Pharmacologic Stem Cell Based Intervention as a New Approach to Osteoporosis Treatment in Rodents Takayoshi Yamaza 1. , Yasuo Miura 2. , Yanming Bi 3 , Yongzhong Liu 3 , Kentaro Akiyama 1 , Wataru Sonoyama 1 , Voymesh Patel 3 , Silvio Gutkind 3 , Marian Young 3 , Stan Gronthos 4 , Anh Le 1 , Cun-Yu Wang 5 , WanJun Chen 3 *, Songtao Shi 1 * 1 Center for Craniofacial Molecular Biology, University of Southern California School of Dentistry, Los Angeles, California, United States of America, 2 Graduate School of Medicine, Kyoto University, Kyoto, Japan, 3 National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, United States of America, 4 Mesenchymal Stem Cell Group, Division of Haematology, Institute of Medical and Veterinary Science, Adelaide, South Australia, Australia, 5 Division of Oral Biology & Medicine, University of California Los Angeles School of Dentistry, Los Angeles, California, United States of America 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 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 ostoeporosis 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. Citation: Yamaza T, Miura Y, Bi Y, Liu Y, Akiyama K, et al. (2008) Pharmacologic Stem Cell Based Intervention as a New Approach to Osteoporosis Treatment in Rodents. PLoS ONE 3(7): e2615. doi:10.1371/journal.pone.0002615 Editor: Thomas Zwaka, Baylor College of Medicine, United States of America Received March 18, 2008; Accepted June 5, 2008; Published July 9, 2008 Copyright: ß 2008 Yamaza et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This research was supported by University of Southern California School of Dentistry starting fund for S.S., an extramural grant from NIH (NIDCR R01DE17449 for S.S.), and NIDCR intramural fund. Competing Interests: The authors have declared that no competing interests exist. * E-mail: wchen@mail.nih.gov (WC); songtaos@usc.edu (SS) . These authors contributed equally to this work. Introduction Osteoporosis is the most prevalent skeletal disorder, character- ized by a low bone mineral density (BMD) and structural deterioration of bone tissue, leading to bone fragility fractures [1]. Postmenopausal osteoporosis is the most common and significant form of osteoporosis in which estrogen deficiency gives rise to a high turnover rate in bone metabolism, as characterized by a over-activated osteoclast activity and a temporal increase in osteoblast activity that is not able to balance osteoclast-mediated bone resorption [1]. Although many systemic and local regulators are involved in estrogen-deficient osteoporosis, it appears that activated T lymphocyte associated osteoclast over-activation play a pivotal role in postmenopausal osteoporosis [2–4]. Clinically, bisphosphonates are widely used and appear to ameliorate the effects of osteoporosis by inhibiting osteoclast functions. However, recent experimental evidences suggest that bisphosphonates may also inhibit apoptosis of both osteocytes and osteoblasts [5] and increase the bone forming potential of osteoblasts [6], implying that BMMSC/osteoblast lineage cells may actively participate in the recovery of osteoporosis. BMMSCs are multipotent postnatal stem cells that are capable of differentiating into osteoblasts, chondrocytes, adipocytes, cardiomyocytes, and myoblasts [7–9]. It is known that osteoblasts form new bone matrix to balance osteoclast-mediated bone resorption during the bone remodeling process so as to maintaining homeostasis of the bone/marrow system [10]. The interplay between the BMMSC/osteoblast lineage and hemato- PLoS ONE | www.plosone.org 1 July 2008 | Volume 3 | Issue 7 | e2615