of fractures independently of BMD. Therefore, PDFF and lipid composition could potentially be future imaging biomarkers for assessing fracture risk. Evidence of the inhibitory effect of osteoporosis treatments on BMAT is still limited to a few randomized controlled trials. Moreover, results from the FRAME biopsy sub-study highlight contradictory findings on the effect of the sclerostin antibody romosozumab on BMAT. Further understanding of the role(s) of BMAT will provide insight into the pathogenesis of osteoporosis and may lead to targeted preventive and therapeutic strategies.
Collapse
Affiliation(s)
- Kerensa M Beekman
- Department of Radiology and Nuclear Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Gustavo Duque
- Department of Medicine and Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada
| | - Alessandro Corsi
- Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | - Michaela Tencerova
- Molecular Physiology of Bone, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic
| | - Peter H Bisschop
- Department of Endocrinology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Julien Paccou
- Department of Rheumatology, MABLaB ULR 4490, CHU Lille, University Lille, Lille, France.
| |
Collapse
|
|
12
|
Entz L, Falgayrac G, Chauveau C, Pasquier G, Lucas S. The extracellular matrix of human bone marrow adipocytes and glucose concentration differentially alter mineralization quality without impairing osteoblastogenesis. Bone Rep 2022; 17:101622. [PMID: 36187598 PMCID: PMC9519944 DOI: 10.1016/j.bonr.2022.101622] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 09/09/2022] [Accepted: 09/19/2022] [Indexed: 11/18/2022] Open
Abstract
Bone marrow adipocytes (BMAds) accrue in various states of osteoporosis and interfere with bone remodeling through the secretion of various factors. However, involvement of the extracellular matrix (ECM) produced by BMAds in the impairment of bone marrow mesenchymal stromal cell (BM-MSC) osteoblastogenesis has received little attention. In type 2 diabetes (T2D), skeletal fragility is associated with several changes in bone quality that are incompletely understood, and BMAd quantity increases in relationship to poor glycemic control. Considering their altered phenotype in this pathophysiological context, we aimed to determine the contribution of the ECM of mature BMAds to osteoblastogenesis and mineralization quality in the context of chronic hyperglycemia. Human BM-MSCs were differentiated for 21 days in adipogenic medium containing either a normoglycemic (LG, 5.5 mM) or a high glucose concentration (HG, 25 mM). The ECM laid down by BMAds were devitalized through cell removal to examine their impact on the proliferation and differentiation of BM-MSCs toward osteoblastogenesis in LG and HG conditions. Compared to control plates, both adipocyte ECMs promoted cell adhesion and proliferation. As shown by the unmodified RUNX2 and osteocalcin mRNA levels, BM-MSC commitment in osteoblastogenesis was hampered by neither the hyperglycemic condition nor the adipocyte matrices. However, adipocyte ECMs or HG condition altered the mineralization phase with perturbed expression levels of type 1 collagen, MGP and osteopontin. Despite higher ALP activity, mineralization levels per cell were decreased for osteoblasts grown on adipocyte ECMs compared to controls. Raman spectrometry revealed that culturing on adipocyte matrices specifically prevents type-B carbonate substitution and favors collagen crosslinking, in contrast to exposure to HG concentration alone. Moreover, the mineral to organic ratio was disrupted according to the presence of adipocyte ECM and the glucose concentration used for adipocyte or osteoblast culture. HG concentration and adipocyte ECM lead to different defects in mineralization quality, recapitulating contradictory changes reported in T2D osteoporosis. Our study shows that ECMs from BMAds do not impair osteoblastogenesis but alter both the quantity and quality of mineralization partly in a glucose concentration-dependent manner. This finding sheds light on the involvement of BMAds, which should be considered in the compromised bone quality of T2D and osteoporosis patients more generally.
Glucose level alters the Extracellular Matrix composition of Bone Marrow adipocytes. Osteoblastogenesis on adipocyte ECMs is unaltered but produced less mineral amount. The quality of the mineral is altered differently by adipocyte ECMs or glucose levels. The presence of BM adipocytes should be valued in damaged osteoporosis bone quality.
Collapse
Key Words
- AGEs, Advanced glycation end-products
- BM-MSC, Bone marrow mesenchymal stromal cell
- BMAd, Bone marrow adipocyte
- ECM, Extracellular matrix
- ECMBMAd HG, Extracellular matrix obtained from BMAds cultured in HG concentration
- ECMBMAd LG, Extracellular matrix obtained from BMAds cultured in LG concentration
- ECMBMAd, Extracellular matrix obtained from BMAds
- Extracellular matrix
- GAG, glycosaminoglycan
- HA, hydroxyapatite
- HG, High glucose
- Hyperglycemia
- LG, Low glucose
- LGM, Low glucose and mannitol
- Marrow adipocytes
- Osteoblast
- Osteoporosis
- Skeletal mesenchymal stromal cells
- T2D, Type 2 diabetes
Collapse
|
|
13
|
Tsai WH, Kong SK, Lin CL, Cheng KH, Cheng YT, Chien MN, Lee CC, Tsai MC. Risk of fracture caused by anti-diabetic drugs in individuals with type 2 diabetes: A network meta-analysis. Diabetes Res Clin Pract 2022; 192:110082. [PMID: 36122867 DOI: 10.1016/j.diabres.2022.110082] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2022] [Revised: 08/28/2022] [Accepted: 09/10/2022] [Indexed: 11/23/2022]
Abstract
AIMS Diabetes is associated with increased risk of fracture. This study aims to evaluate the correlation between anti-diabetic agents and fracture risk in patients with type 2 diabetes. METHODS Literature research was conducted using PubMed, Embase, and ClinicalTrials.gov. Search-term included "type 2 diabetes," "fracture," "randomized controlled trial," and seven kinds of anti-diabetic agents. Random-effect models established fractures in the follow-up period as the primary outcome. A network meta-analysis was performed to compare available treatments within a single Bayesian analytical framework. RESULTS A total of 191,361 patients were included in 161 studies, with 2916 fractures. DPP-4i (risk ratio [RR] 1.76 [95 % confidence interval (CI) 1.21-2.55]), SGLT-2i (RR 1.5 [95 % CI 1.05-2.16]) and placebo (RR 1.44 [95 % CI 1.04-1.98]) increased fracture risk when compared to GLP1-RA. GLP1-RA (RR 0.5 [95 % CI 0.31-0.79]) and SU (RR 0.56 [95 % CI 0.41-0.77]) provided greater protection against fracture than TZD. DPP-4i increased fracture risk when compared to SU (RR 1.55 [95 % CI 1.08-2.22]), and was comparable in effect to TZD. CONCLUSIONS GLP1-RA offered better protection against fracture than placebo. Insulin and SU had effects comparable with GLP1-RA. SU offered greater protection against fractures than TZD and DPP-4i. SGLT-2i increased risk of fracture when compared to GLP1-RA.
Collapse
Affiliation(s)
- Wen-Hsuan Tsai
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Mackay Memorial Hospital, Taipei, Taiwan, ROC
| | - Siang-Ke Kong
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Mackay Memorial Hospital, Taipei, Taiwan, ROC
| | - Chu-Lin Lin
- Department of Medicine, Mackay Medical College, New Taipei City, Taiwan, ROC
| | - Kai-Hsuan Cheng
- Department of Medicine, Mackay Medical College, New Taipei City, Taiwan, ROC
| | - Yi-Ting Cheng
- Department of Medicine, Mackay Medical College, New Taipei City, Taiwan, ROC
| | - Ming-Nan Chien
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Mackay Memorial Hospital, Taipei, Taiwan, ROC; Department of Medicine, Mackay Medical College, New Taipei City, Taiwan, ROC
| | - Chun-Chuan Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Mackay Memorial Hospital, Taipei, Taiwan, ROC; Department of Medicine, Mackay Medical College, New Taipei City, Taiwan, ROC
| | - Ming-Chieh Tsai
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Mackay Memorial Hospital, Taipei, Taiwan, ROC; Department of Medicine, Mackay Medical College, New Taipei City, Taiwan, ROC; Institute of Epidemiology and Preventive Medicine, National Taiwan University, Taipei, Taiwan, ROC.
| |
Collapse
|
|
14
|
Stromal Co-Cultivation for Modeling Breast Cancer Dormancy in the Bone Marrow. Cancers (Basel) 2022; 14:cancers14143344. [PMID: 35884405 PMCID: PMC9320268 DOI: 10.3390/cancers14143344] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 07/05/2022] [Accepted: 07/05/2022] [Indexed: 11/16/2022] Open
Abstract
Cancers metastasize to the bone marrow before primary tumors can be detected. Bone marrow micrometastases are resistant to therapy, and while they are able to remain dormant for decades, they recur steadily and result in incurable metastatic disease. The bone marrow microenvironment maintains the dormancy and chemoresistance of micrometastases through interactions with multiple cell types and through structural and soluble factors. Modeling dormancy in vitro can identify the mechanisms of these interactions. Modeling also identifies mechanisms able to disrupt these interactions or define novel interactions that promote the reawakening of dormant cells. The in vitro modeling of the interactions of cancer cells with various bone marrow elements can generate hypotheses on the mechanisms that control dormancy, treatment resistance and reawakening in vivo. These hypotheses can guide in vivo murine experiments that have high probabilities of succeeding in order to verify in vitro findings while minimizing the use of animals in experiments. This review outlines the existing data on predominant stromal cell types and their use in 2D co-cultures with cancer cells.
Collapse
|
|
15
|
Ma M, Liu X, Jia G, Geng B, Xia Y. The association between body fat distribution and bone mineral density: evidence from the US population. BMC Endocr Disord 2022; 22:170. [PMID: 35787696 PMCID: PMC9254427 DOI: 10.1186/s12902-022-01087-3] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Accepted: 06/27/2022] [Indexed: 12/02/2022] Open
Abstract
OBJECTIVE To investigate the association between different body fat distribution and different sites of BMD in male and female populations. METHODS Use the National Health and Nutrition Examination Survey (NHANES) datasets to select participants. The weighted linear regression model investigated the difference in body fat and Bone Mineral Density (BMD) in different gender. Multivariate adjusted smoothing curve-fitting and multiple linear regression models were used to explore whether an association existed between body fat distribution and BMD. Last, a subgroup analysis was performed according to age and gender group. RESULTS Overall, 2881 participants were included in this study. Compared to males, female participants had lower BMD (P < 0.05) and higher Gynoid fat mass (P < 0.00001), while there was no difference between Android fat mass (P = 0.91). Android fat mass was positively associated with Total femur BMD (Males, β = 0.044, 95% CI = 0.037, 0.051, P < 0.00001; Females, β = 0.044, 95% CI = 0.039, 0.049, P < 0.00001), Femoral neck BMD (Males, β = 0.034, 95% CI = 0.027, 0.041, P < 0.00001; Females, β = 0.032, 95% CI = 0.027, 0.037, P < 0.00001), and Total spine BMD (Males, β = 0.036, 95% CI = 0.029, 0.044, P < 0.00001; Females, β = 0.025, 95% CI = 0.019, 0.031, P < 0.00001). The Gynoid fat mass, subgroup analysis of age and ethnicity reached similar results. CONCLUSION Body fat in different regions was positively associated with BMD in different sites, and this association persisted in subgroup analyses across age and race in different gender.
Collapse
Affiliation(s)
- Ming Ma
- Department of Orthopaedics, Gansu Key Laboratory of Orthopaedics, Lanzhou University Second Hospital, No. 82 Cuiyingmen, Chengguan District, Lanzhou City, 730000 Gansu Province China
- Second Clinical Medical School, Lanzhou University, No. 82 Cuiyingmen, Chengguan District, Lanzhou City, 730000 Gansu Province China
- Orthopaedic Clinical Medical Research Center, No. 82 Cuiyingmen, Chengguan District, Lanzhou City, 730000 Gansu Province China
| | - Xiaolong Liu
- Department of Orthopaedics, Gansu Key Laboratory of Orthopaedics, Lanzhou University Second Hospital, No. 82 Cuiyingmen, Chengguan District, Lanzhou City, 730000 Gansu Province China
- Second Clinical Medical School, Lanzhou University, No. 82 Cuiyingmen, Chengguan District, Lanzhou City, 730000 Gansu Province China
- Orthopaedic Clinical Medical Research Center, No. 82 Cuiyingmen, Chengguan District, Lanzhou City, 730000 Gansu Province China
| | - Gengxin Jia
- Department of Orthopaedics, Gansu Key Laboratory of Orthopaedics, Lanzhou University Second Hospital, No. 82 Cuiyingmen, Chengguan District, Lanzhou City, 730000 Gansu Province China
- Second Clinical Medical School, Lanzhou University, No. 82 Cuiyingmen, Chengguan District, Lanzhou City, 730000 Gansu Province China
- Orthopaedic Clinical Medical Research Center, No. 82 Cuiyingmen, Chengguan District, Lanzhou City, 730000 Gansu Province China
| | - Bin Geng
- Department of Orthopaedics, Gansu Key Laboratory of Orthopaedics, Lanzhou University Second Hospital, No. 82 Cuiyingmen, Chengguan District, Lanzhou City, 730000 Gansu Province China
- Second Clinical Medical School, Lanzhou University, No. 82 Cuiyingmen, Chengguan District, Lanzhou City, 730000 Gansu Province China
- Orthopaedic Clinical Medical Research Center, No. 82 Cuiyingmen, Chengguan District, Lanzhou City, 730000 Gansu Province China
- Technology Center for Intelligent Orthopedic Industry, No. 82 Cuiyingmen, Chengguan District, Lanzhou City, 730000 Gansu Province China
| | - Yayi Xia
- Department of Orthopaedics, Gansu Key Laboratory of Orthopaedics, Lanzhou University Second Hospital, No. 82 Cuiyingmen, Chengguan District, Lanzhou City, 730000 Gansu Province China
- Second Clinical Medical School, Lanzhou University, No. 82 Cuiyingmen, Chengguan District, Lanzhou City, 730000 Gansu Province China
- Orthopaedic Clinical Medical Research Center, No. 82 Cuiyingmen, Chengguan District, Lanzhou City, 730000 Gansu Province China
- Technology Center for Intelligent Orthopedic Industry, No. 82 Cuiyingmen, Chengguan District, Lanzhou City, 730000 Gansu Province China
| |
Collapse
|
|
16
|
Ning K, Liu S, Yang B, Wang R, Man G, Wang DE, Xu H. Update on the Effects of Energy Metabolism in Bone Marrow Mesenchymal Stem Cells Differentiation. Mol Metab 2022; 58:101450. [PMID: 35121170 PMCID: PMC8888956 DOI: 10.1016/j.molmet.2022.101450] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 01/16/2022] [Accepted: 01/27/2022] [Indexed: 11/29/2022] Open
Abstract
Background As common progenitor cells of osteoblasts and adipocytes, bone marrow mesenchymal (stromal) stem cells (BMSCs) play key roles in bone homeostasis, tissue regeneration, and global energy homeostasis; however, the intrinsic mechanism of BMSC differentiation is not well understood. Plasticity in energy metabolism allows BMSCs to match the divergent demands of osteo-adipogenic differentiation. Targeting BMSC metabolic pathways may provide a novel therapeutic perspective for BMSC differentiation unbalance related diseases. Scope of review This review covers the recent studies of glucose, fatty acids, and amino acids metabolism fuel the BMSC differentiation. We also discuss recent findings about energy metabolism in BMSC differentiation. Major conclusions Glucose, fatty acids, and amino acids metabolism provide energy to fuel BMSC differentiation. Moreover, some well-known regulators including environmental stress, hormone drugs, and biological and pathological factors may also influence BMSC differentiation by altering metabolism. This offers insight to the significance of metabolism on BMSC fate determination and provides the possibility of treating diseases related to BMSC differentiation, such as obesity and osteoporosis, from a metabolic perspective.
Collapse
|
|
17
|
Mele C, Caputo M, Ferrero A, Daffara T, Cavigiolo B, Spadaccini D, Nardone A, Prodam F, Aimaretti G, Marzullo P. Bone Response to Weight Loss Following Bariatric Surgery. Front Endocrinol (Lausanne) 2022; 13:921353. [PMID: 35873004 PMCID: PMC9301317 DOI: 10.3389/fendo.2022.921353] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Accepted: 05/23/2022] [Indexed: 11/28/2022] Open
Abstract
Obesity is a global health challenge that warrants effective treatments to avoid its multiple comorbidities. Bariatric surgery, a cornerstone treatment to control bodyweight excess and relieve the health-related burdens of obesity, can promote accelerated bone loss and affect skeletal strength, particularly after malabsorptive and mixed surgical procedures, and probably after restrictive surgeries. The increase in bone resorption markers occurs early and persist for up to 12 months or longer after bariatric surgery, while bone formation markers increase but to a lesser extent, suggesting a potential uncoupling process between resorption and formation. The skeletal response to bariatric surgery, as investigated by dual-energy X-ray absorptiometry (DXA), has shown significant loss in bone mineral density (BMD) at the hip with less consistent results for the lumbar spine. Supporting DXA studies, analyses by high-resolution peripheral quantitative computed tomography (HR-pQCT) showed lower cortical density and thickness, higher cortical porosity, and lower trabecular density and number for up to 5 years after bariatric surgery. These alterations translate into an increased risk of fall injury, which contributes to increase the fracture risk in patients who have been subjected to bariatric surgery procedures. As bone deterioration continues for years following bariatric surgery, the fracture risk does not seem to be dependent on acute weight loss but, rather, is a chronic condition with an increasing impact over time. Among the post-bariatric surgery mechanisms that have been claimed to act globally on bone health, there is evidence that micro- and macro-nutrient malabsorptive factors, mechanical unloading and changes in molecules partaking in the crosstalk between adipose tissue, bone and muscle may play a determining role. Given these circumstances, it is conceivable that bone health should be adequately investigated in candidates to bariatric surgery through bone-specific work-up and dedicated postsurgical follow-up. Specific protocols of nutrients supplementation, motor activity, structured rehabilitative programs and, when needed, targeted therapeutic strategies should be deemed as an integral part of post-bariatric surgery clinical support.
Collapse
Affiliation(s)
- Chiara Mele
- Department of Clinical-Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy
- *Correspondence: Chiara Mele,
| | - Marina Caputo
- Department of Health Sciences, University of Piemonte Orientale, Novara, Italy
- Division of Endocrinology, University Hospital “Maggiore della Carità”, Novara, Italy
| | - Alice Ferrero
- Division of Endocrinology, University Hospital “Maggiore della Carità”, Novara, Italy
| | - Tommaso Daffara
- Division of Endocrinology, University Hospital “Maggiore della Carità”, Novara, Italy
| | - Beatrice Cavigiolo
- Division of Endocrinology, University Hospital “Maggiore della Carità”, Novara, Italy
| | - Daniele Spadaccini
- Department of Health Sciences, University of Piemonte Orientale, Novara, Italy
| | - Antonio Nardone
- Department of Clinical-Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy
- Istituti Clinici Scientifici Maugeri IRCCS, Neurorehabilitation and Spinal Unit of Pavia Institute, Pavia, and Neurorehabilitation of Montescano Institute, Montescano, PV, Italy
| | - Flavia Prodam
- Department of Health Sciences, University of Piemonte Orientale, Novara, Italy
- Division of Endocrinology, University Hospital “Maggiore della Carità”, Novara, Italy
| | - Gianluca Aimaretti
- Division of Endocrinology, University Hospital “Maggiore della Carità”, Novara, Italy
- Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
| | - Paolo Marzullo
- Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
- Istituto Auxologico Italiano, IRCCS, Laboratory of Metabolic Research, S. Giuseppe Hospital, Piancavallo, Italy
| |
Collapse
|
|
18
|
Ali D, Tencerova M, Figeac F, Kassem M, Jafari A. The pathophysiology of osteoporosis in obesity and type 2 diabetes in aging women and men: The mechanisms and roles of increased bone marrow adiposity. Front Endocrinol (Lausanne) 2022; 13:981487. [PMID: 36187112 PMCID: PMC9520254 DOI: 10.3389/fendo.2022.981487] [Citation(s) in RCA: 58] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Accepted: 08/29/2022] [Indexed: 11/13/2022] Open
Abstract
Osteoporosis is defined as a systemic skeletal disease characterized by decreased bone mass and micro-architectural deterioration leading to increased fracture risk. Osteoporosis incidence increases with age in both post-menopausal women and aging men. Among other important contributing factors to bone fragility observed in osteoporosis, that also affect the elderly population, are metabolic disturbances observed in obesity and Type 2 Diabetes (T2D). These metabolic complications are associated with impaired bone homeostasis and a higher fracture risk. Expansion of the Bone Marrow Adipose Tissue (BMAT), at the expense of decreased bone formation, is thought to be one of the key pathogenic mechanisms underlying osteoporosis and bone fragility in obesity and T2D. Our review provides a summary of mechanisms behind increased Bone Marrow Adiposity (BMA) during aging and highlights the pre-clinical and clinical studies connecting obesity and T2D, to BMA and bone fragility in aging osteoporotic women and men.
Collapse
Affiliation(s)
- Dalia Ali
- Department of Molecular Endocrinology, KMEB, University of Southern Denmark and Odense University Hospital, Odense, Denmark
- *Correspondence: Dalia Ali, ; Abbas Jafari,
| | - Michaela Tencerova
- Laboratory of Molecular Physiology of Bone, Institute of Physiology of the Czech Academy of Sciences, Prague, Czechia
| | - Florence Figeac
- Department of Molecular Endocrinology, KMEB, University of Southern Denmark and Odense University Hospital, Odense, Denmark
| | - Moustapha Kassem
- Department of Molecular Endocrinology, KMEB, University of Southern Denmark and Odense University Hospital, Odense, Denmark
| | - Abbas Jafari
- Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark
- *Correspondence: Dalia Ali, ; Abbas Jafari,
| |
Collapse
|
|
19
|
Obesity and Bone Loss at Menopause: The Role of Sclerostin. Diagnostics (Basel) 2021; 11:diagnostics11101914. [PMID: 34679612 PMCID: PMC8534901 DOI: 10.3390/diagnostics11101914] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Revised: 10/06/2021] [Accepted: 10/11/2021] [Indexed: 11/20/2022] Open
Abstract
Background. Peripheral fat tissue is known to positively influence bone health. However, evidence exists that the risk of non-vertebral fractures can be increased in postmenopausal women with obesity as compared to healthy controls. The role of sclerostin, the SOST gene protein product, and body composition in this condition is unknown. Methods. We studied 28 severely obese premenopausal (age, 44.7 ± 3.9 years; BMI, 46.0 ± 4.2 kg/m2) and 28 BMI-matched post-menopausal women (age, 55.5 ± 3.8 years; BMI, 46.1 ± 4.8 kg/m2) thorough analysis of bone density (BMD) and body composition by dual X-ray absorptiometry (DXA), bone turnover markers, sclerostin serum concentration, glucose metabolism, and a panel of hormones relating to bone health. Results. Postmenopausal women harbored increased levels of the bone turnover markers CTX and NTX, while sclerostin levels were non-significantly higher as compared to premenopausal women. There were no differences in somatotroph, thyroid and adrenal hormone across menopause. Values of lumbar spine BMD were comparable between groups. By contrast, menopause was associated with lower BMD values at the hip (p < 0.001), femoral neck (p < 0.0001), and total skeleton (p < 0.005). In multivariate regression analysis, sclerostin was the strongest predictor of lumbar spine BMD (p < 0.01), while menopausal status significantly predicted BMD at total hip (p < 0.01), femoral neck (p < 0.001) and total body (p < 0.05). Finally, lean body mass emerged as the strongest predictor of total body BMD (p < 0.01). Conclusions. Our findings suggest a protective effect of obesity on lumbar spine and total body BMD at menopause possibly through mechanisms relating to lean body mass. Given the mild difference in sclerostin levels between pre- and postmenopausal women, its potential actions in obesity require further investigation.
Collapse
|
|
20
|
Freire EBL, d’Alva CB, Madeira MP, Lima GEDCP, Montenegro APDR, Fernandes VO, Montenegro Junior RM. Bone Mineral Density in Congenital Generalized Lipodystrophy: The Role of Bone Marrow Tissue, Adipokines, and Insulin Resistance. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2021; 18:9724. [PMID: 34574647 PMCID: PMC8465110 DOI: 10.3390/ijerph18189724] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Revised: 07/05/2021] [Accepted: 07/16/2021] [Indexed: 12/31/2022]
Abstract
Congenital Generalized Lipodystrophy (CGL) is a rare syndrome characterized by the almost total absence of subcutaneous adipose tissue due to the inability of storing lipid in adipocytes. Patients present generalized lack of subcutaneous fat and normal to low weight. They evolve with severe metabolic disorders, non-alcoholic fatty liver disease, early cardiac abnormalities, and infectious complications. Although low body weight is a known risk factor for osteoporosis, it has been reported that type 1 and 2 CGL have a tendency of high bone mineral density (BMD). In this review, we discuss the role of bone marrow tissue, adipokines, and insulin resistance in the setting of the normal to high BMD of CGL patients. Data bases from Pubmed and LILACS were searched, and 113 articles published until 10 April 2021 were obtained. Of these, 76 were excluded for not covering the review topic. A manual search for additional literature was performed using the bibliographies of the studies located. The elucidation of the mechanisms responsible for the increase in BMD in this unique model of insulin resistance may contribute to the understanding of the interrelationships between bone, muscle, and adipose tissue in a pathophysiological and therapeutic perspective.
Collapse
Affiliation(s)
| | | | | | | | | | | | - Renan Magalhães Montenegro Junior
- Clinical Research Unit, Walter Cantídio University Hospital, Federal University of Ceará, Fortaleza 60416200, CE, Brazil; (E.B.L.F.); (C.B.d.); (M.P.M.); (G.E.d.C.P.L.); (A.P.D.R.M.); (V.O.F.)
| | | |
Collapse
|
|
21
|
Abstract
Multiple myeloma (MM) is a haematological malignancy characterised by the proliferation and accumulation of terminally differentiated abnormal plasma cells in the bone marrow. Patients suffer from bone pain, factures, anaemia, osteolytic lesions and renal failure. Despite recent advancement in therapy MM remains an incurable disease due to the emergences of drug resistance and frequent relapse. For many decades, research has been heavily focused on understanding the relationship between bone cells such as osteoblast, osteocytes and osteoclasts and the infiltrating tumour cells. However, it is now clear that the tumour-supportive bone microenvironment including cellular and non-cellular components play an important role in driving MM progression and bone disease. One of the most abundant cell types in the bone microenvironment is the bone marrow adipocyte (BMAd). Once thought of as inert space filling cells, they have now been recognised as having specialised functions, signalling in an autocrine, paracrine and endocrine manner to support normal systemic homeostasis. BMAds are both an energy store and a source of secreted adipokines and bioactive substances, MM cells are able to hijack this metabolic machinery to fuel migration, growth and survival. With global obesity on the rise, it has never been more important to further understand the contribution these cells have in both normal and disease settings. The aim of this review is to summarise the large body of emerging evidence supporting the interplay between BMAds and MM cells and to delineate how they fit into the vicious cycle of disease.
Collapse
Affiliation(s)
- Emma V Morris
- Nuffield Dept. of Surgical Sciences, University of Oxford, UK.
| | - Claire M Edwards
- Nuffield Dept. of Surgical Sciences, University of Oxford, UK; Nuffield Dept. of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, UK
| |
Collapse
|
|
22
|
Matsushita Y, Chu AKY, Ono W, Welch JD, Ono N. Intercellular Interactions of an Adipogenic CXCL12-Expressing Stromal Cell Subset in Murine Bone Marrow. J Bone Miner Res 2021; 36:1145-1158. [PMID: 33651379 PMCID: PMC8605623 DOI: 10.1002/jbmr.4282] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Revised: 01/08/2021] [Accepted: 02/24/2021] [Indexed: 01/08/2023]
Abstract
Bone marrow houses a multifunctional stromal cell population expressing C-X-C motif chemokine ligand 12 (CXCL12), termed CXCL12-abundant reticular (CAR) cells, that regulates osteogenesis and adipogenesis. The quiescent pre-adipocyte-like subset of CXCL12+ stromal cells ("Adipo-CAR" cells) is localized to sinusoidal surfaces and particularly enriched for hematopoiesis-supporting cytokines. However, detailed characteristics of these CXCL12+ pre-adipocyte-like stromal cells and how they contribute to marrow adipogenesis remain largely unknown. Here we highlight CXCL12-dependent physical coupling with hematopoietic cells as a potential mechanism regulating the adipogenic potential of CXCL12+ stromal cells. Single-cell computational analyses of RNA velocity and cell signaling reveal that Adipo-CAR cells exuberantly communicate with hematopoietic cells through CXCL12-CXCR4 ligand-receptor interactions but do not interconvert with Osteo-CAR cells. Consistent with this computational prediction, a substantial fraction of Cxcl12-creER+ pre-adipocyte-like cells intertwines with hematopoietic cells in vivo and in single-cell preparation in a protease-sensitive manner. Deletion of CXCL12 in these cells using Col2a1-cre leads to a reduction of stromal-hematopoietic coupling and extensive marrow adipogenesis in adult bone marrow, which appears to involve direct conversion of CXCL12+ cells to lipid-laden marrow adipocytes without altering mesenchymal progenitor cell fates. Therefore, these findings suggest that CXCL12+ pre-adipocyte-like marrow stromal cells prevent their premature differentiation by maintaining physical coupling with hematopoietic cells in a CXCL12-dependent manner, highlighting a possible cell-non-autonomous mechanism that regulates marrow adipogenesis. © 2021 American Society for Bone and Mineral Research (ASBMR).
Collapse
Affiliation(s)
- Yuki Matsushita
- University of Michigan School of Dentistry, Ann Arbor, MI, USA
| | - Angel Ka Yan Chu
- Department of Computational Medicine and Bioinformatics, Department of Computer Science and Engineering, University of Michigan, Ann Arbor, MI, USA
| | - Wanida Ono
- University of Michigan School of Dentistry, Ann Arbor, MI, USA
| | - Joshua D Welch
- Department of Computational Medicine and Bioinformatics, Department of Computer Science and Engineering, University of Michigan, Ann Arbor, MI, USA
| | - Noriaki Ono
- University of Michigan School of Dentistry, Ann Arbor, MI, USA
| |
Collapse
|
|
23
|
Polito R, Monda V, Nigro E, Messina A, Di Maio G, Giuliano MT, Orrù S, Imperlini E, Calcagno G, Mosca L, Mollica MP, Trinchese G, Scarinci A, Sessa F, Salerno M, Marsala G, Buono P, Mancini A, Monda M, Daniele A, Messina G. The Important Role of Adiponectin and Orexin-A, Two Key Proteins Improving Healthy Status: Focus on Physical Activity. Front Physiol 2020; 11:356. [PMID: 32390865 PMCID: PMC7188914 DOI: 10.3389/fphys.2020.00356] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Accepted: 03/27/2020] [Indexed: 12/15/2022] Open
Abstract
Exercise represents the most important integrative therapy in metabolic, immunologic and chronic diseases; it represents a valid strategy in the non-pharmacological intervention of lifestyle linked diseases. A large body of evidence indicates physical exercise as an effective measure against chronic non-communicable diseases. The worldwide general evidence for health benefits are both for all ages and skill levels. In a dysregulated lifestyle such as in the obesity, there is an imbalance in the production of different cytokines. In particular, we focused on Adiponectin, an adipokine producted by adipose tissue, and on Orexin-A, a neuropeptide synthesized in the lateral hypothalamus. The production of both Adiponectin and Orexin-A increases following regular and structured physical activity and both these hormones have similar actions. Indeed, they improve energy and glucose metabolism, and also modulate energy expenditure and thermogenesis. In addition, a relevant biological role of Adiponectin and Orexin A has been recently highlighted in the immune system, where they function as immune-suppressor factors. The strong connection between these two cytokines and healthy status is mediated by physical activity and candidates these hormones as potential biomarkers of the beneficial effects induced by physical activity. For these reasons, this review aims to underly the interconnections among Adiponectin, Orexin-A, physical activity and healthy status. Furthermore, it is analyzed the involvement of Adiponectin and Orexin-A in physical activity as physiological factors improving healthy status through physical exercise.
Collapse
Affiliation(s)
- Rita Polito
- Dipartimento di Scienze e Tecnologie Ambientali Biologiche e Farmaceutiche, University of Campania "Luigi Vanvitelli", Caserta, Italy.,Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy
| | - Vincenzo Monda
- Dipartimento di Medicina Sperimentale, Sezione di Fisiologia Umana e Unità di Dietetica e Medicina dello Sport, Università degli Studi della Campania "Luigi Vanvitelli", Naples, Italy
| | - Ersilia Nigro
- Dipartimento di Scienze e Tecnologie Ambientali Biologiche e Farmaceutiche, University of Campania "Luigi Vanvitelli", Caserta, Italy.,Ceinge Biotecnologie Avanzate S. C. a R. L., Naples, Italy
| | - Antonietta Messina
- Dipartimento di Medicina Sperimentale, Sezione di Fisiologia Umana e Unità di Dietetica e Medicina dello Sport, Università degli Studi della Campania "Luigi Vanvitelli", Naples, Italy
| | - Girolamo Di Maio
- Dipartimento di Medicina Sperimentale, Sezione di Fisiologia Umana e Unità di Dietetica e Medicina dello Sport, Università degli Studi della Campania "Luigi Vanvitelli", Naples, Italy
| | - Maria Teresa Giuliano
- Dipartimento di Medicina Sperimentale, Sezione di Fisiologia Umana e Unità di Dietetica e Medicina dello Sport, Università degli Studi della Campania "Luigi Vanvitelli", Naples, Italy
| | - Stefania Orrù
- Dipartimento di Scienze Motorie e del Benessere, Università degli Studi di Napoli "Parthenope", Naples, Italy.,IRCCS SDN, Naples, Italy
| | | | - Giuseppe Calcagno
- Dipartimento di Medicina e Scienze della Salute "Vincenzo Tiberio", Università degli Studi del Molise, Campobasso, Italy
| | - Laura Mosca
- Dipartimento di Biologia, Universitá degli studi di Napoli Federico II, Naples, Italy
| | - Maria Pina Mollica
- Dipartimento di Biologia, Universitá degli studi di Napoli Federico II, Naples, Italy
| | - Giovanna Trinchese
- Dipartimento di Biologia, Universitá degli studi di Napoli Federico II, Naples, Italy
| | - Alessia Scarinci
- Dipartimento di Scienze della Formazione, Psicologia, Comunicazione, Università degli Studi di Bari Aldo Moro, Bari, Italy
| | - Francesco Sessa
- Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy
| | - Monica Salerno
- Department of Medical, Surgery Sciences and Advanced Technologies "G.F. Ingrassia", University of Catania, Catania, Italy
| | - Gabriella Marsala
- Struttura Complessa di Farmacia, Azienda Ospedaliero Universitaria - Ospedali Riuniti, Foggia, Italy
| | - Pasqualina Buono
- Ceinge Biotecnologie Avanzate S. C. a R. L., Naples, Italy.,Dipartimento di Scienze Motorie e del Benessere, Università degli Studi di Napoli "Parthenope", Naples, Italy.,IRCCS SDN, Naples, Italy
| | - Annamaria Mancini
- Ceinge Biotecnologie Avanzate S. C. a R. L., Naples, Italy.,Dipartimento di Scienze Motorie e del Benessere, Università degli Studi di Napoli "Parthenope", Naples, Italy
| | - Marcellino Monda
- Dipartimento di Medicina Sperimentale, Sezione di Fisiologia Umana e Unità di Dietetica e Medicina dello Sport, Università degli Studi della Campania "Luigi Vanvitelli", Naples, Italy
| | - Aurora Daniele
- Dipartimento di Scienze e Tecnologie Ambientali Biologiche e Farmaceutiche, University of Campania "Luigi Vanvitelli", Caserta, Italy.,Ceinge Biotecnologie Avanzate S. C. a R. L., Naples, Italy
| | - Giovanni Messina
- Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy
| |
Collapse
|
|
24
|
Yang Y, Liu Q, Zhang L, Fu X, Chen J, Hong D. A modified tape transfer approach for rapidly preparing high-quality cryosections of undecalcified adult rodent bones. J Orthop Translat 2020; 26:92-100. [PMID: 33437628 PMCID: PMC7773961 DOI: 10.1016/j.jot.2020.03.001] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Revised: 02/18/2020] [Accepted: 03/02/2020] [Indexed: 12/28/2022] Open
Abstract
Background/Objective Histology-based analyses are important tools to dissect cellular and molecular mechanisms of skeletal homeostasis, diseases, and regeneration. The success of these efforts is highly dependent on rapidly obtaining high-quality sections of mineralized skeletal tissues suitable for various analyses. However, the current techniques for preparing such sections are still far from satisfactory. This study aimed to develop a new approach for preparing high-quality undecalcified bone sections applicable to various histological analyses. Methods Two important modifications were made to the conventional Cryojane Tape-Transfer System, including utilization of an optimized adhesive to prepare adhesive glass slides for improving the transfer efficiency, and a cheap conventional benchtop UV transilluminator for UV curing. Cryosections of undecalcified rodent bones were prepared using this modified tape transfer approach, and their tissue morphology and structural integrity were visually examined. A variety of histological analyses, including calcein labeling, Von kossa staining, immunofluorescence, and enzymatic activity staining as well as 5-Ethynyl-2’-deoxyuridine (EdU) and TUNEL assays, were performed on these sections. Results We developed a modified version of tape transfer approach that can prepare cryosections of undecalcified rodent adult bones within 4 days at a low cost. Bone sections prepared by this approach exhibited good tissue morphology and structural integrity. Moreover, these sections were applicable to a variety of histological analyses, including calcein labeling, Von kossa staining, immunofluorescence, and enzymatic activity staining as well as EdU and TUNEL assays. Conclusion The tape transfer approach we developed provides a rapid, affordable, and easy learning method for preparing high-quality undecalcified bone sections valuable for bone research. The translational potential of this article Our research provides a rapid, affordable, and easy learning method for preparing high-quality undecalcified bone sections that can be potentially used for accurate diagnosis of various bone disorders and evaluation of the efficacy of different therapies in the treatment of these diseases.
Collapse
Affiliation(s)
- Yanjun Yang
- Orthopedic Institute, Medical College, Soochow University, Suzhou, Jiangsu, China.,Department of Orthopedics, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Qingbai Liu
- Department of Orthopedics, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.,Department of Orthopedics, Lianshui County People's Hospital, Huaian, Jiangsu, China
| | - Liwei Zhang
- Orthopedic Institute, Medical College, Soochow University, Suzhou, Jiangsu, China.,Orthopedic Department, Taizhou Hospital Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
| | - Xuejie Fu
- Orthopedic Institute, Medical College, Soochow University, Suzhou, Jiangsu, China.,Department of Orthopedics, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Jianquan Chen
- Orthopedic Institute, Medical College, Soochow University, Suzhou, Jiangsu, China.,Department of Orthopedics, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Dun Hong
- Orthopedic Department, Taizhou Hospital Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
| |
Collapse
|
|
25
|
Abstract
PURPOSE OF REVIEW To review the available literature regarding a possible relationship between vitamin D and bone marrow adipose tissue (BMAT), and to identify future avenues of research that warrant attention. RECENT FINDINGS Results from in vivo animal and human studies all support the hypothesis that vitamin D can suppress BMAT expansion. This is achieved by antagonizing adipogenesis in bone marrow stromal cells, through inhibition of PPARγ2 activity and stimulation of pro-osteogenic Wnt signalling. However, our understanding of the functions of BMAT is still evolving, and studies on the role of vitamin D in modulating BMAT function are lacking. In addition, many diseases and chronic conditions are associated with low vitamin D status and low bone mineral density (BMD), but BMAT expansion has not been studied in these patient populations. Vitamin D suppresses BMAT expansion, but its role in modulating BMAT function is poorly understood.
Collapse
Affiliation(s)
- Hanel Sadie-Van Gijsen
- Division of Medical Physiology, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University Tygerberg Campus, Francie van Zijl Drive, PO Box 241, Parow, Cape Town, 8000, South Africa.
| |
Collapse
|
|
26
|
Li Y, Hao H, Zhong Z, Li M, Li J, Du Y, Wu X, Wang J, Zhang S. Assembly Mechanism of Highly Crystalline Selenium-Doped Hydroxyapatite Nanorods via Particle Attachment and Their Effect on the Fate of Stem Cells. ACS Biomater Sci Eng 2019; 5:6703-6714. [DOI: 10.1021/acsbiomaterials.9b01029] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Affiliation(s)
- Yan Li
- Advanced Biomaterials and Tissue Engineering Center and Department of Biomedical Engineering, Huazhong University of Science and Technology, Wuhan 430074, China
| | - Hang Hao
- Advanced Biomaterials and Tissue Engineering Center and Department of Biomedical Engineering, Huazhong University of Science and Technology, Wuhan 430074, China
| | - Zhengyu Zhong
- Advanced Biomaterials and Tissue Engineering Center and Department of Biomedical Engineering, Huazhong University of Science and Technology, Wuhan 430074, China
| | - Mengdie Li
- Advanced Biomaterials and Tissue Engineering Center and Department of Biomedical Engineering, Huazhong University of Science and Technology, Wuhan 430074, China
| | - Jiaqi Li
- Advanced Biomaterials and Tissue Engineering Center and Department of Biomedical Engineering, Huazhong University of Science and Technology, Wuhan 430074, China
| | - Yingying Du
- Advanced Biomaterials and Tissue Engineering Center and Department of Biomedical Engineering, Huazhong University of Science and Technology, Wuhan 430074, China
| | - Xiaodan Wu
- Advanced Biomaterials and Tissue Engineering Center and Department of Biomedical Engineering, Huazhong University of Science and Technology, Wuhan 430074, China
| | - Jianglin Wang
- Advanced Biomaterials and Tissue Engineering Center and Department of Biomedical Engineering, Huazhong University of Science and Technology, Wuhan 430074, China
| | - Shengmin Zhang
- Advanced Biomaterials and Tissue Engineering Center and Department of Biomedical Engineering, Huazhong University of Science and Technology, Wuhan 430074, China
| |
Collapse
|
|
27
|
Murray CE, Coleman CM. Impact of Diabetes Mellitus on Bone Health. Int J Mol Sci 2019; 20:ijms20194873. [PMID: 31575077 PMCID: PMC6801685 DOI: 10.3390/ijms20194873] [Citation(s) in RCA: 120] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Revised: 09/26/2019] [Accepted: 09/27/2019] [Indexed: 12/21/2022] Open
Abstract
Long-term exposure to a diabetic environment leads to changes in bone metabolism and impaired bone micro-architecture through a variety of mechanisms on molecular and structural levels. These changes predispose the bone to an increased fracture risk and impaired osseus healing. In a clinical practice, adequate control of diabetes mellitus is essential for preventing detrimental effects on bone health. Alternative fracture risk assessment tools may be needed to accurately determine fracture risk in patients living with diabetes mellitus. Currently, there is no conclusive model explaining the mechanism of action of diabetes mellitus on bone health, particularly in view of progenitor cells. In this review, the best available literature on the impact of diabetes mellitus on bone health in vitro and in vivo is summarised with an emphasis on future translational research opportunities in this field.
Collapse
Affiliation(s)
- Cliodhna E Murray
- Regenerative Medicine Institute, National University of Ireland, Galway, Biomedical Sciences Building, Dangan, Newcastle Road, Galway City, County Galway, H91W2TY, Ireland.
| | - Cynthia M Coleman
- Regenerative Medicine Institute, National University of Ireland, Galway, Biomedical Sciences Building, Dangan, Newcastle Road, Galway City, County Galway, H91W2TY, Ireland.
| |
Collapse
|
|
28
|
The Importance of Restoring Body Fat Mass in the Treatment of Anorexia Nervosa: An Expert Commentary. JOURNAL OF POPULATION THERAPEUTICS AND CLINICAL PHARMACOLOGY 2019; 26:e9-e13. [PMID: 31904201 DOI: 10.15586/jptcp.v26i3.629] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Accepted: 08/20/2019] [Indexed: 11/18/2022]
Abstract
Anorexia nervosa is a severe mental disorder that is characterised by dietary restriction, low weight and widespread endocrine abnormalities. Whilst the importance of weight restoration has been recognised in recent guidelines, the significance of normalising body fat mass has received less attention. A recent systematic review and meta-analysis found that a minimum of 20.5% body fat mass is necessary for regular menses in women with anorexia nervosa of reproductive age. This has significant implications for both treatment and research. It is important to help the patient and carers understand that a certain level of body fat percentage is essential for optimal health, such as the return of menstruation. Further research is needed into how best to use this information to help motivation to change as part of treatment. The benefit of the return of menstruation goes beyond improved fertility: it signals the normalisation of sexual hormones, which have a widespread impact on the body and multiple pathways in the brain. Given the complex functions of adipocytes in various organs of the body, the metabolic effects of the normal body fat tissue should not be underestimated. Further research is needed to elucidate the mechanisms behind the link between minimum body fat mass, menstruation, bone and brain health in anorexia nervosa.
Collapse
|
|
29
|
Farahnak Z, Yuan Y, Vanstone CA, Weiler HA. Maternal and neonatal red blood cell n-3 polyunsaturated fatty acids inversely associate with infant whole-body fat mass assessed by dual-energy X-ray absorptiometry. Appl Physiol Nutr Metab 2019; 45:318-326. [PMID: 31437414 DOI: 10.1139/apnm-2019-0311] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Research regarding polyunsaturated fatty acid (PUFA) status and body composition in neonates is limited. This study tested the relationship between newborn docosahexaenoic acid (DHA) status and body composition. Healthy mothers and their term-born infants (n = 100) were studied within 1 month postpartum for anthropometry and whole-body composition using dual-energy X-ray absorptiometry. Maternal and infant red blood cell (RBC) membrane PUFA profiles were measured using gas chromatography (expressed as percentage of total fatty acids). Data were grouped according to infant RBC DHA quartiles and tested for differences in n-3 status and infant body composition using mixed-model ANOVA, Spearman correlations, and regression analyses (P < 0.05). Mothers were 32.2 ± 4.6 years (mean ± SD) of age, infants (54% males) were 0.68 ± 0.23 month of age, and 80% exclusively breastfed. Infant RBC DHA (ranged 3.96% to 7.75% of total fatty acids) inversely associated with infant fat mass (r = -0.22, P = 0.03). Infant and maternal RBC n-6/n-3 PUFA ratio (r2 = 0.28, P = 0.043; r2 = 0.28, P = 0.041 respectively) were positively associated with fat mass. These results demonstrate that both maternal and infant long-chain PUFA status are associated with neonatal body composition. Novelty Our findings support an early window to further explore the relationship between infant n-3 PUFA status and body composition. Maternal and infant n-3 PUFA status is inversely related to neonatal whole-body fat mass. DHA appears to be the best candidate to test in the development of a lean body phenotype.
Collapse
Affiliation(s)
- Zahra Farahnak
- School of Human Nutrition, McGill University, Ste-Anne-de-Bellevue, QC H9X 3V9, Canada.,School of Human Nutrition, McGill University, Ste-Anne-de-Bellevue, QC H9X 3V9, Canada
| | - Ye Yuan
- School of Human Nutrition, McGill University, Ste-Anne-de-Bellevue, QC H9X 3V9, Canada.,School of Human Nutrition, McGill University, Ste-Anne-de-Bellevue, QC H9X 3V9, Canada
| | - Catherine A Vanstone
- School of Human Nutrition, McGill University, Ste-Anne-de-Bellevue, QC H9X 3V9, Canada.,School of Human Nutrition, McGill University, Ste-Anne-de-Bellevue, QC H9X 3V9, Canada
| | - Hope A Weiler
- School of Human Nutrition, McGill University, Ste-Anne-de-Bellevue, QC H9X 3V9, Canada.,School of Human Nutrition, McGill University, Ste-Anne-de-Bellevue, QC H9X 3V9, Canada
| |
Collapse
|
|
30
|
Farahnak Z, Freundorfer MT, Lavery P, Weiler HA. Dietary docosahexaenoic acid contributes to increased bone mineral accretion and strength in young female Sprague-Dawley rats. Prostaglandins Leukot Essent Fatty Acids 2019; 144:32-39. [PMID: 31088624 DOI: 10.1016/j.plefa.2019.04.005] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2018] [Revised: 04/17/2019] [Accepted: 04/17/2019] [Indexed: 11/24/2022]
Abstract
Growing evidence suggests that docosahexaenoic acid (DHA: 22:6n-3) enhances bone mineral content (BMC) and bone mineral density (BMD) in adulthood and during aging, however the effects during and after sexual maturation are unclear. The aim of this study was to examine the dose-response of BMC, BMD and microarchitectural properties of bone to dietary DHA in healthy growing female rats during acquisition of peak bone mass (PBM). Female Sprague-Dawley rats (n = 12/diet) were randomized to receive a control diet (AIN-93 M, 60 g soybean oil/kg diet) or an experimental diet containing 0.1, 0.4, 0.8 and 1.2% DHA (w/w of total diet) for 10 weeks. Dietary DHA increased the whole body, lumbar spine and long bone BMC compared to the control, in addition to higher aBMD and also BMD. Additionally, an increase in cortical bone microarchitecture parameters of lumbar spine as well as peak force were observed in dietary DHA diet groups. Dietary DHA contributes to PBM when consumed during and after sexual maturation, however higher doses of DHA do not provide further benefits.
Collapse
Affiliation(s)
- Zahra Farahnak
- School of Human Nutrition, McGill University, 21111 Lakeshore Rd, Ste-Anne-de-Bellevue, QC H9 × 3V9, Canada
| | - Marie Therese Freundorfer
- School of Human Nutrition, McGill University, 21111 Lakeshore Rd, Ste-Anne-de-Bellevue, QC H9 × 3V9, Canada
| | - Paula Lavery
- School of Human Nutrition, McGill University, 21111 Lakeshore Rd, Ste-Anne-de-Bellevue, QC H9 × 3V9, Canada
| | - Hope A Weiler
- School of Human Nutrition, McGill University, 21111 Lakeshore Rd, Ste-Anne-de-Bellevue, QC H9 × 3V9, Canada.
| |
Collapse
|
|
31
|
Wallner C, Huber J, Drysch M, Schmidt SV, Wagner JM, Dadras M, Dittfeld S, Becerikli M, Jaurich H, Lehnhardt M, Behr B. Activin Receptor 2 Antagonization Impairs Adipogenic and Enhances Osteogenic Differentiation in Mouse Adipose-Derived Stem Cells and Mouse Bone Marrow-Derived Stem Cells In Vitro and In Vivo. Stem Cells Dev 2019; 28:384-397. [PMID: 30654712 DOI: 10.1089/scd.2018.0155] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Tumors, traumata, burn injuries or surgeries can lead to critical-sized bony defects which need to be reconstructed. Mesenchymal stem cells (MSCs) have the ability to differentiate into multiple cell lineages and thus present a promising alternative for use in tissue engineering and reconstruction. However, there is an ongoing debate whether all MSCs are equivalent in their differentiation and proliferation ability. The goal of this study was to assess osteogenic and adipogenic characteristic changes of adipose-derived stem cells (ASCs) and bone marrow-derived stem cells (BMSCs) upon Myostatin inhibition with Follistatin in vitro and in vivo. We harvested ASCs from mice inguinal fat pads and BMSCs from tibiae of mice. By means of histology, real-time cell analysis, immunohistochemistry, and PCR osteogenic and adipogenic proliferation and differentiation in the presence or absence of Follistatin were analyzed. In vivo, osteogenic capacity was investigated in a tibial defect model of wild-type (WT) mice treated with mASCs and mBMSCs of Myo-/- and WT origin. In vitro, we were able to show that inhibition of Myostatin leads to markedly reduced proliferative capacity in mBMSCs and mASCs in adipogenic differentiation and reduced proliferation in osteogenic differentiation in mASCs, whereas proliferation in mBMSCs in osteogenic differentiation was increased. Adipogenic differentiation was inhibited in mASCs and mBMSCs upon Follistatin treatment, whereas osteogenic differentiation was increased in both cell lineages. In vivo, we could demonstrate increased osteoid formation in WT mice treated with mASCs and mBMSCs of Myo-/- origin and enhanced osteogenic differentiation and proliferation of mASCs of Myo-/- origin. We could demonstrate that the osteogenic potential of mASCs could be raised to a level comparable to mBMSCs upon inhibition of Myostatin. Moreover, Follistatin treatment led to inhibition of adipogenesis in both lineages.
Collapse
Affiliation(s)
- Christoph Wallner
- Department of Plastic Surgery, BG University Hospital Bergmannsheil, Ruhr University Bochum, Bochum, Germany
| | - Julika Huber
- Department of Plastic Surgery, BG University Hospital Bergmannsheil, Ruhr University Bochum, Bochum, Germany
| | - Marius Drysch
- Department of Plastic Surgery, BG University Hospital Bergmannsheil, Ruhr University Bochum, Bochum, Germany
| | - Sonja Verena Schmidt
- Department of Plastic Surgery, BG University Hospital Bergmannsheil, Ruhr University Bochum, Bochum, Germany
| | - Johannes Maximilian Wagner
- Department of Plastic Surgery, BG University Hospital Bergmannsheil, Ruhr University Bochum, Bochum, Germany
| | - Mehran Dadras
- Department of Plastic Surgery, BG University Hospital Bergmannsheil, Ruhr University Bochum, Bochum, Germany
| | - Stephanie Dittfeld
- Department of Plastic Surgery, BG University Hospital Bergmannsheil, Ruhr University Bochum, Bochum, Germany
| | - Mustafa Becerikli
- Department of Plastic Surgery, BG University Hospital Bergmannsheil, Ruhr University Bochum, Bochum, Germany
| | - Henriette Jaurich
- Department of Plastic Surgery, BG University Hospital Bergmannsheil, Ruhr University Bochum, Bochum, Germany
| | - Marcus Lehnhardt
- Department of Plastic Surgery, BG University Hospital Bergmannsheil, Ruhr University Bochum, Bochum, Germany
| | - Björn Behr
- Department of Plastic Surgery, BG University Hospital Bergmannsheil, Ruhr University Bochum, Bochum, Germany
| |
Collapse
|
|
32
|
Lombardi G, Ziemann E, Banfi G. Physical Activity and Bone Health: What Is the Role of Immune System? A Narrative Review of the Third Way. Front Endocrinol (Lausanne) 2019; 10:60. [PMID: 30792697 PMCID: PMC6374307 DOI: 10.3389/fendo.2019.00060] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2018] [Accepted: 01/22/2019] [Indexed: 12/12/2022] Open
Abstract
Bone tissue can be seen as a physiological hub of several stimuli of different origin (e.g., dietary, endocrine, nervous, immune, skeletal muscle traction, biomechanical load). Their integration, at the bone level, results in: (i) changes in mineral and protein composition and microarchitecture and, consequently, in shape and strength; (ii) modulation of calcium and phosphorous release into the bloodstream, (iii) expression and release of hormones and mediators able to communicate the current bone status to the rest of the body. Different stimuli are able to act on either one or, as usual, more levels. Physical activity is the key stimulus for bone metabolism acting in two ways: through the biomechanical load which resolves into a direct stimulation of the segment(s) involved and through an indirect load mediated by muscle traction onto the bone, which is the main physiological stimulus for bone formation, and the endocrine stimulation which causes homeostatic adaptation. The third way, in which physical activity is able to modify bone functions, passes through the immune system. It is known that immune function is modulated by physical activity; however, two recent insights have shed new light on this modulation. The first relies on the discovery of inflammasomes, receptors/sensors of the innate immunity that regulate caspase-1 activation and are, hence, the tissue triggers of inflammation in response to infections and/or stressors. The second relies on the ability of certain tissues, and particularly skeletal muscle and adipose tissue, to synthesize and secrete mediators (namely, myokines and adipokines) able to affect, profoundly, the immune function. Physical activity is known to act on both these mechanisms and, hence, its effects on bone are also mediated by the immune system activation. Indeed, that immune system and bone are tightly connected and inflammation is pivotal in determining the bone metabolic status is well-known. The aim of this narrative review is to give a complete view of the exercise-dependent immune system-mediated effects on bone metabolism and function.
Collapse
Affiliation(s)
- Giovanni Lombardi
- Laboratory of Experimental Biochemistry & Molecular Biology, IRCCS Istituto Ortopedico Galeazzi, Milan, Italy
- Department of Physiology and Pharmacology, Faculty of Rehabilitation and Kinesiology, Gdansk University of Physical Education and Sport, Gdansk, Poland
- *Correspondence: Giovanni Lombardi
| | - Ewa Ziemann
- Department of Physiology and Pharmacology, Faculty of Rehabilitation and Kinesiology, Gdansk University of Physical Education and Sport, Gdansk, Poland
| | - Giuseppe Banfi
- Laboratory of Experimental Biochemistry & Molecular Biology, IRCCS Istituto Ortopedico Galeazzi, Milan, Italy
- Vita-Salute San Raffaele University, Milan, Italy
| |
Collapse
|
|
33
|
Stakkestad Ø, Heyward C, Lyngstadaas SP, Medin T, Vondrasek J, Lian AM, Pezeshki G, Reseland JE. An ameloblastin C-terminus variant is present in human adipose tissue. Heliyon 2018; 4:e01075. [PMID: 30603708 PMCID: PMC6307104 DOI: 10.1016/j.heliyon.2018.e01075] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2018] [Revised: 10/02/2018] [Accepted: 12/14/2018] [Indexed: 12/24/2022] Open
Abstract
Objective Transcriptional regulatory elements in the ameloblastin (AMBN) promoter indicate that adipogenesis may influence its expression. The objective here was to investigate if AMBN is expressed in adipose tissue, and have a role during differentiation of adipocytes. Design AMBN expression was examined in adipose tissue and adipocytes by real-time PCR and ELISA. Distribution of ameloblastin was investigated by immunofluorescence in sections of human subcutaneous adipose tissue. The effect of recombinant proteins resembling AMBN and its processed products on proliferation of primary human pre-adipocytes and murine 3T3-L1 cell lines was measured by [3H]-thymidine incorporation. The effect on adipocyte differentiation was evaluated by the expression profile of the adipogenic markers PPARγ and leptin, and the content of lipids droplets (Oil-Red-O staining). Results AMBN was found to be expressed in human adipose tissue, human primary adipocytes, and in 3T3-L1 cells. The C-terminus of the AMBN protein and a 45 bp shorter splice variant was identified in human subcutaneous adipose tissue. The expression of AMBN was found to increase four-fold during differentiation of 3T3-L1 cells. Administration of recombinant AMBN reduced the proliferation, and enhanced the expression of PPARγ and leptin in 3T3-L1 and human pre-adipocytes, respectively. Conclusions The AMBN C-terminus variant was identified in adipocytes. This variant may be encoded from a short splice variant. Increased expression of AMBN during adipogenesis and its effect on adipogenic factors suggests that AMBN also has a role in adipocyte development.
Collapse
Affiliation(s)
- Øystein Stakkestad
- Department of Biomaterials, Institute of Clinical Dentistry, University of Oslo, Norway
| | - Catherine Heyward
- Department of Biomaterials, Institute of Clinical Dentistry, University of Oslo, Norway
| | | | - Tirill Medin
- Department of Nursing and Health Promotion, Faculty of Health Sciences, OsloMet - Oslo Metropolitan University, Norway
| | - Jiri Vondrasek
- Department of Bioinformatics, Institute of Organic Chemistry and Biology, Czech Academy of Sciences, Prague, Czech Republic
| | - Aina-Mari Lian
- Department of Biomaterials, Institute of Clinical Dentistry, University of Oslo, Norway
| | - Gita Pezeshki
- Department of Biomaterials, Institute of Clinical Dentistry, University of Oslo, Norway
| | - Janne Elin Reseland
- Department of Biomaterials, Institute of Clinical Dentistry, University of Oslo, Norway
| |
Collapse
|
|
34
|
Visfatin alters the cytokine and matrix-degrading enzyme profile during osteogenic and adipogenic MSC differentiation. Osteoarthritis Cartilage 2018; 26:1225-1235. [PMID: 29908226 DOI: 10.1016/j.joca.2018.06.001] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2017] [Revised: 05/25/2018] [Accepted: 06/04/2018] [Indexed: 02/02/2023]
Abstract
OBJECTIVES Age-related bone loss is associated with bone marrow adiposity. Adipokines (e.g., visfatin, resistin, leptin) are adipocyte-derived factors with immunomodulatory properties and might influence differentiation of bone marrow-derived mesenchymal stem cells (MSC) in osteoarthritis (OA) and osteoporosis (OP). Thus, the presence of adipokines and MMPs in bone marrow and their effects on MSC differentiation were analyzed. METHODS MSC and ribonucleic acid (RNA) were isolated from femoral heads after hip replacement surgery of OA or osteoporotic femoral neck fracture (FF) patients. Bone structural parameters were evaluated by microcomputed tomography (μCT). MSC were differentiated towards adipocytes or osteoblasts with/without adipokines. Gene expression (adipokines, bone marker genes, MMPs, TIMPs) and cytokine production was evaluated by realtime-polymerase chain reaction (realtime-PCR) and enzyme-linked immunosorbent assay (ELISA). Matrix mineralization was quantified using Alizarin red S staining. RESULTS μCT showed an osteoporotic phenotype of FF compared to OA bone (reduced trabecular thickness and increased ratio of bone surface vs volume of solid bone). Visfatin and leptin were increased in FF vs OA. Visfatin induced the secretion of IL-6, IL-8, and MCP-1 during osteogenic and adipogenic differentiation. In contrast to resistin and leptin, visfatin increased MMP2 and MMP13 during adipogenesis. In osteogenically differentiated cells, MMPs and TIMPs were reduced by visfatin. Visfatin significantly increased matrix mineralization during osteogenesis, whereas collagen type I expression was reduced. CONCLUSION Visfatin-mediated increase of matrix mineralization and reduced collagen type I expression could contribute to bone fragility. Visfatin is involved in impaired bone remodeling at the adipose tissue/bone interface through induction of proinflammatory factors and dysregulated MMP/TIMP balance during MSC differentiation.
Collapse
|
|
35
|
Chiu CY, Sun SC, Chiang CK, Wang CC, Chan DC, Chen HJ, Liu SH, Yang RS. Plasticizer di(2-ethylhexyl)phthalate interferes with osteoblastogenesis and adipogenesis in a mouse model. J Orthop Res 2018; 36:1124-1134. [PMID: 28921615 DOI: 10.1002/jor.23740] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2016] [Accepted: 09/13/2017] [Indexed: 02/04/2023]
Abstract
Plasticizer di(2-ethylhexyl)phthalate (DEHP) can leach from medical devices such as blood storage bags and the tubing. Recently, epidemiological studies showed that phthalate metabolites levels in the urine are associated with low bone mineral density (BMD) in older women. The detailed effect and mechanism of DEHP on osteoblastogenesis and adipogenesis, and bone loss remain to be clarified. Here, we investigated the effect and mechanism of DEHP and its active metabolite mono(2-ethylhexyl)phthalate (MEHP) on osteoblastogenesis and adipogenesis. The in vitro study showed that osteoblast differentiation of bone marrow stromal cells (BMSCs) was significantly and dose-dependently decreased by DEHP and MEHP (10-100 µM) without cytotoxicity to BMSCs. The mRNA expressions of alkaline phosphatase, Runx2, osteocalcin (OCN), Wnt1, and β-catenin were significantly decreased in DEHP- and MEHP-treated BMSCs during differentiation. MEHP, but not DEHP, significantly increased the adipocyte differentiation of BMSCs and PPARγ mRNA expression. Both DEHP and MEHP significantly increased the ratios of phosphorylated β-catenin/β-catenin and inhibited osteoblastogenesis, which could be reversed by Wnt activator lithium chloride and PPARγ inhibitor T0070907. Moreover, exposure of mice to DEHP (1, 10, and 100 mg/kg) for 8 weeks altered BMD and microstructure. In BMSCs isolated from DEHP-treated mice, osteoblastogenesis and Runx2, Wnt1, and β-catenin expression were decreased, but adipogenesis and PPARγ expression were increased. These findings suggest that DEHP and its metabolite MEHP exposure may inhibit osteoblastogenesis and promote adipogenesis of BMSCs through the Wnt/β-catenin-regulated and thus triggering bone loss. PPARγ signaling may play an important role in MEHP- and DEHP-induced suppression of osteogenesis. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1124-1134, 2018.
Collapse
Affiliation(s)
- Chen-Yuan Chiu
- Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan.,Department of Cell and Tissue Engineering, Changhua Christian Hospital, Changhua, Taiwan
| | - Shih-Chun Sun
- Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Chih-Kang Chiang
- Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan.,Departments of Integrated Diagnostics and Therapeutics and Internal Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Ching-Chia Wang
- Department of Pediatrics, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Ding-Cheng Chan
- Department of Geriatrics and Gerontology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Huang-Jen Chen
- Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Shing-Hwa Liu
- Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan.,Department of Pediatrics, College of Medicine, National Taiwan University, Taipei, Taiwan.,Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan
| | - Rong-Sen Yang
- Department of Orthopaedics, College of Medicine, National Taiwan University, Taipei, Taiwan
| |
Collapse
|
|
36
|
Suh YJ, McDonald MLN, Washko GR, Carolan BJ, Bowler RP, Lynch DA, Kinney GL, Bon JM, Cho MH, Crapo JD, Regan EA. Lung, Fat and Bone: Increased Adiponectin Associates with the Combination of Smoking-Related Lung Disease and Osteoporosis. CHRONIC OBSTRUCTIVE PULMONARY DISEASES-JOURNAL OF THE COPD FOUNDATION 2018; 5:134-143. [PMID: 30374451 DOI: 10.15326/jcopdf.5.2.2016.0174] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Background: Adiponectin has been proposed as a biomarker of disease severity and progression in chronic obstructive pulmonary disease (COPD) and associated with spirometry-defined COPD and with computed tomography (CT)-measured emphysema. Increased adiponectin plays a role in other diseases including diabetes/metabolic syndrome, cardiovascular disease and osteoporosis. Previous studies of adiponectin and COPD have not assessed the relationship of adiponectin to airway disease in smokers and have not evaluated the effect of other comorbid diseases on the relationship of adiponectin and lung disease. We postulated that adiponectin levels would associate with both airway disease and emphysema in smokers with and without COPD, and further postulated that body composition and the comorbid diseases of osteoporosis, cardiovascular disease and diabetes might influence adiponectin levels. Methods: Current and former smokers from the COPD Genetic Epidemiology study (COPDGene) (n= 424) were assigned to 4 groups based on CT lung characteristics and volumetric Bone Density (vBMD). Emphysema (% low attenuation area at -950) and airway disease (Wall area %) were used to assess smoking-related lung disease (SRLD). Group 1) Normal Lung with Normal vBMD; Group 2) Normal Lung and Osteoporosis; Group 3) SRLD with Normal vBMD; Group 4) SRLD with Osteoporosis. Cardiovascular disease (CVD), diabetes, C-reactive protein (CRP) and T-cadherin (soluble receptor for adiponectin) levels were defined for each group. Body composition was derived from chest CT. Multivariable regression assessed effects of emphysema, wall area %, bone density, comorbid diseases and other key factors on log adiponectin. Results: Group 4, SRLD with Osteoporosis, had significantly higher adiponectin levels compared to other groups and the effect persisted in adjusted models. Systemic inflammation (by CRP) was associated with SRLD in Groups 3 and 4 but not with osteoporosis alone. In regression models, lower bone density and worse emphysema were associated with higher adiponectin. Airway disease was associated with higher adiponectin levels when T-cadherin was added to the model. Male gender, greater muscle and fat were associated with lower adiponectin. Conclusions: Adiponectin is increased with both airway disease and emphysema in smokers. Bone density, and fat and muscle composition are all significant factors predicting adiponectin that should be considered when it is used as a biomarker of COPD. Increased adiponectin from chronic inflammation may play a role in the progression of bone loss in COPD and other lung diseases.
Collapse
Affiliation(s)
- Young Ju Suh
- Department of Biomedical Sciences, College of Medicine, Inha University, Incheon, Republic of Korea
| | - Merry-Lynn N McDonald
- Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - George R Washko
- Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | | | - Russell P Bowler
- Department of Medicine, National Jewish Health, Denver, Colorado
| | - David A Lynch
- Department of Medicine, National Jewish Health, Denver, Colorado
| | | | | | - Michael H Cho
- Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - James D Crapo
- Department of Medicine, National Jewish Health, Denver, Colorado
| | - Elizabeth A Regan
- Department of Medicine, National Jewish Health, Denver, Colorado.,School of Public Health, University of Colorado, Denver
| | | |
Collapse
|
|
37
|
Guglielmi V, Sbraccia P. Obesity phenotypes: depot-differences in adipose tissue and their clinical implications. Eat Weight Disord 2018; 23:3-14. [PMID: 29230714 DOI: 10.1007/s40519-017-0467-9] [Citation(s) in RCA: 60] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2017] [Accepted: 11/29/2017] [Indexed: 12/17/2022] Open
Abstract
Obesity, defined as excess fat mass, increases risks for multiple chronic diseases, such as type 2 diabetes, cardiovascular disease, and several types of cancer. Beyond adiposity per se, the pattern of fat distribution, android or truncal as compared to gynoid or peripheral, has a profound influence on systemic metabolism and hence risk for obesity complications. Not only factors as genetics, environment, gender, and age account for the apparent compartmentalization of white adipose tissue (WAT) in the body. Indeed, the heterogeneity among different anatomical depots also appears to stem from their intrinsic diversity, including cellular developmental origin, proliferative capacity, glucose and lipid metabolism, insulin sensitivity, cytokine pattern, thermogenic ability, and vascularization. Under the obese condition, these depot-specific differences translate into specific WAT distribution patterns, giving rise to different cardiometabolic consequences. This review summarizes the clinical and mechanistic evidence for the depot-specific differences and the phenotypic characteristics of different WAT depots that link their depot-specific biology to obesity-specific complications.
Collapse
Affiliation(s)
- Valeria Guglielmi
- Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133, Rome, Italy.
- Internal Medicine Unit and Obesity Center, University Hospital Policlinico Tor Vergata, Rome, Italy.
| | - Paolo Sbraccia
- Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133, Rome, Italy
- Internal Medicine Unit and Obesity Center, University Hospital Policlinico Tor Vergata, Rome, Italy
| |
Collapse
|
|
38
|
Sasaki M, Chubachi S, Kameyama N, Sato M, Haraguchi M, Miyazaki M, Takahashi S, Nakano T, Kuroda Y, Betsuyaku T, Matsuo K. Effects of long-term cigarette smoke exposure on bone metabolism, structure, and quality in a mouse model of emphysema. PLoS One 2018; 13:e0191611. [PMID: 29381718 PMCID: PMC5790271 DOI: 10.1371/journal.pone.0191611] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2017] [Accepted: 01/08/2018] [Indexed: 12/19/2022] Open
Abstract
Smoking is a common risk factor for both chronic obstructive pulmonary disease (COPD) and osteoporosis. In patients with COPD, severe emphysema is a risk factor for vertebral fracture; however, the effects of smoking or emphysema on bone health remain largely unknown. We report bone deterioration in a mouse model of emphysema induced by nose-only cigarette smoke (CS) exposure. Unexpectedly, short-term exposure for 4-weeks decreased bone turnover and increased bone volume in mice. However, prolonged exposure for 20- and 40-weeks reversed the effects from suppression to promotion of bone resorption. This long-term CS exposure increased osteoclast number and impaired bone growth, while it increased bone volume. Strikingly, long-term CS exposure deteriorated bone quality of the lumbar vertebrae as illustrated by disorientation of collagen fibers and the biological apatite c-axis. This animal model may provide a better understanding of the mechanisms underlying the deterioration of bone quality in pulmonary emphysema caused by smoking.
Collapse
Affiliation(s)
- Mamoru Sasaki
- Division of Pulmonary Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Shotaro Chubachi
- Division of Pulmonary Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Naofumi Kameyama
- Division of Pulmonary Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Minako Sato
- Division of Pulmonary Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Mizuha Haraguchi
- Division of Pulmonary Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Masaki Miyazaki
- Division of Pulmonary Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Saeko Takahashi
- Division of Pulmonary Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Takayoshi Nakano
- Division of Materials and Manufacturing Science, Graduate School of Engineering, Osaka University, Suita, Japan
| | - Yukiko Kuroda
- Laboratory of Cell and Tissue Biology, Keio University School of Medicine, Tokyo, Japan
| | - Tomoko Betsuyaku
- Division of Pulmonary Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Koichi Matsuo
- Laboratory of Cell and Tissue Biology, Keio University School of Medicine, Tokyo, Japan
- * E-mail:
| |
Collapse
|
|
39
|
Boregowda SV, Krishnappa V, Strivelli J, Haga CL, Booker CN, Phinney DG. Basal p53 expression is indispensable for mesenchymal stem cell integrity. Cell Death Differ 2018; 25:679-692. [PMID: 29311623 PMCID: PMC5883824 DOI: 10.1038/s41418-017-0004-4] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2016] [Revised: 08/31/2017] [Accepted: 09/27/2017] [Indexed: 01/10/2023] Open
Abstract
Marrow-resident mesenchymal stem cells (MSCs) serve as a functional component of the perivascular niche that regulates hematopoiesis. They also represent the main source of bone formed in adult bone marrow, and their bifurcation to osteoblast and adipocyte lineages plays a key role in skeletal homeostasis and aging. Although the tumor suppressor p53 also functions in bone organogenesis, homeostasis, and neoplasia, its role in MSCs remains poorly described. Herein, we examined the normal physiological role of p53 in primary MSCs cultured under physiologic oxygen levels. Using knockout mice and gene silencing we show that p53 inactivation downregulates expression of TWIST2, which normally restrains cellular differentiation to maintain wild-type MSCs in a multipotent state, depletes mitochondrial reactive oxygen species (ROS) levels, and suppresses ROS generation and PPARG gene and protein induction in response to adipogenic stimuli. Mechanistically, this loss of adipogenic potential skews MSCs toward an osteogenic fate, which is further potentiated by TWIST2 downregulation, resulting in highly augmented osteogenic differentiation. We also show that p53−/− MSCs are defective in supporting hematopoiesis as measured in standard colony assays because of decreased secretion of various cytokines including CXCL12 and CSF1. Lastly, we show that transient exposure of wild-type MSCs to 21% oxygen upregulates p53 protein expression, resulting in increased mitochondrial ROS production and enhanced adipogenic differentiation at the expense of osteogenesis, and that treatment of cells with FGF2 mitigates these effects by inducing TWIST2. Together, these findings indicate that basal p53 levels are necessary to maintain MSC bi-potency, and oxygen-induced increases in p53 expression modulate cell fate and survival decisions. Because of the critical function of basal p53 in MSCs, our findings question the use of p53 null cell lines as MSC surrogates, and also implicate dysfunctional MSC responses in the pathophysiology of p53-related skeletal disorders.
Collapse
Affiliation(s)
- Siddaraju V Boregowda
- Department of Molecular Medicine, The Scripps Research Institute - Scripps Florida, Jupiter, FL, 33458, USA
| | - Veena Krishnappa
- Department of Molecular Medicine, The Scripps Research Institute - Scripps Florida, Jupiter, FL, 33458, USA
| | - Jacqueline Strivelli
- Department of Molecular Medicine, The Scripps Research Institute - Scripps Florida, Jupiter, FL, 33458, USA
| | - Christopher L Haga
- Department of Molecular Medicine, The Scripps Research Institute - Scripps Florida, Jupiter, FL, 33458, USA
| | - Cori N Booker
- Department of Molecular Medicine, The Scripps Research Institute - Scripps Florida, Jupiter, FL, 33458, USA
| | - Donald G Phinney
- Department of Molecular Medicine, The Scripps Research Institute - Scripps Florida, Jupiter, FL, 33458, USA.
| |
Collapse
|
|
40
|
|
|
41
|
Silva HF, Abuna RPF, Lopes HB, Francischini MS, de Oliveira PT, Rosa AL, Beloti MM. Participation of extracellular signal-regulated kinases 1/2 in osteoblast and adipocyte differentiation of mesenchymal stem cells grown on titanium surfaces. Eur J Oral Sci 2017; 125:355-360. [DOI: 10.1111/eos.12369] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Affiliation(s)
- Heitor F. Silva
- Cell Culture Laboratory; School of Dentistry of Ribeirão Preto; University of São Paulo; Ribeirão Preto SP Brazil
| | - Rodrigo P. F. Abuna
- Cell Culture Laboratory; School of Dentistry of Ribeirão Preto; University of São Paulo; Ribeirão Preto SP Brazil
| | - Helena B. Lopes
- Cell Culture Laboratory; School of Dentistry of Ribeirão Preto; University of São Paulo; Ribeirão Preto SP Brazil
| | - Marcelo S. Francischini
- Cell Culture Laboratory; School of Dentistry of Ribeirão Preto; University of São Paulo; Ribeirão Preto SP Brazil
| | - Paulo T. de Oliveira
- Cell Culture Laboratory; School of Dentistry of Ribeirão Preto; University of São Paulo; Ribeirão Preto SP Brazil
| | - Adalberto L. Rosa
- Cell Culture Laboratory; School of Dentistry of Ribeirão Preto; University of São Paulo; Ribeirão Preto SP Brazil
| | - Marcio M. Beloti
- Cell Culture Laboratory; School of Dentistry of Ribeirão Preto; University of São Paulo; Ribeirão Preto SP Brazil
| |
Collapse
|
|
42
|
During A. Lipid determination in bone marrow and mineralized bone tissue: From sample preparation to improved high-performance thin-layer and liquid chromatographic approaches. J Chromatogr A 2017; 1515:232-244. [PMID: 28803650 DOI: 10.1016/j.chroma.2017.08.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2017] [Revised: 07/31/2017] [Accepted: 08/01/2017] [Indexed: 10/19/2022]
Abstract
In view of their key roles in the bone physiology (e.g., in the biomineralization process) and their potential implication in bone pathologies, an approach to study lipids in situ is needed. The aim of the present paper is to propose an original procedure to characterize lipids in both bone marrow (BM) and mineralized tissue (MT) compartments, taking into consideration sample preparation, lipid extraction and analytical issues, when using small sample size (≤ 0.5g of rat femurs). The potential contamination of the MT by marrow lipids and the poor accessibility of certain lipids from the MT - two major issues in bone handling - were taking care, respectively by performing two cleaning steps after BM removal and by adding a demineralization step to the overall lipid extraction protocol. For lipid analyses, a multi-one-dimensional HP-TLC method was developed to analyze the major neutral and polar lipids at once and showed an excellent resolution (for 15 standards) and a good precision (inter-day RSD<13%). When subjected to the entire "lipid extraction-HP-TLC" protocol, spike recoveries of the standards ranged between 76 and 122%. This HP-TLC method was suitable for lipid determination in both BM and MT [e.g., the MT had 5-times lesser lipids and a lower TG/phospholipid ratio than the BM (P <0.05)], and was quite reliable in term of lipid quantification. The demineralization step allowed to extract additional phosphatidylserine and esterified cholesterol from the MT, suggesting that these two species were associated to the mineralized matrix possibly in relation to their physiological role in the bone. Moreover, a reverse phase HPLC method for fatty acid determination as naphthacyl esters was set up to study fatty acids in bone samples and was used to validate the HP-TLC data. The fatty acid profile of the MT exhibited lower linoleic acid (18:2 n-6) and linolenic acid (18:3 n-3+n-6) levels and higher arachidonic acid (20:4 n-6) and docosahexaenoic acid (22:6 n-3) levels (P<0.05, compared to BM), suggesting that the MT is more metabolically active than the BM in term of long chain fatty acid production. In sum, the present work should contribute to facilitate future studies in the bone lipid field in view to understand better their implication in the marrow fat expansion-associated bone pathologies, such as osteoporosis.
Collapse
Affiliation(s)
- Alexandrine During
- Univ. Lille, EA449 - PMOI - Physiopathologie des maladies osseuses inflammatoires, F-59000 Lille, France.
| |
Collapse
|
|
43
|
Lombardi G, Barbaro M, Locatelli M, Banfi G. Novel bone metabolism-associated hormones: the importance of the pre-analytical phase for understanding their physiological roles. Endocrine 2017; 56:460-484. [PMID: 28181144 DOI: 10.1007/s12020-017-1239-z] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2016] [Accepted: 01/17/2017] [Indexed: 02/08/2023]
Abstract
The endocrine function of bone is now a recognized feature of this tissue. Bone-derived hormones that modulate whole-body homeostasis, are being discovered as for the effects on bone of novel and classic hormones produced by other tissues become known. Often, however, the data regarding these last generation bone-derived or bone-targeting hormones do not give about a clear picture of their physiological roles or concentration ranges. A certain degree of uncertainty could stem from differences in the pre-analytical management of biological samples. The pre-analytical phase comprises a series of decisions and actions (i.e., choice of sample matrix, methods of collection, transportation, treatment and storage) preceding analysis. Errors arising in this phase will inevitably be carried over to the analytical phase where they can reduce the measurement accuracy, ultimately, leading discrepant results. While the pre-analytical phase is all important, in routine laboratory medicine, it is often not given due consideration in research and clinical trials. This is particularly true for novel molecules, such as the hormones regulating the endocrine function of bone. In this review we discuss the importance of the pre-analytical variables affecting the measurement of last generation bone-associated hormones and describe their, often debated and rarely clear physiological roles.
Collapse
Affiliation(s)
| | - Mosè Barbaro
- Laboratory Medicine Service, San Raffaele Hospital, Milano, Italy
| | | | - Giuseppe Banfi
- IRCCS Istituto Ortopedico Galeazzi, Milano, Italy
- Vita-Salute San Raffaele University, Milano, Italy
| |
Collapse
|
|
44
|
Abdallah BM. Marrow adipocytes inhibit the differentiation of mesenchymal stem cells into osteoblasts via suppressing BMP-signaling. J Biomed Sci 2017; 24:11. [PMID: 28173811 PMCID: PMC5296965 DOI: 10.1186/s12929-017-0321-4] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2016] [Accepted: 01/31/2017] [Indexed: 01/24/2023] Open
Abstract
Background Reduced bone formation is associated with increased bone marrow fat in many bone-loss related diseases including aging, post-menopause, and anorexia nervosa. Several lines of evidence suggested the regulation of osteogenesis and adipogenesis of the bone marrow-derived mesenchymal (skeletal) stem cells (BMSCs) by paracrine mediators. This study aimed to investigate the impact of adipocytes-secreted factors on the cell proliferation and osteoblast differentiation of BMSCs. Methods Serum free conditioned medium (CM-Adipo) was collected from stromal ST2 cells-derived adipocytes. Cell viability, quantitative alkaline phosphatase (ALP) activity assay, Alizarin red staining for matrix mineralization and osteogenic gene array expression were performed to determine the effect of CM-Adipo on cell proliferation and osteoblast differentiation of primary murine BMSCs (mBMSCs). Regulation of BMPs and NF-κB signaling pathways by CM-Adipo were detected by Western blot analysis and gene reporter assay. Results CM-Adipo showed no effect on cell viability/proliferation of primary mBMSCs as compared to CM-control. On the other hand, CM-Adipo significantly inhibited the commitment of mBMSCs into osteoblastic cell lineage in dose-dependent manner. CM-Adipo was found to dramatically inhibit the BMP2-induced osteoblast differentiation and to activate the inflammatory NF-κB signaling in mBMSCs. Interestingly, treatment of mBMSCs with the selective inhibitor of NF-κB pathway, BAY11-770682, showed to retrieve the inhibitory effect of CM-Adipo on BMP2-induced osteoblast differentiation in mBMSCs. Conclusions Our data demonstrated that the marrow adipocytes exert paracrine inhibitory effect on the osteoblast differentiation of mBMSCs by blocking BMPs signaling in a mechanism mediated by adipokines-induced NF-κB pathway activation. Electronic supplementary material The online version of this article (doi:10.1186/s12929-017-0321-4) contains supplementary material, which is available to authorized users.
Collapse
Affiliation(s)
- Basem M Abdallah
- Molecular Endocrinology Laboratory (KMEB), Department of Endocrinology, Odense University Hospital and University of Southern Denmark, Odense, Denmark. .,Department of Biological Sciences, College of Science, King Faisal University, Hofuf, Saudi Arabia. .,Faculty of Science, Helwan University, Cairo, Egypt.
| |
Collapse
|
|
45
|
Lama A, Santoro A, Corrado B, Pirozzi C, Paciello O, Pagano TB, Russo S, Calignano A, Mattace Raso G, Meli R. Extracorporeal shock waves alone or combined with raloxifene promote bone formation and suppress resorption in ovariectomized rats. PLoS One 2017; 12:e0171276. [PMID: 28158228 PMCID: PMC5291474 DOI: 10.1371/journal.pone.0171276] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2016] [Accepted: 01/17/2017] [Indexed: 12/18/2022] Open
Abstract
Osteoporosis is a metabolic skeletal disease characterized by an imbalance between osteoclast-mediated bone resorption and osteoblast-mediated bone formation. We examined the beneficial effect of shock waves (SW) alone or in combination with raloxifene (RAL) on bone loss in ovariectomized rats (OVX). Sixteen weeks after surgery, OVX were treated for five weeks with SW at the antero-lateral side of the right hind leg, one session weekly, at 3 Hz (EFD of 0.33 mJ/mm2), or with RAL (5 mg/kg/die, per os) or with SW+RAL. Sera, femurs, tibiae and vertebrae were sampled for following biochemical and histological analysis. SW, alone or combined with RAL, prevented femur weight reduction and the deterioration of trabecular microarchitecture both in femur and vertebrae. All treatments increased Speed of Sound (SoS) values, improving bone mineral density, altered by OVX. Serum parameters involved in bone remodeling (alkaline phosphatase, receptor activator of nuclear factor kappa-B ligand, osteoprotegerin) and osteoblast proliferation (PTH), altered by ovariectomy, were restored by SW and RAL alone or in combination. In tibiae, SW+RAL significantly reduced cathepsin k and TNF-α levels, indicating the inhibition of osteoclast activity, while all treatments significantly increased runt-related transcription factor 2 and bone morphogenetic-2 expression, suggesting an increase in osteoblastogenic activity. Finally, in bone marrow from tibiae, SW or RAL reduced PPARγ and adiponectin transcription, indicating a shift of mesenchymal cells toward osteoblastogenesis, without showing a synergistic effect. Our data indicate SW therapy, alone and in combination with raloxifene, as an innovative strategy to limit the hypoestrogenic bone loss, restoring the balance between bone formation and resorption.
Collapse
Affiliation(s)
- Adriano Lama
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
| | - Anna Santoro
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
- Program in Integrative Cell Signaling and Neurobiology of Metabolism, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut, United States of America
| | - Bruno Corrado
- Department of Public Health, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Claudio Pirozzi
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
| | - Orlando Paciello
- Department of Veterinary Medicine and Animal Production, University of Naples Federico II, Naples, Italy
| | - Teresa Bruna Pagano
- Department of Veterinary Medicine and Animal Production, University of Naples Federico II, Naples, Italy
| | - Sergio Russo
- Department of Public Health, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Antonio Calignano
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
| | | | - Rosaria Meli
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
- * E-mail:
| |
Collapse
|
|
46
|
Hillard CJ, Beatka M, Sarvaideo J. Endocannabinoid Signaling and the Hypothalamic-Pituitary-Adrenal Axis. Compr Physiol 2016; 7:1-15. [PMID: 28134998 DOI: 10.1002/cphy.c160005] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The elucidation of Δ9-tetrahydrocannabinol as the active principal of Cannabis sativa in 1963 initiated a fruitful half-century of scientific discovery, culminating in the identification of the endocannabinoid signaling system, a previously unknown neuromodulatory system. A primary function of the endocannabinoid signaling system is to maintain or recover homeostasis following psychological and physiological threats. We provide a brief introduction to the endocannabinoid signaling system and its role in synaptic plasticity. The majority of the article is devoted to a summary of current knowledge regarding the role of endocannabinoid signaling as both a regulator of endocrine responses to stress and as an effector of glucocorticoid and corticotrophin-releasing hormone signaling in the brain. We summarize data demonstrating that cannabinoid receptor 1 (CB1R) signaling can both inhibit and potentiate the activation of the hypothalamic-pituitary-adrenal axis by stress. We present a hypothesis that the inhibitory arm has high endocannabinoid tone and also serves to enhance recovery to baseline following stress, while the potentiating arm is not tonically active but can be activated by exogenous agonists. We discuss recent findings that corticotropin-releasing hormone in the amygdala enables hypothalamic-pituitary-adrenal axis activation via an increase in the catabolism of the endocannabinoid N-arachidonylethanolamine. We review data supporting the hypotheses that CB1R activation is required for many glucocorticoid effects, particularly feedback inhibition of hypothalamic-pituitary-adrenal axis activation, and that glucocorticoids mobilize the endocannabinoid 2-arachidonoylglycerol. These features of endocannabinoid signaling make it a tantalizing therapeutic target for treatment of stress-related disorders but to date, this promise is largely unrealized. © 2017 American Physiological Society. Compr Physiol 7:1-15, 2017.
Collapse
Affiliation(s)
- Cecilia J Hillard
- Department of Pharmacology and Toxicology, and Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Margaret Beatka
- Department of Pharmacology and Toxicology, and Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Jenna Sarvaideo
- Department of Medicine, and Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| |
Collapse
|
|
47
|
Lombardi G, Sanchis-Gomar F, Perego S, Sansoni V, Banfi G. Implications of exercise-induced adipo-myokines in bone metabolism. Endocrine 2016; 54:284-305. [PMID: 26718191 DOI: 10.1007/s12020-015-0834-0] [Citation(s) in RCA: 81] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2015] [Accepted: 12/14/2015] [Indexed: 12/12/2022]
Abstract
Physical inactivity has been recognized, by the World Health Organization as the fourth cause of death (5.5 % worldwide). On the contrary, physical activity (PA) has been associated with improved quality of life and decreased risk of several diseases (i.e., stroke, hypertension, myocardial infarction, obesity, malignancies). Bone turnover is profoundly affected from PA both directly (load degree is the key determinant for BMD) and indirectly through the activation of several endocrine axes. Several molecules, secreted by muscle (myokines) and adipose tissues (adipokines) in response to exercise, are involved in the fine regulation of bone metabolism in response to the energy availability. Furthermore, bone regulates energy metabolism by communicating its energetic needs thanks to osteocalcin which acts on pancreatic β-cells and adipocytes. The beneficial effects of exercise on bone metabolism depends on the intermittent exposure to myokines (i.e., irisin, IL-6, LIF, IGF-I) which, instead, act as inflammatory/pro-resorptive mediators when chronically elevated; on the other hand, the reduction in the circulating levels of adipokines (i.e., leptin, visfatin, adiponectin, resistin) sustains these effects as well as improves the whole-body metabolic status. The aim of this review is to highlight the newest findings about the exercise-dependent regulation of these molecules and their role in the fine regulation of bone metabolism.
Collapse
Affiliation(s)
- Giovanni Lombardi
- Laboratory of Experimental Biochemistry & Molecular Biology, I.R.C.C.S. Istituto Ortopedico Galeazzi, Via Riccardo Galeazzi 4, 20161, Milan, Italy.
| | | | - Silvia Perego
- Laboratory of Experimental Biochemistry & Molecular Biology, I.R.C.C.S. Istituto Ortopedico Galeazzi, Via Riccardo Galeazzi 4, 20161, Milan, Italy
| | - Veronica Sansoni
- Laboratory of Experimental Biochemistry & Molecular Biology, I.R.C.C.S. Istituto Ortopedico Galeazzi, Via Riccardo Galeazzi 4, 20161, Milan, Italy
| | - Giuseppe Banfi
- Laboratory of Experimental Biochemistry & Molecular Biology, I.R.C.C.S. Istituto Ortopedico Galeazzi, Via Riccardo Galeazzi 4, 20161, Milan, Italy
- Vita-Salute San Raffaele University, Milan, Italy
| |
Collapse
|
|
48
|
Mesenchymal progenitors in osteopenias of diverse pathologies: differential characteristics in the common shift from osteoblastogenesis to adipogenesis. Sci Rep 2016; 6:30186. [PMID: 27443833 PMCID: PMC4957106 DOI: 10.1038/srep30186] [Citation(s) in RCA: 57] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2016] [Accepted: 06/30/2016] [Indexed: 02/07/2023] Open
Abstract
Osteoporosis is caused by pathologic factors such as aging, hormone deficiency or excess, inflammation, and systemic diseases like diabetes. Bone marrow stromal cells (BMSCs), the mesenchymal progenitors for both osteoblasts and adipocytes, are modulated by niche signals. In differential pathologic states, the pathological characteristics of BMSCs to osteoporoses and functional differences are unknown. Here, we detected that trabecular bone loss co-existed with increased marrow adiposity in 6 osteoporotic models, respectively induced by natural aging, accelerated senescence (SAMP6), ovariectomy (OVX), type 1 diabetes (T1D), excessive glucocorticoids (GIOP) and orchidectomy (ORX). Of the ex vivo characteristics of BMSCs, the colony-forming efficiency and the proliferation rate in aging, SAMP6, OVX, GIOP and ORX models decreased. The apoptosis and cellular senescence increased except in T1D, with up-regulation of p53 and p16 expression. The osteogenesis declined except in GIOP, with corresponding down-regulation of Runt-related transcription factor 2 (RUNX2) expression. The adipogenesis increased in 6 osteoporotic models, with corresponding up-regulation of Peroxisome proliferator activated receptor gamma (PPARγ) expression. These findings revealed differential characteristics of BMSCs in a common shift from osteoblastogenesis to adipogenesis among different osteoporoses and between sexes, and provide theoretical basis for the functional modulation of resident BMSCs in the regenerative therapy for osteoporosis.
Collapse
|
|
49
|
Epstein S, Defeudis G, Manfrini S, Napoli N, Pozzilli P. Diabetes and disordered bone metabolism (diabetic osteodystrophy): time for recognition. Osteoporos Int 2016; 27:1931-51. [PMID: 26980458 DOI: 10.1007/s00198-015-3454-x] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2015] [Accepted: 12/07/2015] [Indexed: 02/06/2023]
Abstract
Diabetes and osteoporosis are rapidly growing diseases. The link between the high fracture incidence in diabetes as compared with the non-diabetic state has recently been recognized. While this review cannot cover every aspect of diabetic osteodystrophy, it attempts to incorporate current information from the First International Symposium on Diabetes and Bone presentations in Rome in 2014. Diabetes and osteoporosis are fast-growing diseases in the western world and are becoming a major problem in the emerging economic nations. Aging of populations worldwide will be responsible for an increased risk in the incidence of osteoporosis and diabetes. Furthermore, the economic burden due to complications of these diseases is enormous and will continue to increase unless public awareness of these diseases, the curbing of obesity, and cost-effective measures are instituted. The link between diabetes and fractures being more common in diabetics than non-diabetics has been widely recognized. At the same time, many questions remain regarding the underlying mechanisms for greater bone fragility in diabetic patients and the best approach to risk assessment and treatment to prevent fractures. Although it cannot cover every aspect of diabetic osteodystrophy, this review will attempt to incorporate current information particularly from the First International Symposium on Diabetes and Bone presentations in Rome in November 2014.
Collapse
Affiliation(s)
- S Epstein
- Division of Endocrinology, Mount Sinai School of Medicine, New York, NY, USA
| | - G Defeudis
- Unit of Endocrinology and Diabetes, Department of Medicine, Università Campus Bio-Medico di Roma, Via Alvaro del Portillo, 21-00128, Rome, Italy.
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.
| | - S Manfrini
- Unit of Endocrinology and Diabetes, Department of Medicine, Università Campus Bio-Medico di Roma, Via Alvaro del Portillo, 21-00128, Rome, Italy
| | - N Napoli
- Unit of Endocrinology and Diabetes, Department of Medicine, Università Campus Bio-Medico di Roma, Via Alvaro del Portillo, 21-00128, Rome, Italy
| | - P Pozzilli
- Unit of Endocrinology and Diabetes, Department of Medicine, Università Campus Bio-Medico di Roma, Via Alvaro del Portillo, 21-00128, Rome, Italy
| | | |
Collapse
|
|
50
|
Zheng Y, Wang C, Zhang H, Shao C, Gao LH, Li SS, Yu WJ, He JW, Fu WZ, Hu YQ, Li M, Liu YJ, Zhang ZL. Polymorphisms in Wnt signaling pathway genes are associated with peak bone mineral density, lean mass, and fat mass in Chinese male nuclear families. Osteoporos Int 2016; 27:1805-15. [PMID: 26733379 DOI: 10.1007/s00198-015-3457-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2015] [Accepted: 12/10/2015] [Indexed: 10/22/2022]
Abstract
UNLABELLED Our objective was to investigate the associations between polymorphisms in Wnt pathway genes and peak bone mineral density (BMD) and body composition in young Chinese men. Our study identified that WNT5B and CTNNBL1 for both BMD and body composition, and WNT4 and CTNNB1 gene polymorphisms contribute to the variation in BMD and body composition in young Chinese men, respectively. INTRODUCTION Our objective was to investigate the associations between polymorphisms in WNT4, WNT5B, WNT10B, WNT16, CTNNB1, and CTNNBL1 genes and peak bone mineral density (BMD), lean mass (LM), and fat mass (FM) in young Chinese men. METHODS Using SNPscan(TM) kits, 51 single-nucleotide polymorphisms (SNPs) located in the 6 genes were genotyped in a total of 1214 subjects from 399 Chinese nuclear families. BMD, total lean mass (TLM), and total fat mass (TFM) were measured using dual energy X-ray absorptiometry (DXA). The associations between the 51 SNPs and peak BMD and body composition [including the TLM, percentage lean mass (PLM), TFM, percentage fat mass (PFM), and the body mass index (BMI)] were analyzed through quantitative transmission disequilibrium tests (QTDTs). RESULTS For peak BMD, we found significant within-family associations of rs2240506, rs7308793, and rs4765830 in the WNT5B gene and rs10917157 in the WNT4 gene with the lumbar spine BMD (all P < 0.05). We detected an association of rs11830202, rs3809269, rs1029628, and rs6489301 in the WNT5B gene and rs2293303 in the CTNNB1 gene with body composition (all P < 0.05). For the CTNNBL1 gene, six SNPs (rs6126098, rs6091103, rs238303, rs6067647, rs8126174, and rs4811144) were associated with peak BMD of the lumbar spine, femoral neck, or total hip (all P < 0.05). Furthermore, two of the six SNPs (rs8126174 and rs4811144) were associated with body composition. CONCLUSIONS This study identified WNT5B and CTNNBL1 for peak BMD and body composition in males from the Han Chinese ethnic group, and the results suggest a site-specific gene regulation. The WNT4 and CTNNB1 gene polymorphisms contribute to the variation in peak BMD and body composition, respectively.
Collapse
Affiliation(s)
- Y Zheng
- Metabolic Bone Disease and Genetic Research Unit, Department of Osteoporosis and Bone Diseases, Shanghai Key Clinical Center for Metabolic Disease, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yi-Shan Road, Shanghai, 200233, People's Republic of China
- Department of Endocrinology, Yueqing Hospital Affiliated with Wenzhou Medical University, 318 Qing-Yuan Road, Yueqing, Zhejiang, 325600, People's Republic of China
| | - C Wang
- Metabolic Bone Disease and Genetic Research Unit, Department of Osteoporosis and Bone Diseases, Shanghai Key Clinical Center for Metabolic Disease, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yi-Shan Road, Shanghai, 200233, People's Republic of China
| | - H Zhang
- Metabolic Bone Disease and Genetic Research Unit, Department of Osteoporosis and Bone Diseases, Shanghai Key Clinical Center for Metabolic Disease, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yi-Shan Road, Shanghai, 200233, People's Republic of China
| | - C Shao
- Metabolic Bone Disease and Genetic Research Unit, Department of Osteoporosis and Bone Diseases, Shanghai Key Clinical Center for Metabolic Disease, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yi-Shan Road, Shanghai, 200233, People's Republic of China
| | - L-H Gao
- Metabolic Bone Disease and Genetic Research Unit, Department of Osteoporosis and Bone Diseases, Shanghai Key Clinical Center for Metabolic Disease, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yi-Shan Road, Shanghai, 200233, People's Republic of China
| | - S-S Li
- Metabolic Bone Disease and Genetic Research Unit, Department of Osteoporosis and Bone Diseases, Shanghai Key Clinical Center for Metabolic Disease, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yi-Shan Road, Shanghai, 200233, People's Republic of China
| | - W-J Yu
- Metabolic Bone Disease and Genetic Research Unit, Department of Osteoporosis and Bone Diseases, Shanghai Key Clinical Center for Metabolic Disease, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yi-Shan Road, Shanghai, 200233, People's Republic of China
| | - J-W He
- Metabolic Bone Disease and Genetic Research Unit, Department of Osteoporosis and Bone Diseases, Shanghai Key Clinical Center for Metabolic Disease, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yi-Shan Road, Shanghai, 200233, People's Republic of China
| | - W-Z Fu
- Metabolic Bone Disease and Genetic Research Unit, Department of Osteoporosis and Bone Diseases, Shanghai Key Clinical Center for Metabolic Disease, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yi-Shan Road, Shanghai, 200233, People's Republic of China
| | - Y-Q Hu
- Metabolic Bone Disease and Genetic Research Unit, Department of Osteoporosis and Bone Diseases, Shanghai Key Clinical Center for Metabolic Disease, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yi-Shan Road, Shanghai, 200233, People's Republic of China
| | - M Li
- Metabolic Bone Disease and Genetic Research Unit, Department of Osteoporosis and Bone Diseases, Shanghai Key Clinical Center for Metabolic Disease, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yi-Shan Road, Shanghai, 200233, People's Republic of China
| | - Y-J Liu
- Metabolic Bone Disease and Genetic Research Unit, Department of Osteoporosis and Bone Diseases, Shanghai Key Clinical Center for Metabolic Disease, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yi-Shan Road, Shanghai, 200233, People's Republic of China
| | - Z-L Zhang
- Metabolic Bone Disease and Genetic Research Unit, Department of Osteoporosis and Bone Diseases, Shanghai Key Clinical Center for Metabolic Disease, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yi-Shan Road, Shanghai, 200233, People's Republic of China.
| |
Collapse
|