title: Zoledronate Attenuates Accumulation of DNA Damage in Mesenchymal Stem Cells and Protects Their Function.
abstract: Mesenchymal stem cells (MSCs) undergo a decline in function following ex vivo expansion and exposure to irradiation. This has been associated with accumulation of DNA damage and has important implications for tissue engineering approaches or in patients receiving radiotherapy. Therefore, interventions, which limit accumulation of DNA damage in MSC, are of clinical significance. We were intrigued by findings showing that zoledronate (ZOL), an anti-resorptive nitrogen containing bisphosphonate, significantly extended survival in patients affected by osteoporosis. The effect was too large to be simply due to the prevention of fractures. Moreover, in combination with statins, it extended the lifespan in a mouse model of Hutchinson Gilford Progeria Syndrome. Therefore, we asked whether ZOL was able to extend the lifespan of human MSC and whether this was due to reduced accumulation of DNA damage, one of the important mechanisms of aging. Here, we show that this was the case both following expansion and irradiation, preserving their ability to proliferate and differentiate in vitro. In addition, administration of ZOL before irradiation protected the survival of mesenchymal progenitors in mice. Through mechanistic studies, we were able to show that inhibition of mTOR signaling, a pathway involved in longevity and cancer, was responsible for these effects. Our data open up new opportunities to protect MSC from the side effects of radiotherapy in cancer patients and during ex vivo expansion for regenerative medicine approaches. Given that ZOL is already in clinical use with a good safety profile, these opportunities can be readily translated for patient benefit.
authors.affiliation: Mellanby Centre for Bone Research and MRC-Arthritis Research Centre for Integrated Research into Musculoskeletal Ageing (CIMA), Department of Human Metabolism, Medical School, University of Sheffield, Sheffield, United Kingdom.
authors.forename: Juhi
authors.initials: J
authors.lastname: Misra
authors.affiliation: Mellanby Centre for Bone Research and MRC-Arthritis Research Centre for Integrated Research into Musculoskeletal Ageing (CIMA), Department of Human Metabolism, Medical School, University of Sheffield, Sheffield, United Kingdom.
authors.forename: Sindhu T
authors.initials: ST
authors.lastname: Mohanty
authors.affiliation: Department of Paediatric Orthopaedic and Trauma Surgery, Sheffield Children's Hospital, Sheffield, United Kingdom.
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Madan
authors.affiliation: Department of Paediatric Orthopaedic and Trauma Surgery, Sheffield Children's Hospital, Sheffield, United Kingdom.
authors.forename: James A
authors.initials: JA
authors.lastname: Fernandes
authors.affiliation: Department of Chemistry, University of Rochester, Rochester, New York, USA.|Structural Genomics Consortium, University of Oxford, United Kingdom.
authors.forename: F
authors.initials: F
authors.lastname: Hal Ebetino
authors.affiliation: Mellanby Centre for Bone Research and MRC-Arthritis Research Centre for Integrated Research into Musculoskeletal Ageing (CIMA), Department of Human Metabolism, Medical School, University of Sheffield, Sheffield, United Kingdom.|Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Oxford NIHR Biomedical Research Unit, The Oxford University Institute of Musculoskeletal Sciences, The Botnar Research Centre, Headington, Oxford, United Kingdom.
authors.forename: R Graham G
authors.initials: RG
authors.lastname: Russell
authors.affiliation: Mellanby Centre for Bone Research and MRC-Arthritis Research Centre for Integrated Research into Musculoskeletal Ageing (CIMA), Department of Human Metabolism, Medical School, University of Sheffield, Sheffield, United Kingdom.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Bellantuono
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage / Q000528:radiation effects; D004164:Diphosphonates / Q000008:administration & dosage*; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage*; D059630:Mesenchymal Stem Cells / Q000187:drug effects* / Q000528:radiation effects; D051379:Mice; D011827:Radiation; D044968:Regenerative Medicine; D015398:Signal Transduction / Q000187:drug effects; D000077211:Zoledronic Acid
chemical_list: D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid
keywords: Aging; Bisphosphonates; DNA damage; Radiation; Stem cells; mTOR