Pharmacologic Stem Cell Based Intervention as a New Approach to Osteoporosis Treatment in Rodents
Penn collection
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Discipline
Subject
Apoptosis
Aspirin
Bone Marrow Cells
Bone Resorption
CD4-Positive T-Lymphocytes
Humans
Interleukin-2 Receptor alpha Subunit
Mesenchymal Stem Cell Transplantation
Mesenchymal Stem Cells
Mice
Mice
Inbred C3H
Mice
Transgenic
Osteoclasts
Osteoporosis
T-Lymphocytes Species Index: Mus
Rodentia EMTREE drug terms: acetylsalicylic acid
Fas antigen
Fas ligand
telomerase
acetylsalicylic acid
interleukin 2 receptor alpha EMTREE medical terms: adult
animal cell
animal experiment
animal model
apoptosis
article
bone density
bone development
controlled study
drug mechanism
enzyme activity
enzyme inhibition
ex vivo study
female
human
human cell
in vitro study
mesenchymal stem cell
mouse
nonhuman
ossification
osteoblast
osteoclast
osteolysis
osteoporosis
ovariectomy
T lymphocyte
T lymphocyte activation
animal
bone marrow cell
C3H mouse
CD4+ T lymphocyte
drug effect
immunology
mesenchymal stem cell
mesenchymal stem cell transplantation
metabolism
transgenic mouse
Dentistry
Oral Biology and Oral Pathology
Periodontics and Periodontology
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Abstract
Background: Osteoporosis is the most prevalent skeletal disorder, characterized by a low bone mineral density (BMD) and bone structural deterioration, leading to bone fragility fractures. Accelerated bone resorption by osteoclasts has been established as a principal mechanism in osteoporosis. However, recent experimental evidences suggest that inappropriate apoptosis of osteoblasts/osteocytes accounts for, at least in part, the imbalance in bone remodeling as occurs in osteoporosis. The aim of this study is to examine whether aspirin, which has been reported as an effective drug improving bone mineral density in human epidemiology studies, regulates the balance between bone resorption and bone formation at stem cell levels. Methods and Findings: We found that T cell-mediated bone marrow mesenchymal stem cell (BMMSC) impairment plays a crucial role in ovariectomized-induced osteoporosis. Ex vivo mechanistic studied revealed that T cell-mediated BMMSC impairment was mainly attributed to the apoptosis of BMMSCs via the Fas/Fas ligand pathway. To explore potential of using pharmacologic stem cell based intervention as an approach for osteoporosis treatment, we selected ovariectomy (OVX)-induced osteoporosis mouse model to examine feasibility and mechanism of aspirin-mediated therapy for osteoporosis. We found that aspirin can inhibit T cell activation and Fas ligand induced BMMSC apoptosis in vitro. Further, we revealed that aspirin increases osteogenesis of BMMSCs by aiming at telomerase activity and inhibits osteoclast activity in OVX mice, leading to ameliorating bone density. Conclusion: Our findings have revealed a novel osteoporosis mechanism in which activated T cells induce BMMSC apoptosis via Fas/Fas ligand pathway and suggested that pharmacologic stem cell based intervention by aspirin may be a new alternative in osteoporosis treatment including activated osteoblasts and inhibited osteoclasts. © 2008 Yamaza et al.