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      Age-related Changes in Bone Marrow Mesenchymal Stromal Cells : A Potential Impact on Osteoporosis and Osteoarthritis Development

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          Abstract

          Aging at the cellular level is a complex process resulting from accumulation of various damages leading to functional impairment and a reduced quality of life at the level of the organism. With a rise in the elderly population, the worldwide incidence of osteoporosis (OP) and osteoarthritis (OA) has increased in the past few decades. A decline in the number and “fitness” of mesenchymal stromal cells (MSCs) in the bone marrow (BM) niche has been suggested as one of the factors contributing to bone abnormalities in OP and OA. It is well recognized that MSCs in vitro acquire culture-induced aging features such as gradual telomere shortening, increased numbers of senescent cells, and reduced resistance to oxidative stress as a result of serial population doublings. In contrast, there is only limited evidence that human BM-MSCs “age” similarly in vivo. This review compares the various aspects of in vitro and in vivo MSC aging and suggests how our current knowledge on rejuvenating cultured MSCs could be applied to develop future strategies to target altered bone formation processes in OP and OA.

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          Most cited references 70

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          Mammalian sirtuins--emerging roles in physiology, aging, and calorie restriction.

          Sir2 is an NAD-dependent deacetylase that connects metabolism with longevity in yeast, worms and flies. Mammals contain seven homologs of yeast Sir2, SIRT1-7. Here, we review recent findings demonstrating the role of these mammalian sirtuins as regulators of physiology, calorie restriction, and aging. The current findings sharpen our understanding of sirtuins as potential pharmacological targets to treat the major diseases of aging.
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            The epidemiology of osteoarthritis.

            Osteoarthritis (OA) is a leading cause of disability and its incidence is rising due to increasing obesity and an ageing population. Risk factors can be divided into person-level factors, such as age, sex, obesity, genetics, race/ethnicity and diet, and joint-level factors including injury, malalignment and abnormal loading of the joints. The interaction of these risk factors is complex and provides a challenge to the managing physician. The purpose of this review is to illustrate how each of these factors interact together to instigate incident OA as well as to outline the need for ongoing epidemiologic studies for the future prevention of both incident and progressive OA. It is only by understanding the impact of this disease and the modifiable risk factors that we will be able to truly target public health prevention interventions appropriately.
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              Age-related intrinsic changes in human bone-marrow-derived mesenchymal stem cells and their differentiation to osteoblasts.

              In vivo and in vitro studies indicate that a subpopulation of human marrow-derived stromal cells (MSCs, also known as mesenchymal stem cells) has potential to differentiate into multiple cell types, including osteoblasts. In this study, we tested the hypothesis that there are intrinsic effects of age in human MSCs (17-90 years). We tested the effect of age on senescence-associated beta-galactosidase, proliferation, apoptosis, p53 pathway genes, and osteoblast differentiation in confluent monolayers by alkaline phosphatase activity and osteoblast gene expression analysis. There were fourfold more human bone MSCs (hMSCs) positive for senescence-associated beta-galactosidase in samples from older than younger subjects (P < 0.001; n = 17). Doubling time of hMSCs was 1.7-fold longer in cells from the older than the younger subjects, and was positively correlated with age (P = 0.002; n = 19). Novel age-related changes were identified. With age, more cells were apoptotic (P = 0.016; n = 10). Further, there were age-related increases in expression of p53 and its pathway genes, p21 and BAX. Consistent with other experiments, there was a significant age-related decrease in generation of osteoblasts both in the STRO-1+ cells (P = 0.047; n = 8) and in adherent MSCs (P < 0.001; n = 10). In sum, there is an age-dependent decrease in proliferation and osteoblast differentiation, and an increase in senescence-associated beta-galactosidase-positive cells and apoptosis in hMSCs. Up-regulation of the p53 pathway with age may have a critical role in mediating the reduction in both proliferation and osteoblastogenesis of hMSCs. These findings support the view that there are intrinsic alterations in human MSCs with aging that may contribute to the process of skeletal aging in humans.
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                Author and article information

                Journal
                Cell Transplant
                Cell Transplant
                CLL
                spcll
                Cell Transplantation
                SAGE Publications (Sage CA: Los Angeles, CA )
                0963-6897
                1555-3892
                08 November 2017
                September 2017
                : 26
                : 9 , Special Issue: Aging
                : 1520-1529
                Affiliations
                [1 ]Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, United Kingdom
                [2 ]Leeds Musculoskeletal Biomedical Research Unit, University of Leeds, Leeds, United Kingdom
                Author notes
                Elena A. Jones, Leeds Institute of Rheumatic and Musculoskeletal Medicine, St. James’s University Hospital, Room 5.24 Clinical Sciences Building, Leeds LS9 7TF, United Kingdom. Email: msjej@ 123456leeds.ac.uk
                Article
                10.1177_0963689717721201
                10.1177/0963689717721201
                5680949
                29113463
                © The Author(s) 2017

                This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License ( http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages ( https://us.sagepub.com/en-us/nam/open-access-at-sage).

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