Pharmacologic stem cell based intervention as a new approach to osteoporosis treatment in rodents.
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.


RESULTS
We found that T cell-mediated bone marrow mesenchymal stem cell (BMMSC) impairment plays a crucial role in ovariectomized-induced osteoporosis. Ex vivo mechanistic studies 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.


CONCLUSIONS
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.
Yamaza
Takayoshi
T
Center for Craniofacial Molecular Biology, University of Southern California School of Dentistry, Los Angeles, California, United States of America.
Miura
Yasuo
Y
Bi
Yanming
Y
Liu
Yongzhong
Y
Akiyama
Kentaro
K
Sonoyama
Wataru
W
Patel
Voymesh
V
Gutkind
Silvio
S
Young
Marian
M
Gronthos
Stan
S
Le
Anh
A
Wang
Cun-Yu
CY
Chen
WanJun
W
Shi
Songtao
S
D000818:Animals; D017209:Apoptosis; D001241:Aspirin / Q000494:pharmacology / Q000627:therapeutic use*; D001854:Bone Marrow Cells / Q000378:metabolism; D001862:Bone Resorption; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D008822:Mice, Transgenic; D010010:Osteoclasts / Q000378:metabolism; D010024:Osteoporosis / Q000188:drug therapy* / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology
D053645:Interleukin-2 Receptor alpha Subunit; D001241:Aspirin