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Khashayar P, Rad FF, Tabatabaei-Malazy O, Golabchi SM, Khashayar P, Mohammadi M, Ebrahimpour S, Larijani B. Hypoglycemic agents and bone health; an umbrella systematic review of the clinical trials' meta-analysis studies. Diabetol Metab Syndr 2024; 16:310. [PMID: 39716250 DOI: 10.1186/s13098-024-01518-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Accepted: 11/09/2024] [Indexed: 12/25/2024] Open
Abstract
BACKGROUND No clear consensus exists regarding the safest anti-diabetic drugs with the least adverse events on bone health. This umbrella systematic review therefore aims to assess the published meta-analysis studies of randomized controlled trials (RCTs) conducted in this field. METHODS All relevant meta-analysis studies of RCTs assessing the effects of anti-diabetic agents on bone health in patients with diabetes mellitus (DM) were collected in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). English articles published until 15 March 2023 were collected through the search of Cochrane Library, Scopus, ISI Web of Sciences, PubMed, and Embase using the terms "Diabetes mellitus", "anti-diabetic drugs", "Bone biomarker", "Bone fracture, "Bone mineral density" and their equivalents. The methodological and evidence quality assessments were performed for all included studies. RESULTS From among 2220 potentially eligible studies, 71 meta-analyses on diabetic patients were included. Sodium-glucose cotransporter-2 inhibitors (SGLT-is) showed no or equivalent effect on the risk of fracture. Dipeptidyl peptidase-4 inhibitors (DPP-4is) and Glucagon-like peptide-1 receptor agonists (GLP-1Ras) were reported to have controversial effects on bone fracture, with some RCTs pointing out the bone protective effects of certain members of these two medication classes. Thiazolidinediones (TZDs) were linked with increased fracture risk as well as higher concentrations of C-terminal telopeptide of type I collagen (CTx), a bone resorption marker. CONCLUSION The present systematic umbrella review observed varied results on the association between the use of anti-diabetic drugs and DM-related fracture risk. The clinical efficacy of various anti-diabetic drugs, therefore, should be weighed against their risks and benefits in each patient.
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Affiliation(s)
- Pouria Khashayar
- School of Life and Medical Sciences, University of Hertfordshire, Hatfield, UK
| | - Farid Farahani Rad
- Non-Communicable Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Ozra Tabatabaei-Malazy
- Non-Communicable Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran.
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran.
| | - Sara MohammadHosseinzadeh Golabchi
- Non-Communicable Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Patricia Khashayar
- Department of Chemistry, Ghent University, Krijgslaan 281-S12, 9000, Gent, Belgium.
| | - Mehdi Mohammadi
- Department of Clinical Pharmacy, School of Pharmacy, Alborz University of Medical Sciences, Karaj, Iran
| | - Sholeh Ebrahimpour
- Department of Clinical Pharmacy, School of Pharmacy, Alborz University of Medical Sciences, Karaj, Iran
| | - Bagher Larijani
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
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Rasouli M, Naeimzadeh Y, Hashemi N, Hosseinzadeh S. Age-Related Alterations in Mesenchymal Stem Cell Function: Understanding Mechanisms and Seeking Opportunities to Bypass the Cellular Aging. Curr Stem Cell Res Ther 2024; 19:15-32. [PMID: 36642876 DOI: 10.2174/1574888x18666230113144016] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 10/28/2022] [Accepted: 11/23/2022] [Indexed: 01/17/2023]
Abstract
Undoubtedly, mesenchymal stem cells (MSCs) are the most common cell therapy candidates in clinical research and therapy. They not only exert considerable therapeutic effects to alleviate inflammation and promote regeneration, but also show low-immunogenicity properties, which ensure their safety following allogeneic transplantation. Thanks to the necessity of providing a sufficient number of MSCs to achieve clinically efficient outcomes, prolonged in vitro cultivation is indisputable. However, either following long-term in vitro expansion or aging in elderly individuals, MSCs face cellular senescence. Senescent MSCs undergo an impairment in their function and therapeutic capacities and secrete degenerative factors which negatively affect young MSCs. To this end, designing novel investigations to further elucidate cellular senescence and to pave the way toward finding new strategies to reverse senescence is highly demanded. In this review, we will concisely discuss current progress on the detailed mechanisms of MSC senescence and various inflicted changes following aging in MSC. We will also shed light on the examined strategies underlying monitoring and reversing senescence in MSCs to bypass the comprised therapeutic efficacy of the senescent MSCs.
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Affiliation(s)
- Mehdi Rasouli
- Department of Tissue Engineering and Applied Cell Science, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Yasaman Naeimzadeh
- Department of Molecular Medicine, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Nader Hashemi
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Simzar Hosseinzadeh
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Zhang L, Guan Q, Wang Z, Feng J, Zou J, Gao B. Consequences of Aging on Bone. Aging Dis 2023; 15:2417-2452. [PMID: 38029404 PMCID: PMC11567267 DOI: 10.14336/ad.2023.1115] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Accepted: 11/16/2023] [Indexed: 12/01/2023] Open
Abstract
With the aging of the global population, the incidence of musculoskeletal diseases has been increasing, seriously affecting people's health. As people age, the microenvironment within skeleton favors bone resorption and inhibits bone formation, accompanied by bone marrow fat accumulation and multiple cellular senescence. Specifically, skeletal stem/stromal cells (SSCs) during aging tend to undergo adipogenesis rather than osteogenesis. Meanwhile, osteoblasts, as well as osteocytes, showed increased apoptosis, decreased quantity, and multiple functional limitations including impaired mechanical sensing, intercellular modulation, and exosome secretion. Also, the bone resorption function of macrophage-lineage cells (including osteoclasts and preosteoclasts) was significantly enhanced, as well as impaired vascularization and innervation. In this study, we systematically reviewed the effect of aging on bone and the within microenvironment (including skeletal cells as well as their intracellular structure variations, vascular structures, innervation, marrow fat distribution, and lymphatic system) caused by aging, and mechanisms of osteoimmune regulation of the bone environment in the aging state, and the causal relationship with multiple musculoskeletal diseases in addition with their potential therapeutic strategy.
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Affiliation(s)
- Lingli Zhang
- College of Athletic Performance, Shanghai University of Sport, Shanghai, China
| | - Qiao Guan
- School of Exercise and Health, Shanghai University of Sport, Shanghai, China
| | - Zhikun Wang
- School of Exercise and Health, Shanghai University of Sport, Shanghai, China
| | - Jie Feng
- School of Exercise and Health, Shanghai University of Sport, Shanghai, China
| | - Jun Zou
- School of Exercise and Health, Shanghai University of Sport, Shanghai, China
| | - Bo Gao
- Department of Orthopedic Surgery, Xijing Hospital, Air Force Medical University, Xi’an, China
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Bruedigam C, van Leeuwen JPTM, van de Peppel J. Gene Expression Analyses in Models of Rosiglitazone-Induced Physiological and Pathological Mineralization Identify Novel Targets to Improve Bone and Vascular Health. Cells 2023; 12:2462. [PMID: 37887306 PMCID: PMC10605243 DOI: 10.3390/cells12202462] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Revised: 09/25/2023] [Accepted: 09/30/2023] [Indexed: 10/28/2023] Open
Abstract
Clinical studies revealed detrimental skeletal and vascular effects of the insulin sensitizer rosiglitazone. We have shown earlier that rosiglitazone accelerates osteoblast differentiation from human mesenchymal stem cells (hMSC) at the expense of increased oxidative stress and cell death. In calcifying human vascular cells, rosiglitazone stimulates pathological mineralization, an effect diminished by the antioxidant resveratrol. Here, we aimed to elucidate transcriptional networks underlying the rosiglitazone-enhanced mineralization phenotype. We performed genome-wide transcriptional profiling of osteogenic hMSCs treated with rosiglitazone for short-term periods of 1 up to 48 h during the first two days of differentiation, a phase that we show is sufficient for rosiglitazone stimulation of mineralization. Microarray-based mRNA expression analysis revealed 190 probes that were differently expressed in at least one condition compared to vehicle-treated control. This rosiglitazone gene signature contained well-known primary PPAR targets and was also endogenously regulated during osteogenic hMSC differentiation and osteoblast-like differentiation of vascular smooth muscle cells (VSMCs) into calcifying vascular cells (CVCs). Comparative analysis revealed rosiglitazone targets that were commonly enriched in osteoblasts and CVCs or specifically enriched in either osteoblasts or CVCs. Finally, we compared expression patterns of CVC-specific genes with patient expression data from carotid plaque versus intact adjacent tissue, and identified five rosiglitazone targets to be differentially regulated in CVCs and carotid plaque but not osteoblasts when compared to their non-mineralizing counterparts. These targets, i.e., PDK4, SDC4, SPRY4, TCF4 and DACT1, may specifically control extracellular matrix mineralization in vascular cells, and hence provide target candidates for further investigations to improve vascular health.
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Vitamin D and Bone: A Story of Endocrine and Auto/Paracrine Action in Osteoblasts. Nutrients 2023; 15:nu15030480. [PMID: 36771187 PMCID: PMC9919888 DOI: 10.3390/nu15030480] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Revised: 01/11/2023] [Accepted: 01/12/2023] [Indexed: 01/19/2023] Open
Abstract
Despite its rigid structure, the bone is a dynamic organ, and is highly regulated by endocrine factors. One of the major bone regulatory hormones is vitamin D. Its renal metabolite 1α,25-OH2D3 has both direct and indirect effects on the maintenance of bone structure in health and disease. In this review, we describe the underlying processes that are directed by bone-forming cells, the osteoblasts. During the bone formation process, osteoblasts undergo different stages which play a central role in the signaling pathways that are activated via the vitamin D receptor. Vitamin D is involved in directing the osteoblasts towards proliferation or apoptosis, regulates their differentiation to bone matrix producing cells, and controls the subsequent mineralization of the bone matrix. The stage of differentiation/mineralization in osteoblasts is important for the vitamin D effect on gene transcription and the cellular response, and many genes are uniquely regulated either before or during mineralization. Moreover, osteoblasts contain the complete machinery to metabolize active 1α,25-OH2D3 to ensure a direct local effect. The enzyme 1α-hydroxylase (CYP27B1) that synthesizes the active 1α,25-OH2D3 metabolite is functional in osteoblasts, as well as the enzyme 24-hydroxylase (CYP24A1) that degrades 1α,25-OH2D3. This shows that in the past 100 years of vitamin D research, 1α,25-OH2D3 has evolved from an endocrine regulator into an autocrine/paracrine regulator of osteoblasts and bone formation.
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Nagai H, Miwa A, Yoneda K, Fujisawa K, Takami T. Optimizing the Seeding Density of Human Mononuclear Cells to Improve the Purity of Highly Proliferative Mesenchymal Stem Cells. BIOENGINEERING (BASEL, SWITZERLAND) 2023; 10:bioengineering10010102. [PMID: 36671674 PMCID: PMC9855129 DOI: 10.3390/bioengineering10010102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Revised: 12/29/2022] [Accepted: 01/06/2023] [Indexed: 01/15/2023]
Abstract
Mesenchymal stem cells (MSCs) hold considerable promise for regenerative medicine. Optimization of the seeding density of mononuclear cells (MNCs) improves the proliferative and differentiation potential of isolated MSCs. However, the underlying mechanism is unclear. We cultured human bone marrow MNCs at various seeding densities (4.0 × 104, 1.25 × 105, 2.5 × 105, 6.0 × 105, 1.25 × 106 cells/cm2) and examined MSC colony formation. At lower seeding densities (4.0 × 104, 1.25 × 105 cells/cm2), colonies varied in diameter and density, from dense to sparse. In these colonies, the proportion of highly proliferative MSCs increased over time. In contrast, lower proliferative MSCs enlarged more rapidly. Senescent cells were removed using a short detachment treatment. We found that these mechanisms increase the purity of highly proliferative MSCs. Thereafter, we compared MSCs isolated under optimized conditions with a higher density (1.25 × 106 cells/cm2). MSCs under optimized conditions exhibited significantly higher proliferative and differentiation potential into adipocytes and chondrocytes, except for osteocytes. We propose the following conditions to improve MSC quality: (1) optimizing MNC seeding density to form single-cell colonies; (2) adjusting incubation times to increase highly proliferative MSCs; and (3) establishing a detachment processing time that excludes senescent cells.
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Affiliation(s)
- Hiroyuki Nagai
- Shibuya Corporation, Kanazawa 920-8681, Ishikawa, Japan
- Department of Clinical Laboratory Science, Faculty of Health Science, Yamaguchi University Graduate School of Medicine, Ube 755-8505, Yamaguchi, Japan
| | - Akihiro Miwa
- Shibuya Corporation, Kanazawa 920-8681, Ishikawa, Japan
| | - Kenji Yoneda
- Shibuya Corporation, Kanazawa 920-8681, Ishikawa, Japan
| | - Koichi Fujisawa
- Department of Gastroenterology and Hepatology, Yamaguchi University School of Medicine, Ube 755-8505, Yamaguchi, Japan
- Department of Environmental Oncology, Institute of Industrial Ecological Sciences, University of Occupational and Environmental Health, Kitakyushu 807-8555, Fukuoka, Japan
| | - Taro Takami
- Department of Gastroenterology and Hepatology, Yamaguchi University School of Medicine, Ube 755-8505, Yamaguchi, Japan
- Correspondence:
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Bouhtit F, Najar M, Rahmani S, Melki R, Najimi M, Sadki K, Boukhatem N, Twizere JC, Meuleman N, Lewalle P, Lagneaux L, Merimi M. Bioscreening and pre-clinical evaluation of the impact of bioactive molecules from Ptychotis verticillata on the multilineage potential of mesenchymal stromal cells towards immune- and inflammation-mediated diseases. Inflamm Res 2022; 71:887-898. [PMID: 35716172 DOI: 10.1007/s00011-022-01573-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2021] [Accepted: 04/07/2022] [Indexed: 11/05/2022] Open
Abstract
OBJECTIVE AND DESIGN Mesenchymal stromal cells (MSCs) are currently used in cell reparative medicine due to their trophic and ant-inflammatory properties. The modulation of stem cell properties by phytochemicals has been suggested as a tool to empower their tissue repair capacity. In vitro, MSCs are characterized by their tri-lineage potential that holds great interest for tissue regeneration. Ptychotis Verticillata (PV), an aromatic and medicinal plant, may be thus used to modulate the in vitro multilineage potential of MSCs. MATERIALS AND METHODS We screened the impact of PV-derived essential oil and their bioactive molecules (thymol and carvacrol) on the in vitro multilineage potential of MSCs. Different concentrations and incubation times of these compounds were assessed during the osteogenesis and adipogenesis of MSCs. RESULTS The analysis of 75 conditions indicates that these compounds are biologically active by promoting two major differentiation lineages from MSCs. In a time- and dose-dependent manner, thymol and carvacrol increased the osteogenesis and adipogenesis. CONCLUSION According to these preliminary observations, the addition of PV extract may stimulate the tissue regenerative and repair functions of MSCs. Further optimization of compound extraction and characterization from PV as well as cell treatment conditions should increase their therapeutic value in combination with MSCs.
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Affiliation(s)
- Fatima Bouhtit
- Laboratory of Experimental Hematology, Jules Bordet Institute, Université Libre de Bruxelles, Brussels, Belgium
- Genetics and Immune Cell Therapy Unit, Faculty of Sciences, University Mohammed Premier, Oujda, Morocco
| | - Mehdi Najar
- Laboratory of Clinical Cell Therapy, Jules Bordet Institute, Université Libre de Bruxelles, Brussels, Belgium.
- Osteoarthritis Research Unit, University of Montreal Hospital Research Center (CRCHUM), Montreal, Canada.
- Department of Medicine, University of Montreal, Montreal, Canada.
| | - Saida Rahmani
- Laboratory of Experimental Hematology, Jules Bordet Institute, Université Libre de Bruxelles, Brussels, Belgium
- Genetics and Immune Cell Therapy Unit, Faculty of Sciences, University Mohammed Premier, Oujda, Morocco
| | - Rahma Melki
- Genetics and Immune Cell Therapy Unit, Faculty of Sciences, University Mohammed Premier, Oujda, Morocco
| | - Mustapha Najimi
- Institut de Recherche Expérimentale et Clinique (IREC), Laboratory of Pediatric Hepatology and Cell Therapy, Université Catholique de Louvain, Brussels, Belgium
| | - Khalid Sadki
- Laboratory of Human Pathologies Biology, Faculty of Sciences, Mohammed V University Rabat, Agdal, Rabat, Morocco
| | - Noreddine Boukhatem
- Genetics and Immune Cell Therapy Unit, Faculty of Sciences, University Mohammed Premier, Oujda, Morocco
| | - Jean-Claude Twizere
- Laboratory of Viral Interactomes, GIGA Institute, University of Liege, Liege, Belgium
- Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, MA, USA
| | - Nathalie Meuleman
- Laboratory of Experimental Hematology, Jules Bordet Institute, Université Libre de Bruxelles, Brussels, Belgium
| | - Philippe Lewalle
- Laboratory of Experimental Hematology, Jules Bordet Institute, Université Libre de Bruxelles, Brussels, Belgium
| | - Laurence Lagneaux
- Laboratory of Clinical Cell Therapy, Jules Bordet Institute, Université Libre de Bruxelles, Brussels, Belgium
| | - Makram Merimi
- Laboratory of Experimental Hematology, Jules Bordet Institute, Université Libre de Bruxelles, Brussels, Belgium
- Genetics and Immune Cell Therapy Unit, Faculty of Sciences, University Mohammed Premier, Oujda, Morocco
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Urquiza P, Solesio ME. Inorganic Polyphosphate, Mitochondria, and Neurodegeneration. PROGRESS IN MOLECULAR AND SUBCELLULAR BIOLOGY 2022; 61:27-49. [PMID: 35697936 DOI: 10.1007/978-3-031-01237-2_3] [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] [Indexed: 06/15/2023]
Abstract
With an aging population, the presence of aging-associated pathologies is expected to increase within the next decades. Regrettably, we still do not have any valid pharmacological or non-pharmacological tools to prevent, revert, or cure these pathologies. The absence of therapeutical approaches against aging-associated pathologies can be at least partially explained by the relatively lack of knowledge that we still have regarding the molecular mechanisms underlying them, as well as by the complexity of their etiopathology. In fact, a complex number of changes in the physiological function of the cell has been described in all these aging-associated pathologies, including neurodegenerative disorders. Based on multiple scientific manuscripts produced by us and others, it seems clear that mitochondria are dysfunctional in many of these aging-associated pathologies. For example, mitochondrial dysfunction is an early event in the etiopathology of all the main neurodegenerative disorders, and it could be a trigger of many of the other deleterious changes which are present at the cellular level in these pathologies. While mitochondria are complex organelles and their regulation is still not yet entirely understood, inorganic polyphosphate (polyP) could play a crucial role in the regulation of some mitochondrial processes, which are dysfunctional in neurodegeneration. PolyP is a well-preserved biopolymer; it has been identified in every organism that has been studied. It is constituted by a series of orthophosphates connected by highly energetic phosphoanhydride bonds, comparable to those found in ATP. The literature suggests that the role of polyP in maintaining mitochondrial physiology might be related, at least partially, to its effects as a key regulator of cellular bioenergetics. However, further research needs to be conducted to fully elucidate the molecular mechanisms underlying the effects of polyP in the regulation of mitochondrial physiology in aging-associated pathologies, including neurodegenerative disorders. With a significant lack of therapeutic options for the prevention and/or treatment of neurodegeneration, the search for new pharmacological tools against these conditions has been continuous in past decades, even though very few therapeutic approaches have shown potential in treating these pathologies. Therefore, increasing our knowledge about the molecular mechanisms underlying the effects of polyP in mitochondrial physiology as well as its metabolism could place this polymer as a promising and innovative pharmacological target not only in neurodegeneration, but also in a wide range of aging-associated pathologies and conditions where mitochondrial dysfunction has been described as a crucial component of its etiopathology, such as diabetes, musculoskeletal disorders, and cardiovascular disorders.
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Affiliation(s)
- Pedro Urquiza
- Department of Biology, Rutgers University, Camden, NJ, USA
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Kirk AB, Michelsen-Correa S, Rosen C, Martin CF, Blumberg B. PFAS and Potential Adverse Effects on Bone and Adipose Tissue Through Interactions With PPARγ. Endocrinology 2021; 162:6364127. [PMID: 34480479 PMCID: PMC9034324 DOI: 10.1210/endocr/bqab194] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Indexed: 01/06/2023]
Abstract
Perfluoroalkyl and polyfluoroalkyl substances (PFAS) are a widely dispersed, broad class of synthetic chemicals with diverse biological effects, including effects on adipose and bone differentiation. PFAS most commonly occur as mixtures and only rarely, if ever, as single environmental contaminants. This poses significant regulatory questions and a pronounced need for chemical risk assessments, analytical methods, and technological solutions to reduce the risk to public and environmental health. The effects of PFAS on biological systems may be complex. Each may have several molecular targets initiating multiple biochemical events leading to a number of different adverse outcomes. An exposure to mixtures or coexposures of PFAS complicates the picture further. This review illustrates how PFAS target peroxisome proliferator-activated receptors. Additionally, we describe how such activation leads to changes in cell differentiation and bone development that contributes to metabolic disorder and bone weakness. This discussion sheds light on the importance of seemingly modest outcomes observed in test animals and highlights why the most sensitive end points identified in some chemical risk assessments are significant from a public health perspective.
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Affiliation(s)
- Andrea B Kirk
- Correspondence: Andrea Kirk, PhD, US EPA Headquarters, William Jefferson Clinton Bldg, 1200 Pennsylvania Ave NW, Mail Code 5201P, Washington, DC 20460, USA.
| | - Stephani Michelsen-Correa
- EPA Office of Chemical Safety and Pollution Prevention, Biopesticides and Pollution Prevention Division, Washington, District of Columbia 20460, USA
| | - Cliff Rosen
- Tufts University School of Medicine, Boston, Massachusetts 02111, USA
| | | | - Bruce Blumberg
- University of California, Irvine, Irvine, California 92697, USA
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Liu J, Ding Y, Liu Z, Liang X. Senescence in Mesenchymal Stem Cells: Functional Alterations, Molecular Mechanisms, and Rejuvenation Strategies. Front Cell Dev Biol 2020; 8:258. [PMID: 32478063 PMCID: PMC7232554 DOI: 10.3389/fcell.2020.00258] [Citation(s) in RCA: 166] [Impact Index Per Article: 33.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Accepted: 03/27/2020] [Indexed: 12/12/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are multipotent cells capable of self-renewal and differentiation. There is increasing evidence of the therapeutic value of MSCs in various clinical situations, however, these cells gradually lose their regenerative potential with age, with a concomitant increase in cellular dysfunction. Stem cell aging and replicative exhaustion are considered as hallmarks of aging and functional attrition in organisms. MSCs do not proliferate infinitely but undergo only a limited number of population doublings before becoming senescent. This greatly hinders their clinical application, given that cultures must be expanded to obtain a sufficient number of cells for cell-based therapy. Here, we review the current knowledge of the phenotypic and functional characteristics of senescent MSCs, molecular mechanisms underlying MSCs aging, and strategies to rejuvenate senescent MSCs, which can broaden their range of therapeutic applications.
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Affiliation(s)
- Jing Liu
- Research Center for Translational Medicine, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
- Department of Cardiovascular Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yue Ding
- Department of Organ Transplantation, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Zhongmin Liu
- Research Center for Translational Medicine, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
- Department of Cardiovascular Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Xiaoting Liang
- Research Center for Translational Medicine, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
- Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China
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Ni LH, Tang RN, Yuan C, Song KY, Wang LT, Zhang XL, Lv LL, Wang B, Wu M, Tang TT, Li ZL, Yin D, Cao JY, Wang XC, Liu H, Chen Q, Liu BC. Cinacalcet attenuated bone loss via inhibiting parathyroid hormone-induced endothelial-to-adipocyte transition in chronic kidney disease rats. ANNALS OF TRANSLATIONAL MEDICINE 2019; 7:312. [PMID: 31475182 DOI: 10.21037/atm.2019.06.44] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Background Recently, cinacalcet (CINA) has been shown to be effective for attenuating bone loss in the treatment of secondary hyperparathyroidism (SHPT) in patients with chronic kidney disease (CKD), which might be associated with the reduction in serum parathyroid hormone (PTH) levels. However, the exact mechanism is largely unclear. Emerging studies have revealed that an increased number of bone marrow adipocytes (BMAs) are involved in bone loss and the endothelial-to-adipocyte transition via the endothelial-to-mesenchymal transition (EndMT) might play a key role in this pathological process. Here, we assessed whether CINA could attenuate bone loss via inhibiting endothelial-to-adipocyte transition in CKD rats. Methods A rat model of CKD was induced by adenine and a high phosphorus diet. CINA was orally administrated to CKD animals (10 mg/kg once a day). Dual energy X-ray absorptiometry, micro-computed tomography, bone histomorphometry, and bone mechanical tests were used to determine the skeletal changes. The bone marrow expression of EndMT markers was also examined. The effect of elevated PTH levels on the endothelial-to-adipocyte transition was studied in endothelial cells (ECs). Results Elevation of serum PTH levels, remarkable bone loss and increased numbers of BMAs were observed in rats with CKD compared with the controls, and these changes were attenuated after treatment with CINA. Furthermore, the CINA treatment abolished the upregulation of mesenchymal markers (FSP1 and α-SMA) and the downregulation of an endothelial marker (CD31) in bone tissues from rats with CKD. The serum PTH concentrations were correlated with the bone marrow protein levels of these EndMT-related proteins. An in vitro treatment in ECs demonstrated that PTH induced the EndMT in a concentration- and time-dependent manner. Accordingly, ECs treated with PTH exhibited adipogenic potential following growth in adipogenic culture medium. Conclusions Our study indicated CINA treatment attenuated bone loss in CKD rats, which might be associated with inhibiting PTH-induced endothelial-to-adipocyte transition in CKD rats.
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Affiliation(s)
- Li-Hua Ni
- Institute of Nephrology, Zhongda Hospital, Southeast University School of Medicine, Nanjing 210009, China
| | - Ri-Ning Tang
- Institute of Nephrology, Zhongda Hospital, Southeast University School of Medicine, Nanjing 210009, China.,NanJing Lishui People's Hospital, Zhongda Hospital Lishui Branch, Nanjing 210009, China
| | - Cheng Yuan
- Department of Radiation and Medical Oncology, Zhongnan Hospital, Wuhan University, Wuhan 430071, China
| | - Kai-Yun Song
- Institute of Nephrology, Zhongda Hospital, Southeast University School of Medicine, Nanjing 210009, China
| | - Li-Ting Wang
- Institute of Nephrology, Zhongda Hospital, Southeast University School of Medicine, Nanjing 210009, China
| | - Xiao-Liang Zhang
- Institute of Nephrology, Zhongda Hospital, Southeast University School of Medicine, Nanjing 210009, China
| | - Lin-Li Lv
- Institute of Nephrology, Zhongda Hospital, Southeast University School of Medicine, Nanjing 210009, China
| | - Bin Wang
- Institute of Nephrology, Zhongda Hospital, Southeast University School of Medicine, Nanjing 210009, China
| | - Min Wu
- Institute of Nephrology, Zhongda Hospital, Southeast University School of Medicine, Nanjing 210009, China
| | - Tao-Tao Tang
- Institute of Nephrology, Zhongda Hospital, Southeast University School of Medicine, Nanjing 210009, China
| | - Zuo-Lin Li
- Institute of Nephrology, Zhongda Hospital, Southeast University School of Medicine, Nanjing 210009, China
| | - Di Yin
- Institute of Nephrology, Zhongda Hospital, Southeast University School of Medicine, Nanjing 210009, China
| | - Jing-Yuan Cao
- Institute of Nephrology, Zhongda Hospital, Southeast University School of Medicine, Nanjing 210009, China
| | - Xiao-Chen Wang
- Institute of Nephrology, Zhongda Hospital, Southeast University School of Medicine, Nanjing 210009, China
| | - Hong Liu
- Institute of Nephrology, Zhongda Hospital, Southeast University School of Medicine, Nanjing 210009, China
| | - Qiang Chen
- Biomechanics Laboratory, School of Biological Science and Medical Engineering, Southeast University, Nanjing 210096, China
| | - Bi-Cheng Liu
- Institute of Nephrology, Zhongda Hospital, Southeast University School of Medicine, Nanjing 210009, China
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12
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Progress and Applications of Polyphosphate in Bone and Cartilage Regeneration. BIOMED RESEARCH INTERNATIONAL 2019; 2019:5141204. [PMID: 31346519 PMCID: PMC6620837 DOI: 10.1155/2019/5141204] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Revised: 04/29/2019] [Accepted: 06/11/2019] [Indexed: 02/06/2023]
Abstract
Patients with bone and cartilage defects due to infection, tumors, and trauma are quite common. Repairing bone and cartilage defects is thus a major problem for clinicians. Autologous and artificial bone transplantations are associated with many challenges, such as limited materials and immune rejection. Bone and cartilage regeneration has become a popular research topic. Inorganic polyphosphate (polyP) is a widely occurring biopolymer with high-energy phosphoanhydride bonds that exists in organisms from bacteria to mammals. Much data indicate that polyP acts as a regulator of gene expression in bone and cartilage tissues and exerts morphogenetic effects on cells involved in bone and cartilage formation. Exposure of these cells to polyP leads to the increase of cytokines that promote the differentiation of mesenchymal stem cells into osteoblasts, accelerates the osteoblast mineralization process, and inhibits the differentiation of osteoclast precursors to functionally active osteoclasts. PolyP-based materials have been widely reported in in vivo and in vitro studies. This paper reviews the current cellular mechanisms and material applications of polyP in bone and cartilage regeneration.
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Peroxiredoxin II negatively regulates BMP2-induced osteoblast differentiation and bone formation via PP2A Cα-mediated Smad1/5/9 dephosphorylation. Exp Mol Med 2019; 51:1-11. [PMID: 31160554 PMCID: PMC6546700 DOI: 10.1038/s12276-019-0263-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Revised: 02/08/2019] [Accepted: 02/18/2019] [Indexed: 12/12/2022] Open
Abstract
Peroxiredoxin II (Prx II), an antioxidant enzyme in the Prx family, reduces oxidative stress by decreasing the intracellular ROS levels. Osteoblast differentiation is promoted by bone morphogenetic protein 2 (BMP2), which upregulates the expression of osteoblast differentiation marker genes, through Smad1/5/9 phosphorylation. We found that Prx II expression was increased by a high dose of lipopolysaccharide (LPS) but was not increased by a low dose of LPS. Prx II itself caused a decrease in the osteogenic gene expression, alkaline phosphatase (ALP) activity, and Smad1/5/9 phosphorylation induced by BMP2. In addition, BMP2-induced osteogenic gene expression and ALP activity were higher in Prx II knockout (KO) cells than they were in wild-type (WT) cells. These inhibitory effects were mediated by protein phosphatase 2A Cα (PP2A Cα), which was increased and is known to induce the dephosphorylation of Smad1/5/9. The overexpression of Prx II increased the expression of PP2A Cα, and PP2A Cα was not expressed in Prx II KO cells. Moreover, PP2A Cα reduced the level of BMP2-induced osteogenic gene expression and Smad1/5/9 phosphorylation. LPS inhibited BMP2-induced Smad1/5/9 phosphorylation and the suppressed phosphorylation was restored by the PP2A inhibitor okadaic acid (OA). Bone phenotype analyses using microcomputed tomography (μCT) revealed that the Prx II KO mice had higher levels of bone mass than the levels of the WT mice. We hypothesize that Prx II has a negative role in osteoblast differentiation through the PP2A-dependent dephosphorylation of Smad1/5/9. An antioxidant enzyme actively works to reduce bone synthesis under oxidative stress conditions in order to protect bone cells from damage and cell death. Bone is generated by cells called osteoblasts, which differentiate from stem cells. In osteoporosis and diabetes, excessive reactive oxygen species (ROS) within cells can disrupt osteoblast differentiation. South Korean researchers led by Eun-jung Kim at Kyungpook National University, Daegu, and Won-Gu Jang at Daegu University, Gyeongbuk, have shown that an antioxidant enzyme, peroxiredoxin II (PrxII), helps regulate bone formation under oxidative stress. The team generated PrxII-deficient mice and compared them with healthy normal mice. Under oxidative stress conditions, the mice had higher bone mass and higher expression of genes related to bone formation than the normal mice. PrxII limits osteoblast differentiation during elevated ROS by influencing associated protein activity and signalling pathways.
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Bae HK, Jung BD, Lee S, Park CK, Yang BK, Cheong HT. Correlation of spontaneous adipocyte generation with osteogenic differentiation of porcine skin-derived stem cells. J Vet Sci 2019; 20:16-26. [PMID: 30481989 PMCID: PMC6351758 DOI: 10.4142/jvs.2019.20.1.16] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2018] [Revised: 10/18/2018] [Accepted: 11/06/2018] [Indexed: 12/13/2022] Open
Abstract
The objective of this study was to examine effects of spontaneous adipocyte generation on osteogenic differentiation of porcine skin-derived stem cells (pSSCs). Correlation between osteogenic differentiation and adipocyte differentiation induced by osteocyte induction culture was determined using different cell lines. Osteogenic differentiation efficiency of pSSCs was then analyzed by controlling the expression of adipocyte-specific transcription factors during osteogenic induction culture. Among four cell lines, pSSCs-II had the lowest lipid droplet level but the highest calcium content (p ＜ 0.05). It also expressed significantly low levels of peroxisome proliferator-activated receptor gamma 2 (PPARγ2) and adipocyte protein 2 (aP2) mRNAs but very high levels of runt-related transcription factor 2 (Runx2) and alkaline phosphatase (ALP) mRNAs as osteogenic makers (p ＜ 0.05). Oil red O extraction was increased by 0.1 µM troglitazone (TGZ) treatment but decreased by 50 µM bisphenol A diglycidyl ether (BADGE) (p ＜ 0.05). Calcium content was drastically increased after BADGE treatment compared to that in osteogenic induction control and TGZ-treated pSSCs (p ＜ 0.05). Relative expression levels of PPARγ2 and aP2 mRNAs were increased by TGZ but decreased by BADGE. Expression levels of Rucx2 and ALP mRNAs, osteoblast-specific marker genes, were significantly increased by BADGE treatment (p ＜ 0.05). The expression level of BCL2 like 1 was significantly higher in BADGE-treated pSSCs than that in TGZ-treated ones (p ＜ 0.05). The results demonstrate that spontaneous adipocyte generation does not adversely affect osteogenic differentiation. However, reducing spontaneous adipocyte generation by inhibiting PPARγ2 mRNA expression can enhance in vitro osteogenic differentiation of pSSCs.
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Affiliation(s)
- Hyo-Kyung Bae
- College of Veterinaryy Medicine and Institute of Veterinary Science, Kangwon National University, Chuncheon 24341, Korea
| | - Bae-Dong Jung
- College of Veterinaryy Medicine and Institute of Veterinary Science, Kangwon National University, Chuncheon 24341, Korea
| | - Seunghyung Lee
- College of Animal Life Sciences, Kangwon National University, Chuncheon 24341, Korea
| | - Choon-Keun Park
- College of Animal Life Sciences, Kangwon National University, Chuncheon 24341, Korea
| | - Boo-Keun Yang
- College of Animal Life Sciences, Kangwon National University, Chuncheon 24341, Korea
| | - Hee-Tae Cheong
- College of Veterinaryy Medicine and Institute of Veterinary Science, Kangwon National University, Chuncheon 24341, Korea
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15
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Rharass T, Lucas S. High Glucose Level Impairs Human Mature Bone Marrow Adipocyte Function Through Increased ROS Production. Front Endocrinol (Lausanne) 2019; 10:607. [PMID: 31551934 PMCID: PMC6746912 DOI: 10.3389/fendo.2019.00607] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2019] [Accepted: 08/21/2019] [Indexed: 12/20/2022] Open
Abstract
Bone marrow adipocytes (BMAds) accumulate in aging, menopause, and metabolic diseases such as Type 2 diabetes. These osteoporotic conditions are associated with oxidative stress and hyperglycemia which are both considered as critical factors underlying bone fragility. Glucose excess and reactive oxygen species (ROS) are known to favor adipogenesis over osteoblastogenesis. In this study, we investigated whether high glucose exposure could determine dysfunction of mature BMAds, specifically through ROS production. The effects of low (LG, 5 mM) or high glucose (HG, 25 mM) concentrations were examined using human bone mesenchymal stromal cells (hBMSCs) in the time course of differentiation, and, up to 21 days once adipocytes were mature. HG did not alter the adipocyte differentiation process of hBMSCs. Yet, after 21 days under HG exposure, PPARG, CEBPA, and adiponectin mRNA expressions were decreased. These alterations were also observed following adipogenic inducer withdrawal as well as in adipocytes fully differentiated in LG then cultured in HG for the last 11 days. Without inducers, HG condition also led to decreased leptin mRNA level. Importantly, intracellular and extracellular ROS concentrations measured using Amplex Red were significantly raised by 50% under HG exposure. This rise was observed once adipocytes ended differentiation and was reproduced within the different cell culture settings without any cytotoxicity. Among genes involved in ROS metabolism, the mRNA level of the H2O2 generating enzyme NOX4 was found upregulated in the presence of HG. Following cell separation, mature BMAds were shown to overproduce ROS and to display the gene alterations in contrast to non-lipid-laden cells. Finally, a non-lethal treatment with a pro-oxidant agent under LG condition reduces the mRNA levels of PPARG, adiponectin, and leptin as the HG condition does in the absence of inducers, and amplifies the effect of glucose excess on gene expression. HG concentration drives mature BMAds toward altered expression of the main adipokines and transcriptional factors. These perturbations are associated with a rise in ROS generation likely mediated through enhanced expression of NOX4. Mature BMAds are thus responsive to changes in glucose and ROS concentrations, which is relevant regarding with their phenotype and function in age- or metabolic disease-related osteoporosis.
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VCE-004.8, A Multitarget Cannabinoquinone, Attenuates Adipogenesis and Prevents Diet-Induced Obesity. Sci Rep 2018; 8:16092. [PMID: 30382123 PMCID: PMC6208444 DOI: 10.1038/s41598-018-34259-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2018] [Accepted: 10/06/2018] [Indexed: 01/01/2023] Open
Abstract
Over the past few years, the endocannabinoid system (ECs) has emerged as a crucial player for the regulation of food intake and energy metabolism, and its pharmacological manipulation represents a novel strategy for the management of metabolic diseases. The discovery that VCE-004.8, a dual PPARγ and CB2 receptor agonist, also inhibits prolyl-hydroxylases (PHDs) and activates the HIF pathway provided a rationale to investigate its effect in in vitro models of adipogenesis and in a murine model of metabolic syndrome, all processes critically regulated by these targets of VCE-004.8. In accordance with its different binding mode to PPARγ compared to rosiglitazone (RGZ), VCE-004.8 neither induced adipogenic differentiation, nor affected osteoblastogenesis. Daily administration of VCE-004.8 (20 mg/kg) to HFD mice for 3-wks induced a significant reduction in body weight gain, total fat mass, adipocyte volume and plasma triglycerides levels. VCE-004.8 could also significantly ameliorate glucose tolerance, reduce leptin levels (a marker of adiposity) and increase adiponectin and incretins (GLP-1 and GIP) levels. Remarkably, VCE-004.8 increased the FGF21 mRNA expression in white and brown adipose, as well as in a BAT cell line, qualifying cannabinoaminoquinones as a class of novel therapeutic candidates for the management of obesity and its common metabolic co-morbidities.
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Bei J, Zhang X, Wu J, Hu Z, Xu B, Lin S, Cui L, Wu T, Zou L. Ginsenoside Rb1 does not halt osteoporotic bone loss in ovariectomized rats. PLoS One 2018; 13:e0202885. [PMID: 30212470 PMCID: PMC6136715 DOI: 10.1371/journal.pone.0202885] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2018] [Accepted: 08/12/2018] [Indexed: 11/19/2022] Open
Abstract
Osteoporosis (OP) is a systemic skeletal disorder, manifesting with a reduction in bone mass and deterioration of the microarchitecture. Mesenchymal stem cells (MSCs) have an innate ability to differentiate into several cell types, including osteoblasts (OB). Ginsenoside Rb1 (GRb1) is an ethanol extract from ginseng and contains a highly concentrated form of ginsenoside. GRb1 shows extensive beneficial health effects such as anti-oxidative and anti-inflammatory functions, modulating the immune system and inhibiting osteoclastogenesis. We hypothesized that GRb1 can promote MSC differentiation into OBs and inhibit bone loss. In the present study, we aimed to address two questions: (1) Will GRb1 have a positive effect on osteogenic differentiation of MSCs? and (2) Will GRb1 halt bone loss in ovariectomized (OVX) rats? We investigated the effects of GRb1 on viability and osteogenic differentiation of rat mesenchymal stem cells (rMSCs). Our results showed that GRb1 at concentrations of 10-8 M and 10-6 M can increase alkaline phosphatase activity, mineralization and the expression of osteogenic related proteins, such as osteopontin and osteoprotegerin, while incubating rMSCs with osteogenic induction medium and GRb1. Adding GRb1 into the medium can prevent rMSCs from Oxidative damage at the concentration of 25μM H2O2. Furthermore, 40 4-month-old rats were assigned to 5 groups(8 rats per group): the basal group, the sham group, the OVX group, the high dose of GRb1 group (6 mg/kg/day) and the low dose of GRb1 group (3 mg/kg/day). Rats recrived treatment 3days after surgery and last for 14 weeks. Examinations included serum analysis, mechanical testing, Masson-Goldner trichrome staining and bone histomorphometry analysis. The results showed that OVX can lead to dyslipidemia and excessive oxidative stress, whereas GRb1 cannot significantly halt dyslipidemia and excessive oxidative stress in OVX rats. In addition, the bone density of the lumbar vertebra and femur were decreased significantly in the OVX rats, and GRb1 could not inhibit bone loss. Bone histomorphometry analysis showed that the number and width of bone trabecula of the tibia were reduced in OVX rats, and GRb1 could not prevent their occurrence. A bone biomechanics assay showed that GRb1 cannot improve the ability of bone structure to resist fracture of the femur in OVX rats. The current study demonstrated that GRb1 has an obvious effect on osteogenic differentiation in rMSCs but no obvious effect on bone loss in OVX rats. These findings indicate GRb1 has a positive effect on rMSCs but does not have an effect on bone loss in OVX rats at the concentration we used.
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Affiliation(s)
- JiaXin Bei
- Department of Pharmacology, Guangdong Medical University, Zhanjiang, China
| | - XinLe Zhang
- Department of Pharmacology, Guangdong Medical University, Zhanjiang, China
| | - JingKai Wu
- Department of Pharmacology, Guangdong Medical University, Zhanjiang, China
| | - ZhuoQing Hu
- Guangdong Key Laboratory for Research and Development of Natural Drugs, Guangdong Medical University, Zhanjiang, China
| | - BiLian Xu
- Department of Pharmacology, Guangdong Medical University, Zhanjiang, China
| | - Sien Lin
- Guangdong Key Laboratory for Research and Development of Natural Drugs, Guangdong Medical University, Zhanjiang, China
| | - Liao Cui
- Guangdong Key Laboratory for Research and Development of Natural Drugs, Guangdong Medical University, Zhanjiang, China
| | - Tie Wu
- Research Center of CoQ10, Guangdong Runhe Biochemical Technology Company, Dongguan, China
| | - LiYi Zou
- Department of Pharmacology, Guangdong Medical University, Zhanjiang, China
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Davidson MA, Mattison DR, Azoulay L, Krewski D. Thiazolidinedione drugs in the treatment of type 2 diabetes mellitus: past, present and future. Crit Rev Toxicol 2017; 48:52-108. [PMID: 28816105 DOI: 10.1080/10408444.2017.1351420] [Citation(s) in RCA: 65] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Thiazolidinedione (TZD) drugs used in the treatment of type 2 diabetes mellitus (T2DM) have proven effective in improving insulin sensitivity, hyperglycemia, and lipid metabolism. Though well tolerated by some patients, their mechanism of action as ligands of peroxisome proliferator-activated receptors (PPARs) results in the activation of several pathways in addition to those responsible for glycemic control and lipid homeostasis. These pathways, which include those related to inflammation, bone formation, and cell proliferation, may lead to adverse health outcomes. As treatment with TZDs has been associated with adverse hepatic, cardiovascular, osteological, and carcinogenic events in some studies, the role of TZDs in the treatment of T2DM continues to be debated. At the same time, new therapeutic roles for TZDs are being investigated, with new forms and isoforms currently in the pre-clinical phase for use in the prevention and treatment of some cancers, inflammatory diseases, and other conditions. The aims of this review are to provide an overview of the mechanism(s) of action of TZDs, a review of their safety for use in the treatment of T2DM, and a perspective on their current and future therapeutic roles.
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Affiliation(s)
- Melissa A Davidson
- a Faculty of Health Sciences , University of Ottawa , Ottawa , Canada.,b McLaughlin Centre for Population Health Risk Assessment , Ottawa , Canada
| | - Donald R Mattison
- b McLaughlin Centre for Population Health Risk Assessment , Ottawa , Canada.,c Risk Sciences International , Ottawa , Canada
| | - Laurent Azoulay
- d Center for Clinical Epidemiology , Lady Davis Research Institute, Jewish General Hospital , Montreal , Canada.,e Department of Oncology , McGill University , Montreal , Canada
| | - Daniel Krewski
- a Faculty of Health Sciences , University of Ottawa , Ottawa , Canada.,b McLaughlin Centre for Population Health Risk Assessment , Ottawa , Canada.,c Risk Sciences International , Ottawa , Canada.,f Faculty of Medicine , University of Ottawa , Ottawa , Canada
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19
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Baghel MS, Thakur MK. Differential proteome profiling in the hippocampus of amnesic mice. Hippocampus 2017; 27:845-859. [PMID: 28449397 DOI: 10.1002/hipo.22735] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2016] [Revised: 04/06/2017] [Accepted: 04/12/2017] [Indexed: 12/20/2022]
Abstract
Amnesia or memory loss is associated with brain aging and several neurodegenerative pathologies including Alzheimer's disease (AD). This can be induced by a cholinergic antagonist scopolamine but the underlying molecular mechanism is poorly understood. This study of proteome profiling in the hippocampus could provide conceptual insights into the molecular mechanisms involved in amnesia. To reveal this, mice were administered scopolamine to induce amnesia and memory impairment was validated by novel object recognition test. Using two-dimensional gel electrophoresis coupled with MALDI-MS/MS, we have analyzed the hippocampal proteome and identified 18 proteins which were differentially expressed. Out of these proteins, 11 were downregulated and 7 were upregulated in scopolamine-treated mice as compared to control. In silico analysis showed that the majority of identified proteins are involved in metabolism, catalytic activity, and cytoskeleton architectural functions. STRING interaction network analysis revealed that majority of identified proteins exhibit common association with Actg1 cytoskeleton and Vdac1 energy transporter protein. Furthermore, interaction map analysis showed that Fascin1 and Coronin 1b individually interact with Actg1 and regulate the actin filament dynamics. Vdac1 was significantly downregulated in amnesic mice and showed interaction with other proteins in interaction network. Therefore, we silenced Vdac1 in the hippocampus of normal young mice and found similar impairment in recognition memory of Vdac1 silenced and scopolamine-treated mice. Thus, these findings suggest that Vdac1-mediated disruption of energy metabolism and cytoskeleton architecture might be involved in scopolamine-induced amnesia.
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Affiliation(s)
- Meghraj Singh Baghel
- Department of Zoology, Biochemistry and Molecular Biology Laboratory, Centre of Advanced Study, Banaras Hindu University, Varanasi, 221005, India
| | - Mahendra Kumar Thakur
- Department of Zoology, Biochemistry and Molecular Biology Laboratory, Centre of Advanced Study, Banaras Hindu University, Varanasi, 221005, India
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20
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Casado-Díaz A, Túnez-Fiñana I, Mata-Granados JM, Ruiz-Méndez MV, Dorado G, Romero-Sánchez MC, Navarro-Valverde C, Quesada-Gómez JM. Serum from postmenopausal women treated with a by-product of olive-oil extraction process stimulates osteoblastogenesis and inhibits adipogenesis in human mesenchymal stem-cells (MSC). Exp Gerontol 2017; 90:71-78. [PMID: 28167238 DOI: 10.1016/j.exger.2017.01.024] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2016] [Revised: 01/24/2017] [Accepted: 01/26/2017] [Indexed: 12/23/2022]
Abstract
Aging may enhance both oxidative stress and bone-marrow mesenchymal stem-cell (MSC) differentiation into adipocytes. That reduces osteoblastogenesis, thus favoring bone-mass loss and fracture, representing an important worldwide health-issue, mainly in countries with aging populations. Intake of antioxidant products may help to retain bone-mass density. Interestingly, a novel olive-pomace physical treatment to generate olive oil also yields by-products rich in functional antioxidants. Thus, diet of postmenopausal women was supplemented for two months with one of such by-products (distillate 6; D6), being rich in squalene. After treatment, serum from such women showed reduced both lipidic peroxidation and oxidized low-density lipoprotein (LDL). Besides, vitamin E and coenzyme Q10 levels increased. Furthermore, culture medium containing 10% of such serum both increased osteoblastogenesis and reduced adipogenesis in human MSC from bone marrow. Therefore, highly antioxidant by-products like D6 may represent a relevant source for development of functional products, for both prevention and treatment of degenerative pathologies associated with aging, like osteoporosis.
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Affiliation(s)
- Antonio Casado-Díaz
- Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Unidad de Gestión Clínica (UGC) de Endocrinología y Nutrición, Hospital Universitario Reina Sofía, Universidad de Córdoba, Avda. Menéndez Pidal s/n, 14004 Córdoba, Spain; RETICEF & CIBER de Fragilidad y Envejecimento Saludable (CIBERFES), Spain
| | - Isaac Túnez-Fiñana
- Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Unidad de Gestión Clínica (UGC) de Endocrinología y Nutrición, Hospital Universitario Reina Sofía, Universidad de Córdoba, Avda. Menéndez Pidal s/n, 14004 Córdoba, Spain; Dep. Bioquímica y Biología Molecular, Facultad de Medicina y Enfermería, Universidad de Córdoba, Avda. Menéndez Pidal s/n, 14004 Córdoba, Spain
| | - José María Mata-Granados
- Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Unidad de Gestión Clínica (UGC) de Endocrinología y Nutrición, Hospital Universitario Reina Sofía, Universidad de Córdoba, Avda. Menéndez Pidal s/n, 14004 Córdoba, Spain
| | - María Victoria Ruiz-Méndez
- Instituto de la Grasa, Consejo Superior de Investigaciones Científicas (CSIC), Campus Universitario Pablo de Olavide E46, Ctra. de Utrera km 1, 41013 Sevilla, Spain
| | - Gabriel Dorado
- Dep. Bioquímica y Biología Molecular, Universidad de Córdoba, Campus de Excelencia Internacional Agroalimentario (ceiA3), Campus Rabanales C6-1-E17, 14071 Córdoba, Spain; RETICEF & CIBER de Fragilidad y Envejecimento Saludable (CIBERFES), Spain
| | - María Concepción Romero-Sánchez
- Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Unidad de Gestión Clínica (UGC) de Endocrinología y Nutrición, Hospital Universitario Reina Sofía, Universidad de Córdoba, Avda. Menéndez Pidal s/n, 14004 Córdoba, Spain; RETICEF & CIBER de Fragilidad y Envejecimento Saludable (CIBERFES), Spain
| | | | - José Manuel Quesada-Gómez
- Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Unidad de Gestión Clínica (UGC) de Endocrinología y Nutrición, Hospital Universitario Reina Sofía, Universidad de Córdoba, Avda. Menéndez Pidal s/n, 14004 Córdoba, Spain; RETICEF & CIBER de Fragilidad y Envejecimento Saludable (CIBERFES), Spain.
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21
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Abstract
Obesity is a worldwide epidemic that predisposes individuals to cardiometabolic complications, such as type 2 diabetes mellitus (T2DM) and nonalcoholic fatty liver disease (NAFLD), which are all related to inappropriate ectopic lipid deposition. Identification of the pathogenic molecular mechanisms and effective therapeutic approaches are highly needed. The peroxisome proliferator-activated receptors (PPARs) modulate several biological processes that are perturbed in obesity, including inflammation, lipid and glucose metabolism and overall energy homeostasis. Here, we review how PPARs regulate the functions of adipose tissues, such as adipogenesis, lipid storage and adaptive thermogenesis, under healthy and pathological conditions. We also discuss the clinical use and mechanism of PPAR agonists in the treatment of obesity comorbidities such as dyslipidaemia, T2DM and NAFLD. First generation PPAR agonists, primarily those acting on PPARγ, are associated with adverse effects that outweigh their clinical benefits, which led to the discontinuation of their development. An improved understanding of the physiological roles of PPARs might, therefore, enable the development of safe, new PPAR agonists with improved therapeutic potential.
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Affiliation(s)
- Barbara Gross
- Université de Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1011-EGID, F-59000 Lille, France
| | - Michal Pawlak
- International Institute of Molecular and Cell Biology, 4 Ks. Trojdena Street, 02-109 Warsaw, Poland
| | - Philippe Lefebvre
- Université de Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1011-EGID, F-59000 Lille, France
| | - Bart Staels
- Université de Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1011-EGID, F-59000 Lille, France
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Hardouin P, Marie PJ, Rosen CJ. New insights into bone marrow adipocytes: Report from the First European Meeting on Bone Marrow Adiposity (BMA 2015). Bone 2016; 93:212-215. [PMID: 26608519 DOI: 10.1016/j.bone.2015.11.013] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2015] [Revised: 11/05/2015] [Accepted: 11/18/2015] [Indexed: 02/08/2023]
Affiliation(s)
- Pierre Hardouin
- PMOI, Université de Lille and Université du Littoral Côte d'Opale, Boulogne sur Mer, France
| | - Pierre J Marie
- UMR-1132 INSERM and Université Paris Diderot, Sorbonne Paris Cité, Paris, France
| | - Clifford J Rosen
- Maine Medical Center Research Institute Scarborough, ME 04074, USA
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Peroxisome Proliferator-Activated Receptor Gamma Promotes Mesenchymal Stem Cells to Express Connexin43 via the Inhibition of TGF-β1/Smads Signaling in a Rat Model of Myocardial Infarction. Stem Cell Rev Rep 2016; 11:885-99. [PMID: 26275398 DOI: 10.1007/s12015-015-9615-7] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND In this study, we hypothesized that activation of PPAR-γ enhanced MSCs survival and their therapeutic efficacy via upregulating the expression of Cx43. METHODS MI was induced in 50 male Sprague-Dawley rats. The rats were randomized into five groups: MI group and four intervention groups, including the MSCs group, combined therapy group (MSCs+ pioglitazone), pioglitazone group and PBS group. Two weeks later, 5 × 10(6) MSCs labeled with PKH26 in PBS were injected into the infarct anterior ventricular free wall in the MSCs and combined therapy groups, and PBS alone was injected into the infarct anterior ventricular free wall in the PBS group. Pioglitazone (3 mg/kg/day) was given to the combined therapy and pioglitazone groups by oral gavage at the same time for another 2 weeks. Myocardial function and relevant signaling molecules involved were all examined thereafter. RESULTS Heart function was enhanced after MSCs treatment for 2 weeks post MI. A significant improvement of heart function was observed in the combined therapy group in contrast to the other three intervention groups. Compared with the MSCs group, there was a higher level of PPAR-γ in the combined therapy group; Cx43 was remarkably increased in different regions of the left ventricle; TGF-β1 was decreased in the infarct zone and border zone. To the downstream signaling molecules, mothers against Smad proteins including Smad2 and Smad3 presented a synchronized alteration with TGF-β1; no differences of the expressions of ERK1/2 and p38 could be discovered in the left ventricular cardiac tissue. CONCLUSIONS MSCs transplantation combined with pioglitazone administration improved cardiac function more effectively after MI. Activation of PPAR-γ could promote MSCs to express Cx43. Inhibition of TGF-β1/Smads signaling pathway might be involved in the process.
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Pioglitazone affects the OPG/RANKL/RANK system and increase osteoclastogenesis. Mol Med Rep 2016; 14:2289-96. [DOI: 10.3892/mmr.2016.5515] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2015] [Accepted: 04/07/2016] [Indexed: 11/05/2022] Open
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Fate decision of mesenchymal stem cells: adipocytes or osteoblasts? Cell Death Differ 2016; 23:1128-39. [PMID: 26868907 PMCID: PMC4946886 DOI: 10.1038/cdd.2015.168] [Citation(s) in RCA: 862] [Impact Index Per Article: 95.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2015] [Revised: 11/03/2015] [Accepted: 12/01/2015] [Indexed: 12/18/2022] Open
Abstract
Mesenchymal stem cells (MSCs), a non-hematopoietic stem cell population first discovered in bone marrow, are multipotent cells capable of differentiating into mature cells of several mesenchymal tissues, such as fat and bone. As common progenitor cells of adipocytes and osteoblasts, MSCs are delicately balanced for their differentiation commitment. Numerous in vitro investigations have demonstrated that fat-induction factors inhibit osteogenesis, and, conversely, bone-induction factors hinder adipogenesis. In fact, a variety of external cues contribute to the delicate balance of adipo-osteogenic differentiation of MSCs, including chemical, physical, and biological factors. These factors trigger different signaling pathways and activate various transcription factors that guide MSCs to commit to either lineage. The dysregulation of the adipo-osteogenic balance has been linked to several pathophysiologic processes, such as aging, obesity, osteopenia, osteopetrosis, and osteoporosis. Thus, the regulation of MSC differentiation has increasingly attracted great attention in recent years. Here, we review external factors and their signaling processes dictating the reciprocal regulation between adipocytes and osteoblasts during MSC differentiation and the ultimate control of the adipo-osteogenic balance.
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Billington EO, Grey A, Bolland MJ. The effect of thiazolidinediones on bone mineral density and bone turnover: systematic review and meta-analysis. Diabetologia 2015; 58:2238-46. [PMID: 26109213 DOI: 10.1007/s00125-015-3660-2] [Citation(s) in RCA: 98] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2015] [Accepted: 05/19/2015] [Indexed: 12/17/2022]
Abstract
AIMS/HYPOTHESIS Thiazolidinediones (TZDs) are associated with an increased risk of fracture but the mechanism is unclear. We sought to determine the effect of TZDs on bone mineral density (BMD) and bone turnover markers. METHODS PubMed, EMBASE and Cochrane CENTRAL databases were searched from inception until January 2015 for randomised controlled trials comparing TZDs with metformin, sulfonylureas or placebo, and those reporting changes in BMD and/or bone turnover markers. The primary outcome was percentage change in BMD from baseline and results were pooled with random effects meta-analyses. RESULTS In all, 18 trials were included in the primary analyses and another two were included in the sensitivity analyses (n = 3,743, 50% women, mean age 56 years, median trial duration 48 weeks). TZDs decreased BMD at the lumbar spine (difference -1.1% [95% CI -1.6, -0.7]; p < 0.0001), total hip (-1.0% [-1.4, -0.6]; p < 0.0001) and forearm (-0.9% [-1.6, -0.3]; p = 0.007). There were statistically non-significant decreases in BMD at the femoral neck (-0.7% [-1.4, 0.0]; p = 0.06) and total body (-0.3% [-0.5, 0.0]; p = 0.08). Five trials (n = 450) showed no statistically significant difference in percentage change in BMD between the TZD group and controls up to 1 year following TZD withdrawal. In 14 trials, the effect of TZD treatment on turnover markers varied considerably between individual studies. CONCLUSIONS/INTERPRETATION Treatment with TZDs results in modest bone loss that may not be reversed 1 year after cessation of treatment.
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Affiliation(s)
- Emma O Billington
- Division of Endocrinology, University of Calgary, Calgary, Canada.
- Bone & Joint Research Group, Faculty of Medical and Health Sciences, University of Auckland, 85 Park Road, Grafton, Auckland, 1010, New Zealand.
| | - Andrew Grey
- Bone & Joint Research Group, Faculty of Medical and Health Sciences, University of Auckland, 85 Park Road, Grafton, Auckland, 1010, New Zealand
| | - Mark J Bolland
- Bone & Joint Research Group, Faculty of Medical and Health Sciences, University of Auckland, 85 Park Road, Grafton, Auckland, 1010, New Zealand
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Kang JH, Kwak HJ, Choi HE, Kim J, Hong S, Kim OH, Oh BC, Cheon HG. Involvement of Prolyl Hydroxylase Domain Protein in the Rosiglitazone-Induced Suppression of Osteoblast Differentiation. PLoS One 2015; 10:e0139093. [PMID: 26418009 PMCID: PMC4587972 DOI: 10.1371/journal.pone.0139093] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2014] [Accepted: 09/09/2015] [Indexed: 01/10/2023] Open
Abstract
Rosiglitazone is a well-known anti-diabetic drug that increases insulin sensitivity via peroxisome proliferator-activated receptor γ (PPARγ) activation, but unfortunately it causes bone loss in animals and humans. A previous study showed that prolyl hydroxylase domain protein (PHD) plays a role in rosiglitazone-induced adipocyte differentiation. Based on the inverse relationship between adipocyte and osteoblast differentiation, we investigated whether PHD is involved in the effects of rosiglitazone on osteoblast differentiation. Rosiglitazone inhibited osteoblast differentiation in a concentration-dependent manner, and in parallel induced three PHD isoforms (PHD1, 2, and 3). PHD inhibitors and knockdown of each isoform prevented the inhibitory effects of rosiglitazone on osteoblast differentiation and increased the expression of Runx2, a transcription factor essential for osteoblastogenesis. MG-132, a proteasomal inhibitor also prevented the rosiglitazone-induced degradation of Runx2. Furthermore, both increased PHD isoform expressions and reduced osteoblast differentiation by rosiglitazone were prevented by PPARγ antagonists, indicating these effects were mediated via PPARγ activation. In vivo oral administration of rosiglitazone to female ICR mice for 8 weeks reduced bone mineral densities and plasma alkaline phosphatase (ALP) activity, and increased PHD expression in femoral primary bone marrow cells and the ubiquitination of Runx2. Together, this suggests that the rosiglitazone-induced suppression of osteoblast differentiation is at least partly induced via PPARγ-mediated PHD induction and subsequent promotion of the ubiquitination and degradation of Runx2.
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Affiliation(s)
- Ju-Hee Kang
- Department of Pharmacology, School of Medicine, Gachon University, Incheon, Republic of Korea
| | - Hyun Jeong Kwak
- Department of Pharmacology, School of Medicine, Gachon University, Incheon, Republic of Korea
| | - Hye-Eun Choi
- Department of Pharmacology, School of Medicine, Gachon University, Incheon, Republic of Korea
| | - Juyoung Kim
- Department of Pharmacology, School of Medicine, Gachon University, Incheon, Republic of Korea
| | - Sangmee Hong
- Department of Molecular Medicine, Gachon University, Incheon, Republic of Korea
| | - Ok-Hee Kim
- Department of Molecular Medicine, Gachon University, Incheon, Republic of Korea
| | - Byung Chul Oh
- Department of Molecular Medicine, Gachon University, Incheon, Republic of Korea
| | - Hyae Gyeong Cheon
- Department of Pharmacology, School of Medicine, Gachon University, Incheon, Republic of Korea
- Gachon Medical Research Institute, Gil Medical Center, Incheon, Republic of Korea
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de Lima CL, Coelho MS, Royer C, Resende AP, Borges GA, Rodrigues da Silva J, Amato AA, Guerra E, Neves FDAR, Acevedo AC. Rosiglitazone Inhibits Proliferation and Induces Osteopontin Gene Expression in Human Dental Pulp Cells. J Endod 2015; 41:1486-91. [DOI: 10.1016/j.joen.2015.05.010] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2015] [Revised: 05/15/2015] [Accepted: 05/21/2015] [Indexed: 11/29/2022]
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Starup-Linde J, Vestergaard P. Management of endocrine disease: Diabetes and osteoporosis: cause for concern? Eur J Endocrinol 2015; 173:R93-9. [PMID: 26243638 DOI: 10.1530/eje-15-0155] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Diabetes and osteoporosis are both frequent conditions, and they may thus occur simultaneously by chance. However, a growing body of evidence suggests that hyperglycemia may impair bone matrix formation and biochemical competence. Decreased biomechanical competence may be present even in a setting of increased bone mineral density, as assessed by traditional dual energy X-ray absorptiometry or normal structural parameters by quantitative computed tomography. Also, the absence of endogenous insulin secretion in type 1 diabetes (T1D) and insulin resistance or, in some cases, frank hyperinsulinemia in T2D may play a role.
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Affiliation(s)
- Jakob Starup-Linde
- Department of Clinical MedicineAalborg University Hospital, Mølleparkvej 4, DK-9100 Aalborg, DenmarkDepartment of Endocrinology and Internal MedicineAarhus University Hospital, Aarhus, DenmarkDepartment of EndocrinologyMedicinerhuset, Aalborg University Hospital, Mølleparkvej 4, DK-9100 Aalborg, Denmark Department of Clinical MedicineAalborg University Hospital, Mølleparkvej 4, DK-9100 Aalborg, DenmarkDepartment of Endocrinology and Internal MedicineAarhus University Hospital, Aarhus, DenmarkDepartment of EndocrinologyMedicinerhuset, Aalborg University Hospital, Mølleparkvej 4, DK-9100 Aalborg, Denmark
| | - Peter Vestergaard
- Department of Clinical MedicineAalborg University Hospital, Mølleparkvej 4, DK-9100 Aalborg, DenmarkDepartment of Endocrinology and Internal MedicineAarhus University Hospital, Aarhus, DenmarkDepartment of EndocrinologyMedicinerhuset, Aalborg University Hospital, Mølleparkvej 4, DK-9100 Aalborg, Denmark Department of Clinical MedicineAalborg University Hospital, Mølleparkvej 4, DK-9100 Aalborg, DenmarkDepartment of Endocrinology and Internal MedicineAarhus University Hospital, Aarhus, DenmarkDepartment of EndocrinologyMedicinerhuset, Aalborg University Hospital, Mølleparkvej 4, DK-9100 Aalborg, Denmark
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The Effect of Age on Osteogenic and Adipogenic Differentiation Potential of Human Adipose Derived Stromal Stem Cells (hASCs) and the Impact of Stress Factors in the Course of the Differentiation Process. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2015; 2015:309169. [PMID: 26246868 PMCID: PMC4515302 DOI: 10.1155/2015/309169] [Citation(s) in RCA: 114] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/08/2015] [Revised: 06/02/2015] [Accepted: 06/18/2015] [Indexed: 12/21/2022]
Abstract
Human adipose tissue is a great source of autologous mesenchymal stem cells (hASCs), which are recognized for their vast therapeutic applications. Their ability to self-renew and differentiate into several lineages makes them a promising tool for cell-based therapies in different types of degenerative diseases. Thus it is crucial to evaluate age-related changes in hASCs, as the elderly are a group that will benefit most from their considerable potential. In this study we investigated the effect of donor age on growth kinetics, cellular senescence marker levels, and osteogenic and adipogenic potential of hASCs. It also has been known that, during life, organisms accumulate oxidative damage that negatively affects cell metabolism. Taking this into consideration, we evaluated the levels of nitric oxide, reactive oxygen species, and superoxide dismutase activity. We observed that ROS and NO increase with aging, while SOD activity is significantly reduced. Moreover cells obtained from older patients displayed senescence associated features, for example, β-galactosidase activity, enlarged morphology, and p53 protein upregulation. All of those characteristics seem to contribute to decreased proliferation potential of those cells. Our results suggest that due to aging some cellular modification may be required before applying aged cells efficiently in therapies such as tissue engineering and regenerative medicine.
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Liu H, Xia X, Li B. Mesenchymal stem cell aging: Mechanisms and influences on skeletal and non-skeletal tissues. Exp Biol Med (Maywood) 2015; 240:1099-106. [PMID: 26088863 DOI: 10.1177/1535370215591828] [Citation(s) in RCA: 68] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
The aging population and the incidence of aging-related diseases such as osteoporosis are on the rise. Aging at the tissue and organ levels usually involves tissue stem cells. Human and animal model studies indicate that aging affects two aspects of mesenchymal stem cell (MSC): a decrease in the bone marrow MSC pool and biased differentiation into adipocyte at the cost of osteoblast, which underlie the etiology of osteoporosis. Aging of MSC cells is also detrimental to some non-skeletal tissues, in particular the hematopoietic system, where MSCs serve as a niche component. In addition, aging compromises the therapeutic potentials of MSC cells, including cells isolated from aged individuals or cells cultured for many passages. Here we discuss the recent progress on our understanding of MSC aging, with a focus on the effects of MSC aging on bone remodeling and hematopoiesis and the mechanisms of MSC aging.
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Affiliation(s)
- Huijuan Liu
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Xuechun Xia
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Baojie Li
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai 200240, China
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Policastro GM, Lin F, Smith Callahan LA, Esterle A, Graham M, Sloan Stakleff K, Becker ML. OGP Functionalized Phenylalanine-Based Poly(ester urea) for Enhancing Osteoinductive Potential of Human Mesenchymal Stem Cells. Biomacromolecules 2015; 16:1358-71. [DOI: 10.1021/acs.biomac.5b00153] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Affiliation(s)
| | | | | | - Andrew Esterle
- Calhoun
Research Laboratory, Akron General Medical Center, Akron, Ohio 44307, United States
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Fukunaga T, Zou W, Rohatgi N, Colca JR, Teitelbaum SL. An insulin-sensitizing thiazolidinedione, which minimally activates PPARγ, does not cause bone loss. J Bone Miner Res 2015; 30:481-8. [PMID: 25257948 PMCID: PMC4472363 DOI: 10.1002/jbmr.2364] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2014] [Revised: 09/10/2014] [Accepted: 09/17/2014] [Indexed: 12/11/2022]
Abstract
Rosiglitazone is an insulin-sensitizing thiazolidinedione (TZD) that activates the transcription factor peroxisome proliferator-activated receptor gamma (PPARγ). Although rosiglitazone effectively treats type II diabetes mellitus (T2DM), it carries substantial complications, including increased fracture risk. This predisposition to fracture is consistent with the fact that PPARγ preferentially promotes formation of adipocytes at the cost of osteoblasts. Rosiglitazone-activated PPARγ, however, also stimulates osteoclast formation. A new TZD analog with low affinity for binding and activation of PPARγ but whose insulin-sensitizing properties mirror those of rosiglitazone has been recently developed. Because of its therapeutic implications, we investigated the effects of this new TZD analog (MSDC-0602) on skeletal homeostasis, in vitro and in vivo. Confirming it activates the nuclear receptor in osteoclasts, rosiglitazone enhances expression of the PPARγ target gene, CD36. MSDC-0602, in contrast, minimally activates PPARγ and does not alter CD36 expression in the bone-resorptive cells. Consistent with this finding, rosiglitazone increases receptor activator of NF-κB ligand (RANKL)-induced osteoclast differentiation and number, whereas MSDC-0602 fails to do so. To determine if this new TZD analog is bone sparing, in vivo, we fed adult male C57BL/6 mice MSDC-0602 or rosiglitazone. Six months of a rosiglitazone diet results in a 35% decrease in bone mass with increased number of osteoclasts, whereas that of MSDC-0602-fed mice is indistinguishable from control. Thus, PPARγ sparing eliminates the skeletal side effects of TZDs while maintaining their insulin-sensitizing properties.
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Affiliation(s)
- Tomohiro Fukunaga
- Department of Pathology and Immunology, Washington University in St. Louis School of Medicine, St. Louis, MO, USA
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Nyandege AN, Slattum PW, Harpe SE. Risk of Fracture and the Concomitant Use of Bisphosphonates With Osteoporosis-Inducing Medications. Ann Pharmacother 2015; 49:437-47. [DOI: 10.1177/1060028015569594] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Objective: To review the literature on the concomitant use of bisphosphonates and medications that can influence bone metabolism and potentially attenuate bisphosphonate antifracture efficacy. Data Sources: MEDLINE and CINAHL were searched for articles published in English through December 2014 using the following terms: bisphosphonates, bone density conservation agents, acid-suppressive therapy, levothyroxine, thiazolidinediones (TZDs), selective serotonin reuptake inhibitors (SSRIs), bone fractures. Study Selection and Data Extraction: Studies were included if they reported results of concomitant use of any listed medications with bisphosphonates and risk of fractures and focused on women. Articles that focused generally on the use of one of the listed medications and fractures without explicitly examining the potential antifracture efficacy or attenuation of bisphosphonates were excluded. Data Synthesis: A total of 6 relevant studies were identified. Four epidemiological studies reported a statistically significant dose-dependent increase in the risk of fractures when bisphosphonates and acid-suppressive drugs were used together. One post hoc analysis of clinical trial data suggested no attenuation of the antifracture effects of bisphosphonates when used concomitantly with acid-suppressive therapy. One study involving bisphosphonates and SSRIs noted a statistically significant association between fracture risk and SSRI use. No study examining TZDs or levothyroxine with bisphosphonates was identified. Conclusions: Existing research suggests potential attenuation of bisphosphonate antifracture efficacy among patients taking acid-suppressive medications. Based on their pharmacological actions, TZDs, SSRIs, and levothyroxine have similar implications. The paucity of evidence in the literature associating the attenuation of bisphosphonate antifracture efficacy when combined with other medications suggests that further investigation is needed.
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Affiliation(s)
| | | | - Spencer E. Harpe
- Midwestern University Chicago College of Pharmacy, Downers Grove, IL, USA
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Liu HY, Huang CF, Lin TC, Tsai CY, Tina Chen SY, Liu A, Chen WH, Wei HJ, Wang MF, Williams DF, Deng WP. Delayed animal aging through the recovery of stem cell senescence by platelet rich plasma. Biomaterials 2014; 35:9767-9776. [DOI: 10.1016/j.biomaterials.2014.08.034] [Citation(s) in RCA: 103] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2014] [Accepted: 08/21/2014] [Indexed: 11/28/2022]
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van de Vyver M, Andrag E, Cockburn IL, Ferris WF. Thiazolidinedione-induced lipid droplet formation during osteogenic differentiation. J Endocrinol 2014; 223:119-32. [PMID: 25210048 DOI: 10.1530/joe-14-0425] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Chronic administration of the insulin-sensitising drugs, thiazolidinediones (TZDs), results in low bone mineral density and 'fatty bones'. This is thought to be due, at least in part, to aberrant differentiation of progenitor mesenchymal stem cells (MSCs) away from osteogenesis towards adipogenesis. This study directly compared the effects of rosiglitazone, pioglitazone, and netoglitazone treatment on osteogenesis and adipogenesis in MSCs derived from subcutaneous (SC) or visceral (PV) white adipose tissue. MSCs were isolated from adipose tissue depots of male Wistar rats and characterised using flow cytometry. The effects of TZD treatment on osteogenic and adipogenic differentiation were assessed histologically (day 14) and by quantitative PCR analysis (Pparγ2 (Pparg2), Ap2 (Fabp4), Adipsin (Adps), Msx2, Collagen I (Col1a1), and Alp) on days 0, 7, and 10. Uniquely, lipid droplet formation and mineralisation were found to occur concurrently in response to TZD treatment during osteogenesis. Compared with SC MSCs, PV MSCs were more prone to lipid accumulation under controlled osteogenic and adipogenic differentiation conditions. This study demonstrated that the extent of lipid accumulation is dependent on the nature of the Ppar ligand and that SC and PV MSCs respond differently to in vitro TZD treatment, suggesting that metabolic status can contribute to the adverse effects associated with TZD treatment.
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Affiliation(s)
- M van de Vyver
- Division of EndocrinologyDepartment of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, PO Box 19063, Tygerberg 7505, South Africa
| | - E Andrag
- Division of EndocrinologyDepartment of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, PO Box 19063, Tygerberg 7505, South Africa
| | - I L Cockburn
- Division of EndocrinologyDepartment of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, PO Box 19063, Tygerberg 7505, South Africa
| | - W F Ferris
- Division of EndocrinologyDepartment of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, PO Box 19063, Tygerberg 7505, South Africa
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Activation of PPAR-γ inhibits differentiation of rat osteoblasts by reducing expression of connective tissue growth factor. ACTA ACUST UNITED AC 2014; 34:652-656. [PMID: 25318873 DOI: 10.1007/s11596-014-1332-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2014] [Revised: 06/28/2014] [Indexed: 12/28/2022]
Abstract
Long-term treatment with an agonist of peroxisome proliferator-activated receptor (PPAR)-γ is associated with bone fractures in the clinical practice. However, the mechanisms underlying the fractures are not fully understood. This study was aimed to examine the effect of rosiglitazone (an agonist of PPAR-γ) of different doses on the proliferation, differentiation, and transforming growth factor beta 1 (TGF-β1)-induced expression of connective tissue growth factor (CTGF) in primary rat osteoblasts in vitro. Osteoblasts were isolated from newly born SD rats and treated with different doses of rosiglitazone (0-20 μmol/L). The proliferation and differentiation of osteoblasts were measured by MTT assay and NPP assay, respectively. The expression of CTGF was determined by RT-PCR and Western blotting. The results showed that most isolated osteoblasts displayed strong alkaline phosphatase (ALP) activity and treatment with different doses of rosiglitazone did not affect their proliferation, but significantly inhibited the differentiation of osteoblasts in a dose-dependent manner. Moreover, treatment with different doses of rosiglitazone significantly reduced the TGF-β1-induced CTGF mRNA transcription and protein expression in a dose-dependent manner in rat osteoblasts. It was concluded that the activation of PPAR-γ may inhibit the differentiation of osteoblasts by reducing the TGF-β1-induced CTGF expression in vitro.
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Nallamshetty S, Le PT, Wang H, Issacsohn MJ, Reeder DJ, Rhee EJ, Kiefer FW, Brown JD, Rosen CJ, Plutzky J. Retinaldehyde dehydrogenase 1 deficiency inhibits PPARγ-mediated bone loss and marrow adiposity. Bone 2014; 67:281-91. [PMID: 25064526 PMCID: PMC4209126 DOI: 10.1016/j.bone.2014.07.005] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2014] [Revised: 06/16/2014] [Accepted: 07/02/2014] [Indexed: 10/25/2022]
Abstract
PPARγ, a ligand-activated nuclear receptor, regulates fundamental aspects of bone homeostasis and skeletal remodeling. PPARγ-activating anti-diabetic thiazolidinediones in clinical use promote marrow adiposity, bone loss, and skeletal fractures. As such, delineating novel regulatory pathways that modulate the action of PPARγ, and its obligate heterodimeric partner RXR, may have important implications for our understanding and treatment of disorders of low bone mineral density. We present data here establishing retinaldehyde dehydrogenase 1 (Aldh1a1) and its substrate retinaldehyde (Rald) as novel determinants of PPARγ-RXR actions in the skeleton. When compared to wild type (WT) controls, retinaldehyde dehydrogenase-deficient (Aldh1a1(-/-)) mice were protected against bone loss and marrow adiposity induced by either the thiazolidinedione rosiglitazone or a high fat diet, both of which potently activate the PPARγ-RXR complex. Consistent with these results, Rald, which accumulates in vivo in Aldh1a1(-/-) mice, protects against rosiglitazone-mediated inhibition of osteoblastogenesis in vitro. In addition, Rald potently inhibits in vitro adipogenesis and osteoclastogenesis in WT mesenchymal stem cells (MSCs) and hematopoietic stem cells (HSCs) respectively. Primary Aldh1a1(-/-) HSCs also demonstrate impaired osteoclastogenesis in vitro compared to WT controls. Collectively, these findings identify Rald and retinoid metabolism through Aldh1a1 as important novel modulators of PPARγ-RXR transactivation in the marrow niche.
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Affiliation(s)
- Shriram Nallamshetty
- Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
| | - Phuong T. Le
- Center for Clinical & Translational Research, Maine Medical Center Research Institute, Scarborough, Maine
| | - Hong Wang
- Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
| | - Maya J. Issacsohn
- Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
| | - David J. Reeder
- Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
| | - Eun-Jung Rhee
- Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
| | - Florian W. Kiefer
- Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
| | - Jonathan D. Brown
- Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
| | - Clifford J. Rosen
- Center for Clinical & Translational Research, Maine Medical Center Research Institute, Scarborough, Maine
- Corresponding authors. Address all correspondence and requests for reprints to: Jorge Plutzky, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, 77 Ave. Louis Pasteur, NRB 742, Boston, Massachusetts 02115. Telephone: 617-525-4360 Fax: 617-525-4366
| | - Jorge Plutzky
- Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
- Corresponding authors. Address all correspondence and requests for reprints to: Jorge Plutzky, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, 77 Ave. Louis Pasteur, NRB 742, Boston, Massachusetts 02115. Telephone: 617-525-4360 Fax: 617-525-4366
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Piccinin MA, Khan ZA. Pathophysiological role of enhanced bone marrow adipogenesis in diabetic complications. Adipocyte 2014; 3:263-72. [PMID: 26317050 DOI: 10.4161/adip.32215] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2014] [Revised: 07/16/2014] [Accepted: 07/30/2014] [Indexed: 12/12/2022] Open
Abstract
Diabetes leads to complications in select organ systems primarily by disrupting the vasculature of the target organs. These complications include both micro- (cardiomyopathy, retinopathy, nephropathy, and neuropathy) and macro-(atherosclerosis) angiopathies. Bone marrow angiopathy is also evident in both experimental models of the disease as well as in human diabetes. In addition to vascular disruption, bone loss and increased marrow adiposity have become hallmarks of the diabetic bone phenotype. Emerging evidence now implicates enhanced marrow adipogenesis and changes to cellular makeup of the marrow in a novel mechanistic link between various secondary complications of diabetes. In this review, we explore the mechanisms of enhanced marrow adipogenesis in diabetes and the link between changes to marrow cellular composition, and disruption and depletion of reparative stem cells.
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Khanmohammadi M, Khanjani S, Edalatkhah H, Zarnani AH, Heidari-Vala H, Soleimani M, Alimoghaddam K, Kazemnejad S. Modified protocol for improvement of differentiation potential of menstrual blood-derived stem cells into adipogenic lineage. Cell Prolif 2014; 47:615-23. [PMID: 25252214 DOI: 10.1111/cpr.12133] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2014] [Accepted: 06/27/2014] [Indexed: 12/24/2022] Open
Abstract
OBJECTIVES To characterize potency of menstrual blood-derived stem cells (MenSCs) for future cell therapies, we examined differentiation potential of MenSCs into adipocytes. MATERIALS AND METHODS Differentiation potential of MenSCs in comparison to bone marrow stem cells (BMSCs) was assessed in conventional culture medium. Differentiation potential of MenSCs into adipocytes was improved using different combinations of growth factors and hormones. RESULTS First, we demonstrated that MenSCs preserve their appearance and karyotypic stability during passages. Although these cells express mesenchymal stem cells markers, they cannot simply be classified as mesenchymal stem cells due to expression of embryonic stem cells marker, OCT-4. Oil red O staining showed that differentiated MenSCs in conventional medium with/without retinoic acid (protocols 1 and 2) did not attain adipocyte characteristics, whereas differentiated BMSCs in conventional medium accumulated oil vacuoles typically. Nevertheless, real-time RT-PCR results showed that LPL gene expression was up-regulated in both protocols 1 and 2, whereas LEPR was up-regulated only in protocol 2 (fortified with retinoic acid). Surprisingly, protocol 3 (including rosiglitazone) had odd influence on mRNA expression of all genes (LEPR, LPL and PPAR-γ). Oil red O staining confirmed fat-producing ability of MenSCs under protocol 3. CONCLUSIONS Presented data suggest an efficient differentiation protocol for in vitro production of MenSC-derived adipocytes. These cells are suggested to be an apt alternative to BMSCs for future stem cell therapy of soft tissue injuries.
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Affiliation(s)
- M Khanmohammadi
- Reproductive Biotechnology Research Center, Avicenna Research Institute, ACECR, Tehran, 19615-1177, Iran
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41
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van de Peppel J, van Leeuwen JPTM. Vitamin D and gene networks in human osteoblasts. Front Physiol 2014; 5:137. [PMID: 24782782 PMCID: PMC3988399 DOI: 10.3389/fphys.2014.00137] [Citation(s) in RCA: 79] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2014] [Accepted: 03/20/2014] [Indexed: 12/27/2022] Open
Abstract
Bone formation is indirectly influenced by 1,25-dihydroxyvitamin D3 (1,25D3) through the stimulation of calcium uptake in the intestine and re-absorption in the kidneys. Direct effects on osteoblasts and bone formation have also been established. The vitamin D receptor (VDR) is expressed in osteoblasts and 1,25D3 modifies gene expression of various osteoblast differentiation and mineralization-related genes, such as alkaline phosphatase (ALPL), osteocalcin (BGLAP), and osteopontin (SPP1). 1,25D3 is known to stimulate mineralization of human osteoblasts in vitro, and recently it was shown that 1,25D3 induces mineralization via effects in the period preceding mineralization during the pre-mineralization period. For a full understanding of the action of 1,25D3 in osteoblasts it is important to get an integrated network view of the 1,25D3-regulated genes during osteoblast differentiation and mineralization. The current data will be presented and discussed alluding to future studies to fully delineate the 1,25D3 action in osteoblast. Describing and understanding the vitamin D regulatory networks and identifying the dominant players in these networks may help develop novel (personalized) vitamin D-based treatments. The following topics will be discussed in this overview: (1) Bone metabolism and osteoblasts, (2) Vitamin D, bone metabolism and osteoblast function, (3) Vitamin D induced transcriptional networks in the context of osteoblast differentiation and bone formation.
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Affiliation(s)
- Jeroen van de Peppel
- Department of Internal Medicine, Bone and Calcium Metabolism Erasmus MC, Rotterdam, Netherlands
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42
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van Driel M, van Leeuwen JPTM. Vitamin D endocrine system and osteoblasts. BONEKEY REPORTS 2014; 3:493. [PMID: 24605210 DOI: 10.1038/bonekey.2013.227] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/13/2013] [Accepted: 12/04/2013] [Indexed: 01/12/2023]
Abstract
The interaction between vitamin D and osteoblasts is complex. In the current review we will give an overview of the current knowledge of the vitamin D endocrine system in osteoblasts. The presence of the vitamin D receptor in osteoblasts enables direct effects of 1α,25dihydroxyvitamin D3 (1α,25D3) on osteoblasts, but the magnitude of the effects is subject to the presence of many other factors. Vitamin D affects osteoblast proliferation, as well as differentiation and mineralization, but these effects vary with the timing of treatment, dosage and origin of the osteoblasts. Vitamin D effects on differentiation and mineralization are mostly stimulatory in human and rat osteoblasts, and inhibitory in murine osteoblasts. Several genes and mechanisms are studied to explain the effects of 1α,25D3 on osteoblast differentiation and bone formation. Besides the classical VDR, osteoblasts also express a membrane-localized receptor, and in vitro studies have shown that osteoblasts are capable of the synthesis of 1α,25D3.
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Chen H, Liu X, Chen H, Cao J, Zhang L, Hu X, Wang J. Role of SIRT1 and AMPK in mesenchymal stem cells differentiation. Ageing Res Rev 2014; 13:55-64. [PMID: 24333965 DOI: 10.1016/j.arr.2013.12.002] [Citation(s) in RCA: 78] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2013] [Revised: 11/18/2013] [Accepted: 12/02/2013] [Indexed: 12/21/2022]
Abstract
The differentiation capabilities of mesenchymal stem cells (MSCs) compromise with age and with in vitro passages which could impair the efficacy of cell therapy and tissue engineering. However, how to maintain these capabilities is not fully understood. Calorie restriction (CR, decreasing caloric intake by 30-40%) could extend longevity and reduce aging-related diseases. Recent studies revealed that CR could influence the lineage determination of stem cells including MSCs. Two important mediators of CR might be silent mating type information regulation 2 homolog 1 (SIRT1), a NAD(+)-dependent deacetylase, and AMP-activated protein kinase (AMPK), an energy-sensing kinase. Evidences are mounting that both SIRT1 and AMPK play important roles in cell fate determination of MSCs. Herein, we intend to sum up our understanding about the role of SIRT1 and AMPK in osteogenic and adipogenic potential of MSCs. Metabolic process of MSCs differentiation and the putative interplay of SIRT1 and AMPK in this process was also discussed.
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44
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Hernandez-Vallejo SJ, Beaupere C, Larghero J, Capeau J, Lagathu C. HIV protease inhibitors induce senescence and alter osteoblastic potential of human bone marrow mesenchymal stem cells: beneficial effect of pravastatin. Aging Cell 2013; 12:955-65. [PMID: 23795945 DOI: 10.1111/acel.12119] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/09/2013] [Indexed: 12/22/2022] Open
Abstract
HIV-infected patients receiving antiretroviral therapy present an increased prevalence of age-related comorbidities, including osteoporosis. HIV protease inhibitors (PIs) have been suspected to participate to bone loss, but the mechanisms involved are unknown. In endothelial cells, some PIs have been shown to induce the accumulation of farnesylated prelamin-A, a biomarker of cell aging leading to cell senescence. Herein, we hypothesized that these PIs could induce premature aging of osteoblast precursors, human bone marrow mesenchymal stem cells (MSCs), and affect their capacity to differentiate into osteoblasts. Senescence was studied in proliferating human MSCs after a 30-day exposure to atazanavir and lopinavir with or without ritonavir. When compared to untreated cells, PI-treated MSCs had a reduced proliferative capacity that worsened with increasing passages. PI treatment led to increased oxidative stress and expression of senescence markers, including prelamin-A. Pravastatin, which blocks prelamin-A farnesylation, prevented PI-induced senescence and oxidative stress, while treatment with antioxidants partly reversed these effects. Moreover, senescent MSCs presented a decreased osteoblastic potential, which was restored by pravastatin treatment. Because age-related bone loss is associated with increased bone marrow fat, we also evaluated the capacity of PI-treated MSCs to differentiate into adipocyte. We observed an altered adipocyte differentiation in PI-treated MSCs that was reverted by pravastatin. We have shown that some PIs alter osteoblast formation by affecting their differentiation potential in association with altered senescence in MSCs, with a beneficial effect of statin. These data corroborate the clinical observations and allow new insight into pathophysiological mechanisms of PI-induced bone loss in HIV-infected patients.
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Affiliation(s)
- Sandra J. Hernandez-Vallejo
- INSERM UMRS938; Paris France
- UPMC Univ Paris 06; UMRS 938; Paris France
- Institute of Cardiometabolism and Nutrition; Paris France
| | - Carine Beaupere
- INSERM UMRS938; Paris France
- UPMC Univ Paris 06; UMRS 938; Paris France
- Institute of Cardiometabolism and Nutrition; Paris France
| | - Jerome Larghero
- Cell Therapy Unit; Hôpital Saint Louis; Paris France
- Univ Paris Diderot; Sorbonne Paris Cite; Paris France
- INSERM UMRS940; Hôpital Saint-Louis; Paris France
| | - Jacqueline Capeau
- INSERM UMRS938; Paris France
- UPMC Univ Paris 06; UMRS 938; Paris France
- Institute of Cardiometabolism and Nutrition; Paris France
- APHP; Hôpital Tenon; Paris France
| | - Claire Lagathu
- INSERM UMRS938; Paris France
- UPMC Univ Paris 06; UMRS 938; Paris France
- Institute of Cardiometabolism and Nutrition; Paris France
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Fakhry M, Hamade E, Badran B, Buchet R, Magne D. Molecular mechanisms of mesenchymal stem cell differentiation towards osteoblasts. World J Stem Cells 2013; 5:136-148. [PMID: 24179602 PMCID: PMC3812518 DOI: 10.4252/wjsc.v5.i4.136] [Citation(s) in RCA: 183] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2013] [Revised: 08/01/2013] [Accepted: 09/17/2013] [Indexed: 02/06/2023] Open
Abstract
Bone is a dynamic tissue that is constantly renewed by the coordinated action of two cell types, i.e., the bone-resorbing osteoclasts and the bone-forming osteoblasts. However, in some circumstances, bone regeneration exceeds bone self repair capacities. This is notably often the case after bone fractures, osteolytic bone tumor surgery, or osteonecrosis. In this regard, bone tissue engineering with autologous or allogenic mesenchymal stem cells (MSCs) is been widely developed. MSCs can be isolated from bone marrow or other tissues such as adipose tissue or umbilical cord, and can be implanted in bone defects with or without prior amplification and stimulation. However, the outcome of most pre-clinical studies remains relatively disappointing. A better understanding of the successive steps and molecular mechanisms involved in MSC-osteoblastic differentiation appears to be crucial to optimize MSC-bone therapy. In this review, we first present the important growth factors that stimulate osteoblastogenesis. Then we review the main transcription factors that modulate osteoblast differentiation, and the microRNAs (miRs) that inhibit their expression. Finally, we also discuss articles dealing with the use of these factors and miRs in the development of new bone MSC therapy strategies. We particularly focus on the studies using human MSCs, since significant differences exist between osteoblast differentiation mechanisms in humans and mice for instance.
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Liu L, Yang Z, Xu Y, Li J, Xu D, Zhang L, Sun J, Xia S, Zou F, Liu Y. Inhibition of oxidative stress-elicited AKT activation facilitates PPARγ agonist-mediated inhibition of stem cell character and tumor growth of liver cancer cells. PLoS One 2013; 8:e73038. [PMID: 24023668 PMCID: PMC3758331 DOI: 10.1371/journal.pone.0073038] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2013] [Accepted: 07/16/2013] [Indexed: 12/11/2022] Open
Abstract
Emerging evidence suggests that tumor-initiating cells (TICs) are the most malignant cell subpopulation in tumors because of their resistance to chemotherapy or radiation treatment. Targeting TICs may be a key innovation for cancer treatment. In this study, we found that PPARγ agonists inhibited the cancer stem cell-like phenotype and attenuated tumor growth of human hepatocellular carcinoma (HCC) cells. Reactive oxygen species (ROS) initiated by NOX2 upregulation were partially responsible for the inhibitory effects mediated by PPARγ agonists. However, PPARγ agonist-mediated ROS production significantly activated AKT, which in turn promoted TIC survival by limiting ROS generation. Inhibition of AKT, by either pharmacological inhibitors or AKT siRNA, significantly enhanced PPARγ agonist-mediated inhibition of cell proliferation and stem cell-like properties in HCC cells. Importantly, in nude mice inoculated with HCC Huh7 cells, we demonstrated a synergistic inhibitory effect of the PPARγ agonist rosiglitazone and the AKT inhibitor triciribine on tumor growth. In conclusion, we observed a negative feedback loop between oxidative stress and AKT hyperactivation in PPARγ agonist-mediated suppressive effects on HCCs. Combinatory application of an AKT inhibitor and a PPARγ agonist may provide a new strategy for inhibition of stem cell-like properties in HCCs and treatment of liver cancer.
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Affiliation(s)
- Lanlan Liu
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Department of Developmental and Regenerative Biology, College of Life Science and Technology, Jinan University, Guangzhou, China
| | - Zhaojuan Yang
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yingqian Xu
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jingyi Li
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Dongxu Xu
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Li Zhang
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jiabin Sun
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Suhua Xia
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Feiyan Zou
- Department of Developmental and Regenerative Biology, College of Life Science and Technology, Jinan University, Guangzhou, China
| | - Yongzhong Liu
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- * E-mail:
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Nicolaije C, van de Peppel J, van Leeuwen JP. Oxygen-induced transcriptional dynamics in human osteoblasts are most prominent at the onset of mineralization. J Cell Physiol 2013; 228:1863-72. [DOI: 10.1002/jcp.24348] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2012] [Accepted: 02/06/2013] [Indexed: 02/03/2023]
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Bilezikian JP, Josse RG, Eastell R, Lewiecki EM, Miller CG, Wooddell M, Northcutt AR, Kravitz BG, Paul G, Cobitz AR, Nino AJ, Fitzpatrick LA. Rosiglitazone decreases bone mineral density and increases bone turnover in postmenopausal women with type 2 diabetes mellitus. J Clin Endocrinol Metab 2013; 98:1519-28. [PMID: 23450056 DOI: 10.1210/jc.2012-4018] [Citation(s) in RCA: 76] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
CONTEXT Postmenopausal status and type 2 diabetes mellitus (T2DM) are independent risk factors for fractures. An increased fracture risk has been observed with rosiglitazone (RSG), a thiazolidinedione, in patients with T2DM. DESIGN AND SETTING This was a randomized, double-blind study in postmenopausal women with T2DM. A 52-week double-blind phase (RSG or metformin [MET]) was followed by a 24-week open-label phase, during which time all patients received MET. MAIN OUTCOME MEASURES The primary endpoint was to assess the mean percentage change in bone mineral density (BMD) at the femoral neck (FN) by dual-energy x-ray absorptiometry from baseline to week 52 in the RSG treatment group. Key secondary objectives included assessment of changes in BMD at the total hip, trochanter, and lumbar spine and to evaluate RSG effects on bone turnover markers. RESULTS From baseline to week 52, RSG was associated with a reduction in FN BMD by dual-energy x-ray absorptiometry (-1.47%). During the open-label phase (weeks 52-76), no further loss in FN BMD was observed. A decrease in BMD occurred at the total hip during RSG or MET treatment at 52 weeks (-1.62 and -0.72%, respectively). Total hip BMD loss by RSG was attenuated after switching to MET and was similar between treatment groups at the end of the open-label phase. From baseline to week 52, bone turnover markers significantly increased with RSG compared with MET, but decreased significantly during the open-label phase. CONCLUSIONS RSG for 52 weeks in postmenopausal women with T2DM was associated with small reductions in FN, total hip, and lumbar spine BMD and increased bone turnover markers. These effects are attenuated after cessation of RSG treatment.
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Affiliation(s)
- John P Bilezikian
- Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
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The effects of thiazolidinediones on human bone marrow stromal cell differentiation in vitro and in thiazolidinedione-treated patients with type 2 diabetes. Transl Res 2013; 161:145-55. [PMID: 23022285 PMCID: PMC3546231 DOI: 10.1016/j.trsl.2012.08.006] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2012] [Revised: 08/24/2012] [Accepted: 08/28/2012] [Indexed: 02/07/2023]
Abstract
Thiazolidinedione (TZD) therapy has been associated with an increased risk of bone fractures. Studies in rodents have led to a model in which decreased bone quality in response to TZDs is due to a competition of lineage commitment between osteoblasts (OBs) and adipocytes (ADs) for a common precursor cell, resulting in decreased OB numbers. Our goal was to investigate the effects of TZD exposure on OB-AD lineage determination from primary human bone marrow stromal cells (hBMSCs) both in vitro and in vivo from nondiabetic subjects and patients with type 2 diabetics. Our experimental design included 2 phases. Phase 1 was an in vitro study of TZD effects on the differentiation of hBMSCs into OBs and ADs in nondiabetic subjects. Phase 2 was a randomized, placebo-controlled trial to determine the effects of 6-month pioglitazone treatment in vivo on hBMSC differentiation using AD/OB colony forming unit assays in patients with type 2 diabetes. In vitro, TZDs (pioglitazone and rosiglitazone) enhanced the adipogenesis of hBMSCs, whereas neither altered OB differentiation or function as measured by alkaline phosphatase activity, gene expression, and mineralization. The ability of TZDs to enhance adipogenesis occurred at a specific time/stage of the differentiation process, and pretreating with TZDs did not further enhance adipogenesis. In vivo, 6-month TZD treatment decreased OB precursors, increased AD precursors, and increased total colony number in patients with type 2 diabetes. Our results indicate that TZD exposure in vitro potently stimulates adipogenesis but does not directly alter OB differentiation/mineralization or lineage commitment from hBMSCs. However, TZD treatment in type 2 diabetic patients results in decreased osteoblastogenesis from hBMSCs compared with placebo, indicating an indirect negative effect on OBs and suggesting an alternative model by which TZDs might negatively regulate bone quality.
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Albiero M, Avogaro A, Fadini GP. Restoring stem cell mobilization to promote vascular repair in diabetes. Vascul Pharmacol 2013; 58:253-8. [PMID: 23369723 DOI: 10.1016/j.vph.2013.01.003] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2012] [Revised: 01/12/2013] [Accepted: 01/15/2013] [Indexed: 12/30/2022]
Abstract
Diabetes triggers endothelial dysfunction, which is linked to increased risk of cardiovascular diseases. Stem and progenitor cells from the bone marrow are involved in the maintenance of vascular integrity. Diabetic patients show a dysfunction of these cells, which might represent a novel pathophysiological mechanism of vascular disease. Specifically, stem and progenitor cells fail to egress from the bone marrow (BM) due to BM pathological alterations and unresponsiveness to mobilizing stimuli. In this review, we describe impaired stem cell mobilization in diabetes as a mechanism of failed vascular repair and we provide evidence that pharmacological strategies can restore mobilization. We discuss recent advances in the knowledge of aberrant organization of the diabetic BM and its implications for impaired mobilization. Finally, we describe in detail the pharmacological exploitation of the G-CSF/DPP-4(CD26)/SDF-1α axis as a novel strategy to improve mobilization and attain vascular repair in diabetes.
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Affiliation(s)
- Mattia Albiero
- Venetian Institute of Molecular Medicine, Laboratory of Experimental Diabetology, 35100 Padova, Italy
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