title: Allogeneic Mesenchymal Stem Cell Therapy Promotes Osteoblastogenesis and Prevents Glucocorticoid-Induced Osteoporosis.
abstract: : Gene-modified mesenchymal stem cell (MSC)-like cells with enhanced bone marrow homing and osteogenesis have been used in treating glucocorticoid-induced murine osteoporosis (GIOP). Recent preclinical studies have further demonstrated the immunomodulatory and anticatabolic potential of allogeneic MSCs in treating osteoporosis under inflammatory and autoimmune conditions. In this study, we investigated whether systemic infusion of allogeneic MSCs without genetic manipulation could prevent GIOP, whether anabolic and anticatabolic effects existed, and whether homing or immunomodulation underlay the putative therapeutic effects. Allogeneic bone marrow-derived MSCs (BMMSCs) were isolated, identified, and systemically infused into mice treated with excessive dexamethasone. We revealed that allogeneic MSC transplantation prevented the reduction of bone mass and strength in GIOP. Bone histomorphometric analyses of bone remodeling demonstrated the maintenance of bone formation and osteoblast survival after MSC therapy. Using green fluorescent protein (GFP)-labeled BMMSCs, we showed that donor BMMSCs(GFP) homed and inhabited recipient bone marrow for at least 4 weeks and prevented recipient bone marrow cell apoptosis, as shown by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling. Furthermore, donor BMMSCs(GFP) committed to Osterix (Osx)(+) osteoblast progenitors and induced recipient osteoblastogenesis, as exhibited by GFP-Osx double-labeling immunofluorescence analysis. No anticatabolic effects or systemic immunomodulatory effects of infused BMMSCs were detected. These findings demonstrated that allogeneic MSC therapy prevented GIOP by inhabiting and functioning in recipient bone marrow, which promoted osteoblastogenesis, which in turn maintained bone formation. Our findings provide important information regarding cell-based anabolic therapy for GIOP and uncover MSC behaviors following the homing event.
  
  
  
  This study revealed the therapeutic potential of systemically infused, genetically unmodified allogeneic MSCs in glucocorticoid-induced osteoporosis. The donor MSCs inhabited recipient bone marrow and promoted osteoblastogenesis. The therapeutic effects were based on maintenance of bone formation. These results provide important information regarding cell-based anabolic therapy for glucocorticoid-induced osteoporosis and uncover previously unrecognized mesenchymal stem cell behaviors following a homing event. The current study also indicates that minimizing the time of cell culture confers an advantage for increasing transplanted mesenchymal stem cells to the targeted organ to promote therapeutic effects.
authors.affiliation: State Key Laboratory of Military Stomatology, Center for Tissue Engineering, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China Research and Development Center for Tissue Engineering, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China State Key Laboratory of Military Stomatology, Department of Dental Materials, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China Department of Dental Materials, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China.
authors.forename: Bingdong
authors.initials: B
authors.lastname: Sui
authors.affiliation: State Key Laboratory of Military Stomatology, Center for Tissue Engineering, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China Research and Development Center for Tissue Engineering, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China.
authors.forename: Chenghu
authors.initials: C
authors.lastname: Hu
authors.affiliation: State Key Laboratory of Military Stomatology, Center for Tissue Engineering, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China Research and Development Center for Tissue Engineering, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China.
authors.forename: Xinyi
authors.initials: X
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Military Stomatology, Center for Tissue Engineering, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China Research and Development Center for Tissue Engineering, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China.
authors.forename: Pan
authors.initials: P
authors.lastname: Zhao
authors.affiliation: State Key Laboratory of Military Stomatology, Center for Tissue Engineering, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China Research and Development Center for Tissue Engineering, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China.
authors.forename: Tao
authors.initials: T
authors.lastname: He
authors.affiliation: State Key Laboratory of Military Stomatology, Center for Tissue Engineering, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China Research and Development Center for Tissue Engineering, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China.
authors.forename: Cuihong
authors.initials: C
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Military Stomatology, Center for Tissue Engineering, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China Research and Development Center for Tissue Engineering, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China.
authors.forename: Xinyu
authors.initials: X
authors.lastname: Qiu
authors.affiliation: State Key Laboratory of Military Stomatology, Center for Tissue Engineering, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China Research and Development Center for Tissue Engineering, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China.
authors.forename: Nan
authors.initials: N
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Military Stomatology, Department of Dental Materials, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China Department of Dental Materials, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China yanjin@fmmu.edu.cn zhaoxinyi@fmmu.edu.cn.
authors.forename: Xinyi
authors.initials: X
authors.lastname: Zhao
authors.affiliation: State Key Laboratory of Military Stomatology, Center for Tissue Engineering, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China Research and Development Center for Tissue Engineering, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China yanjin@fmmu.edu.cn zhaoxinyi@fmmu.edu.cn.
authors.forename: Yan
authors.initials: Y
authors.lastname: Jin
mesh_terms: D064591:Allografts; D000818:Animals; D003907:Dexamethasone / Q000633:toxicity; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D005938:Glucocorticoids / Q000633:toxicity; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010006:Osteoblasts / Q000166:cytology*; D010012:Osteogenesis / Q000502:physiology; D010024:Osteoporosis / Q000139:chemically induced / Q000473:pathology*; D055114:X-Ray Microtomography
chemical_list: D005938:Glucocorticoids; D003907:Dexamethasone
keywords: Bone remodeling; Cell homing; Glucocorticoid-induced osteoporosis; Mesenchymal stem cell therapy; Osteoblastogenesis