ARTHRITIS & RHEUMATISM Vol. 62, No. 8, August 2010, pp 2328–2338 DOI 10.1002/art.27535 © 2010, American College of Rheumatology Increased Bone Density and Resistance to Ovariectomy-Induced Bone Loss in FoxP3-Transgenic Mice Based on Impaired Osteoclast Differentiation Mario M. Zaiss, Kerstin Sarter, Andreas Hess, Klaus Engelke, Christina Bo ¨hm, Falk Nimmerjahn, Reinhard Voll, Georg Schett, and Jean-Pierre David Objective. Immune activation triggers bone loss. Activated T cells are the cellular link between immune activation and bone destruction. The aim of this study was to determine whether immune regulatory mecha- nisms, such as naturally occurring Treg cells, also extend their protective effects to bone homeostasis in vivo. Methods. Bone parameters in FoxP3-transgenic (Tg) mice were compared with those in their wild-type (WT) littermate controls. Ovariectomy was performed in FoxP3-Tg mice as a model of postmenopausal osteo- porosis, and the bone parameters were analyzed. The bones of RAG-1 –/– mice were analyzed following the adoptive transfer of isolated CD4CD25 T cells. CD4CD25 T cells and CD4 T cells isolated from FoxP3-Tg mice and WT mice were cocultured with monocytes to determine their ability to suppress oste- oclastogenesis in vitro. Results. FoxP3-Tg mice developed higher bone mass and were protected from ovariectomy-induced bone loss. The increase in bone mass was found to be the result of impaired osteoclast differentiation and bone resorption in vivo. Bone formation was not affected. Adoptive transfer of CD4CD25 T cells into T cell– deficient RAG-1 –/– mice also increased the bone mass, indicating that Treg cells directly affect bone homeosta- sis without the need to engage other T cell lineages. Conclusion. These data demonstrate that Treg cells can control bone resorption in vivo and can preserve bone mass during physiologic and pathologic bone remodeling. During life, our skeleton is subjected to a process of continuous remodeling. This process allows the skel- eton not only to gain peak bone mass during adolescence and to individually model bone architecture during adulthood, but also to maintain bone mass during aging. Bone loss results in a reduced quantity and quality of bone, leading to osteopenia and osteoporosis, which are considered to be major health problems because they enhance the risk of fractures. The mechanism of bone remodeling that leads to the degradation of bone is a net imbalance between bone formation and bone resorption. With regard to local regulation of bone remodeling, the RANKL/ RANK/osteoprotegerin (OPG) system plays the most prominent role (1). Initiation of osteoclastogenesis largely depends on the direct local interaction between osteoclast precursor cells with cells from the osteoblast lineage that are the local source of macrophage colony- stimulating factor (M-CSF) and RANKL. Strikingly, bone resorption mediated by osteoclasts (2,3) is en- hanced and is not compensated by sufficient osteoblast- mediated bone formation (4). Several factors can aggra- vate this imbalance and speed up bone loss. The most prominent are older age, low body mass, postmeno- pausal state, and genetic variables. Supported in part by the University of Erlangen–Nuremberg (intramural ELAN grant), the Sonderforschungsbereich 643, the Schw- erpunktprogram 1468, and the Forschergruppe 661 of the Deutsche Forschungsgemeinschaft (DFG), and the European Union (projects Masterswitch, Adipoa, and Kinacept). Drs. Zaiss and Sarter’s work was supported by PhD Training Grant GK592 from the DFG. Mario M. Zaiss, PhD, Kerstin Sarter, Dipl Biol, Andreas Hess, PhD, Klaus Engelke, PhD, Christina Bo ¨hm, Dipl Biol Univ, Falk Nimmerjahn, PhD, Reinhard Voll, MD, Georg Schett, MD, Jean- Pierre David, PhD: University of Erlangen–Nuremberg, Erlangen, Germany. Dr. Nimmerjahn has received consulting fees, speaking fees, and/or honoraria from SuppreMol. Dr. Voll has submitted a patent application for the use of bortezomib for the depletion of plasma cells. Address correspondence and reprint requests to Georg Schett, MD, Department of Internal Medicine 3, Rheumatology and Immunology, University of Erlangen–Nuremberg, Krankenhausstrasse 12, Erlangen D-91054, Germany. E-mail: georg.schett@uk- erlangen.de. Submitted for publication December 17, 2009; accepted in revised form April 20, 2010. 2328