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In vivo studies have shown T cells to be central to the mechanism by which estrogen deficiency induces bone loss, but the mechanism involved remains, in part, undefined. In vitro, T cells from ovariectomized mice produce increased amounts of tumor necrosis factor (TNF), which augments receptor activator of NF-B ligand (RANKL)-induced osteoclastogenesis. However, both the mechanism and the relevance of this phenomenon in vivo remain to be established. In this study, we found that ovariectomy increased the number of bone marrow T cell-producing TNF without altering production of TNF per T cell. Attesting to the essential contribution of TNF, ovariectomy induced rapid bone loss in wild type (wt) mice but failed to do so in TNF-deficient (TNF ؊͞؊ ) mice. Furthermore, ovariectomy induced bone loss, which was absent in T cell-deficient nude mice, was restored by adoptive transfer of wt T cells, but not by reconstitution with T cells from TNF ؊͞؊ mice. These findings demonstrate the key causal role of T cell-produced TNF in the bone loss after estrogen withdrawal. Finally, ovariectomy caused bone loss in wt mice and in mice lacking p75 TNF receptor but failed to do so in mice lacking the p55 TNF receptor. These findings demonstrate that enhanced T cell production of TNF resulting from increased bone marrow T cell number is a key mechanism by which estrogen deficiency induces bone loss in vivo. The data also demonstrate that the bone-wasting effect of TNF in vivo is mediated by the p55 TNF receptor.ovariectomy ͉ osteoporosis ͉ mouse ͉ pQCT I t is now recognized that one of the main mechanisms by which estrogen deficiency causes bone loss is by stimulating osteoclast formation (1), a process induced by the simultaneous stimulation of osteoclast precursors by macrophage colonystimulating factor (M-CSF) and a tumor necrosis factor (TNF)-related factor known as receptor activator of NF-B ligand (RANKL) (also known as OPGL, TRANCE, or ODF) (2-4).In physiologic, unstimulated conditions, the differentiation of osteoclast precursors into mature osteoclasts in the bone marrow depends on the production of M-CSF by monocytes and stromal cells and RANKL by stromal cells and osteoblasts (5). However, in stimulated conditions, additional bone marrow cells contribute to regulating osteoclast formation by producing soluble and membrane-bound pro-and antiosteoclastogenic cytokines. Among them are naïve and activated T cells, which modulate osteoclast formation trough increased production of RANKL (6-8), osteoprotegerin (9), and IFN-␥ (10).During inflammation and autoimmune arthritis, activated T cell production of RANKL promotes bone resorption and bone loss (6) whereas release of IFN-␥ limits T cell-induced bone wasting (10). Recent studies from our laboratory have disclosed that activated T cells play an essential causal role not only in inflammation-induced bone loss, but also in the bone wasting induced by estrogen deficiency (11). In fact, whereas ovariectomy (ovx) stimulated bone resorption and induced rapid bone loss in T cell-re...

Background-The underlying molecular mechanisms of the vasculoprotective effects of physical exercise are incompletely understood. Telomere erosion is a central component of aging, and telomere-associated proteins regulate cellular senescence and survival. This study examines the effects of exercising on vascular telomere biology and endothelial apoptosis in mice and the effects of long-term endurance training on telomere biology in humans. Methods and Results-C57/Bl6 mice were randomized to voluntary running or no running wheel conditions for 3 weeks.Exercise upregulated telomerase activity in the thoracic aorta and in circulating mononuclear cells compared with sedentary controls, increased vascular expression of telomere repeat-binding factor 2 and Ku70, and reduced the expression of vascular apoptosis regulators such as cell-cycle-checkpoint kinase 2, p16, and p53. Mice preconditioned by voluntary running exhibited a marked reduction in lipopolysaccharide-induced aortic endothelial apoptosis. Transgenic mouse studies showed that endothelial nitric oxide synthase and telomerase reverse transcriptase synergize to confer endothelial stress resistance after physical activity. To test the significance of these data in humans, telomere biology in circulating leukocytes of young and middle-aged track and field athletes was analyzed. Peripheral blood leukocytes isolated from endurance athletes showed increased telomerase activity, expression of telomere-stabilizing proteins, and downregulation of cell-cycle inhibitors compared with untrained individuals. Long-term endurance training was associated with reduced leukocyte telomere erosion compared with untrained controls. Conclusions-Physical activity regulates telomere-stabilizing proteins in mice and in humans and thereby protects from stress-induced vascular apoptosis. (Circulation. 2009;120:2438-2447.)Key Words: aging Ⅲ exercise Ⅲ nitric oxide synthase Ⅲ prevention Ⅲ telomeres P hysical training is associated with improvements in exercise capacity, blood pressure regulation, insulin sensitivity, abdominal fat reduction, lipid profile, and psychosocial, hemodynamic, and inflammatory parameters. These effects contribute to an augmentation of endothelial function, delayed atherosclerotic lesion progression, and enhanced vascular collateralization in patients with diabetes mellitus, coronary artery disease, and chronic heart failure. However, despite the wealth of evidence, our understanding of the underlying molecular mechanisms, especially with regard to cellular survival and senescence, is limited. Clinical Perspective on p 2447Aging is a predominant and independent risk factor for the development of atherosclerotic diseases. Vascular aging is characterized by impaired endothelial function and arterial stiffening. 1 On the cellular level, telomere biology is a central regulator of the aging process. Telomeres and their regulatory proteins compose t-loop structures at both ends of eukaryotic chromosomes and protect the genome from degradation during repetitive cellul...

Expansion of the pool of tumor necrosis factor (TNF)-␣-producing T cells is instrumentalovariectomy ͉ osteoporosis ͉ tumor necrosis factor ͉ sex steroids