14 www.nature.com/bonekey P33 Wolff’s Law and the Interplay between Bone Structure and External Loading Davide Ruffoni1, Patrik Christen2, Heike Scherf3, Richard Weinkamer4 1Department of Aerospace and Mechanical Engineering, University of Liege, Liege, Belgium, 2Institute for Biomechanics, ETH Zurich, Zurich, Switzerland, 3Institute for Archaeological Sciences, University of Tubingen, Tubingen, Germany, 4Department of Biomaterials, Max Planck Institute of Colloids and Interfaces, Potsdam, Germany
Number: 1040 T cells provide proliferative and survival cues to stromal cells through CD40L, a surface molecule of activated T cells that induce CD40 signaling in marrow stromal cells. iPTH treatment in CD40L / mice produced a smaller increase in bone volume in CD40L / mice than it did in WTcontrols. To investigate the specific role of T-cell-expressed CD40L, T-cell-deficient TCRb / mice were subjected to adaptive transfer of WT T cells and CD40L / T cells. Reconstituted mice were then treated with vehicle or iPTH. It was found that iPTH induced a significant increase in trabecular bone mass in TCRb / mice reconstituted with WT T cells, whereas no significant anabolic activity was found in T-cell-deficient mice and mice with T cells lacking CD40L expression. These data demonstrated that T-cellexpressed CD40L potentiates the bone anabolic activity of iPTH. Inflammation-Induced Hypercytokinemia and Myeloproliferation Underlie Osteopenia in Scurfy Mice, the Animal Model For Heritable Autoimmune Disease IPEX. Abstract Number: 1043 Dr Gabriel Mbalaviele at Washington University in St Louis showed the importance of regulatory T cells (Tregs) in bone homeostasis. The development and function of Tregs requires the Foxp3 gene product. The mouse model of autoimmune disease IPEX (Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked) syndrome is the Scurfy (Sf) mouse. This animal has a loss-of-function mutation in Foxp3, resulting in multiorgan inflammation. Sf mice exhibit severe bone loss mediated by accelerated osteoclastogenesis. Sf hematopoietic stem cells (LSK HSCs) exhibited greater sensitivity to M-CSF signaling and contained more PU.1þSf LSK HSCs than did WT. Biochemical studies suggest that Foxp3 deficiency results in upregulation of the NEMO/IKKg gene in T helper cells through loss of Foxp3/NEMO interaction, thereby trigging NF-kBmediated overproduction of M-CSF, RANKL, IL-17 and TNF. In vivo administration of M-CSF-neutralizing antibody as well as crossing of an Sf hemizygous female with an Op heterozygous male, which produces decreased amountsof M-CSF, attenuated osteopenia in Sf mice. Mechanistically, M-CSF antibody, M-CSF genetic ablation and inhibitors of mToR all reduced granulocyte– macrophage precursor frequency in Sf BM, suggesting that they act either directly or indirectly at the hematopoietic stem cell level. These studies suggest that Foxp3 deficiency leads to osteopenia because of dysregulation of NF-kB and subsequent cytokine-mediated hyperproliferation of myeloid precursors. Bone Anabolic Effect in Ovariectomized Mice by low-dose RANKL Mediated by FoxP3þ CD8 T Cells. Abstract Number: FR0357 Dr Richard Di Paolo’s group from Washington University in St Louis examined the role of FoxP3þ CD8 T cells in ovariectomized mice. Estrogen loss increases the levels of RANKL resulting in enhanced differentiation and bone resorption by osteoclasts. It was found that, although all doses of RANKL promote osteoclast activity in control mice, in ovariectomized (OVX) mice treatment with low-dose RANKL (0.125 mg/kg) on two consecutive days at 2 weeks post OVX improved osteoporosis. It was reported that low-dose RANKL activated osteoclasts to induce FoxP3 expression in CD8 T cells, which resulted in the suppression of aberrant activation of selfreactive T cells. These cells in addition to suppressing osteoclasts also suppress the ability of dendritic cells to stimulate the proliferation of CD4 and CD8 T cells. The effect of low-dose RANKL was superior to bisphosphonate treatment because it reduced the levels of proinflammatory effector Tcells in the bone marrow, increasing bone formation. Conflict of Interest The authors declare no conflict of interest. Meeting Report 2 MARCH 2015 | www.nature.com/bonekey
Rare bone diseases account for 5% of all birth defects and can cause significant morbidity throughout patients' lives. Significant progress is being made to elucidate the pathophysiological mechanisms underlying these diseases. This paper summarizes presentation highlights of a workshop on Rare Skeletal Diseases convened to explore how the study of rare diseases has influenced the field's understanding of bone anabolism and catabolism and directed the search for new therapies benefiting patients with rare conditions as well as patients with common skeletal disorders.
Bisphosphonates are the first-line and commonly prescribed drugs for the treatment of osteoporosis. They act by decreasing bone resorption, hence altering bone remodeling, which may lead to a low bone turnover state. Atypical femur fracture is one of the rare complications seen following prolonged use of bisphosphonates. We report a 1-year follow-up of our previously published case of atypical femur fracture and its response to Teriparatide, and a brief review of literature.
