Biomedical subjects

Roberto Pacifici

Publications and source records attributed to Roberto Pacifici.

12 recordsLinked to original sources

PubMed2006

IFN-gamma stimulates osteoclast formation and bone loss in vivo via antigen-driven T cell activation.

T cell-produced cytokines play a pivotal role in the bone loss caused by inflammation, infection, and estrogen deficiency. IFN-gamma is a major product of activated T helper cells that can function as a pro- or antiresorptive cytokine, but the reason why IFN-gamma has variable effects in bone is unknown. Here we show that IFN-gamma blunts osteoclast formation through direct targeting of osteoclast precursors but indirectly stimulates osteoclast formation and promotes bone resorption by stimulating antigen-dependent T cell activation and T cell secretion of the osteoclastogenic factors RANKL and TNF-alpha. Analysis of the in vivo effects of IFN-gamma in 3 mouse models of bone loss - ovariectomy, LPS injection, and inflammation via silencing of TGF-beta signaling in T cells - reveals that the net effect of IFN-gamma in these conditions is that of stimulating bone resorption and bone loss. In summary, IFN-gamma has both direct anti-osteoclastogenic and indirect pro-osteoclastogenic properties in vivo. Under conditions of estrogen deficiency, infection, and inflammation, the net balance of these 2 opposing forces is biased toward bone resorption. Inhibition of IFN-gamma signaling may thus represent a novel strategy to simultaneously reduce inflammation and bone loss in common forms of osteoporosis.

Alveolar Bone Loss↗

PubMed2006

Estrogen deficiency and bone loss: an inflammatory tale.

Estrogen plays a fundamental role in skeletal growth and bone homeostasis in both men and women. Although remarkable progress has been made in our understanding of how estrogen deficiency causes bone loss, the mechanisms involved have proven to be complex and multifaceted. Although estrogen is established to have direct effects on bone cells, recent animal studies have identified additional unexpected regulatory effects of estrogen centered at the level of the adaptive immune response. Furthermore, a potential role for reactive oxygen species has now been identified in both humans and animals. One major challenge is the integration of a multitude of redundant pathways and cytokines, each apparently capable of playing a relevant role, into a comprehensive model of postmenopausal osteoporosis. This Review presents our current understanding of the process of estrogen deficiency-mediated bone destruction and explores some recent findings and hypotheses to explain estrogen action in bone. Due to the inherent difficulties associated with human investigation, many of the lessons learned have been in animal models. Consequently, many of these principles await further validation in humans.

Animals↗

PubMed2006

Estrogen regulation of immune cell bone interactions.

Estrogen deficiency is one of the most frequent causes of osteoporosis in women and a possible cause of bone loss and insufficient skeletal development in men. Estrogen deficiency results from menopause but also by a number of conditions, such as stress, excessive physical activity, and low body weight. The mechanism by which estrogen deficiency causes bone loss remains largely unknown. Estrogen deficiency leads to an increase in the immune function, which culminates in an increased production of TNF by activated T cells. TNF increases osteoclast formation and bone resorption both directly and by augmenting the sensitivity of maturing osteoclasts to the essential osteoclastogenic factor RANKL. Increased T cell production of TNF is induced by estrogen deficiency via a complex mechanism mediated by antigen-presenting cells and involving the cytokines IFN-gamma, IL-7, and TGF-beta. Herein we review the experimental evidence that suggests that estrogen prevents bone loss by regulating T cell function and immune cell bone interactions.

Animals↗

PubMed2006

IL-7 drives T cell-mediated bone loss following ovariectomy.

Ovariectomy-induced bone loss stems in large measure from a realignment of adaptive immune responses leading to the activation and expansion of tumor necrosis factor (TNF)-producing T cells. The mechanisms driving this T cell expansion are complex but we have recently reported that the pro-osteoclastogenic cytokine interleukin (IL)-7 plays a critical role in this process. The mechanisms of IL-7 action are intricate and poorly defined. We present herein an overview of our current understanding of IL-7 action on bone turnover and the role of IL-7 in ovariectomy-induced bone loss.

Animals↗

PubMed2005

An IL-7-dependent rebound in thymic T cell output contributes to the bone loss induced by estrogen deficiency.

The bone wasting induced by estrogen deficiency is, in part, a consequence of increased T cell production of the osteoclastogenic cytokine TNF-alpha. This phenomenon is due to an expansion of T cells, but the responsible mechanism is unknown. We now show that ovariectomy (ovx) disregulates T lymphopoiesis and induces bone loss by stimulating, through a rise in IL-7 levels, both thymic-dependent differentiation of bone marrow-derived progenitors and thymic-independent, peripheral expansion of mature T cells. Attesting to the relevance of the thymic effects, thymectomy decreases by approximately 50% the bone loss and the stimulation of T lymphopoiesis induced by ovx. In contrast, in vivo attenuation of the elevated IL-7 completely prevents the stimulation of T lymphopoiesis and the bone loss that follow ovx. Thus, the disruption of both T cell and bone homeostasis induced by ovx is mediated by IL-7 and due to both the thymic and extrathymic mechanisms. We conclude that IL-7 is a pivotal upstream target through which estrogen regulates hematopoietic and immune functions that are critical for bone homeostasis.

Animals↗

PubMed2005

Role of the immune system in postmenopausal bone loss.

Postmenopausal osteoporosis stems from estrogen deficiency. The mechanisms by which estrogen deficiency drives bone destruction are complex and poorly understood. Recent findings from animal models suggest that postmenopausal bone loss may stem in large measure from a pathologic upregulation of the adaptive immune response. While the role of activated T cells in the bone loss driven by inflammatory conditions such as rheumatoid arthritis has been well documented, only recently has the role of T cells in the bone destruction associated with estrogen deficiency begun to be appreciated. In vivo and in vitro models of postmenopausal osteoporosis demonstrate that the activation and expansion of tumor necrosis factor-a producing T cells is a key step in estrogen deficiency driven bone loss and is regulated by multiple interacting cytokines including transforming growth factor-b, interleukin-7, and interferon-g, as well as by the process of antigen presentation. This paper presents recent findings pertaining to this new view of postmenopausal osteoporosis.

Animals↗

PubMed2005

The role of T lymphocytes in bone metabolism.

Recent findings from animal models suggest that the bone loss induced by estrogen deficiency may stem in large measure from a pathological upregulation of the adaptive immune response. While the role of activated T cells in the osteoporosis driven by inflammatory conditions and infection has been well documented, only recently has the role of T cells in the bone destruction associated with estrogen deficiency begun to be appreciated. In vivo and in vitro models of postmenopausal osteoporosis demonstrate that estrogen deficiency leads to an increase in the adaptive immune function that culminates in an increased production of tumor necrosis factor alpha (TNF) by activated T cells. TNF increases osteoclast (OC) formation and bone resorption both directly and by augmenting the sensitivity of maturing OCs to the essential osteoclastogenic factor receptor activator of nuclear factor kappaB ligand. The activation and expansion of TNF-producing T cells are key steps in estrogen deficiency-driven bone loss and are regulated by multiple interacting cytokines including transforming growth factor-beta, interleukin-7, and interferon-gamma, as well as by the process of antigen presentation. Herein, we review the experimental evidence that suggests estrogen prevents bone loss by regulating T-cell function and immune cell bone interactions.

Animals↗

PubMed2004

Estrogen prevents bone loss through transforming growth factor beta signaling in T cells.

Estrogen (E) deficiency leads to an expansion of the pool of tumor necrosis factor (TNF)-producing T cells through an IFN-gamma-dependent pathway that results in increased levels of the osteoclastogenic cytokine TNF in the bone marrow. Disregulated IFN-gamma production is instrumental for the bone loss induced by ovariectomy (ovx), but the responsible mechanism is unknown. We now show that mice with T cell-specific blockade of type beta transforming growth factor (TGFbeta) signaling are completely insensitive to the bone-sparing effect of E. This phenotype results from a failure of E to repress IFN-gamma production, which, in turn, leads to increased T cell activation and T cell TNF production. Furthermore, ovx blunts TGFbeta levels in the bone marrow, and overexpression of TGFbeta in vivo prevents ovx-induced bone loss. These findings demonstrate that E prevents bone loss through a TGFbeta-dependent mechanism, and that TGFbeta signaling in T cells preserves bone homeostasis by blunting T cell activation. Thus, stimulation of TGFbeta production in the bone marrow is a critical "upstream" mechanism by which E prevents bone loss, and enhancement of TGFbeta levels in vivo may constitute a previously undescribed therapeutic approach for preventing bone loss.

Animals↗

PubMed2003

Estrogen deficiency induces bone loss by increasing T cell proliferation and lifespan through IFN-gamma-induced class II transactivator.

Expansion of the pool of tumor necrosis factor (TNF)-alpha-producing T cells is instrumental for the bone loss induced by estrogen deficiency, but the responsible mechanism is unknown. Here we show that ovariectomy up-regulates IFN-gamma-induced class II transactivator, a multitarget immune modulator, resulting in increased antigen presentation by macrophages, enhanced T cell activation, and prolonged lifespan of active T cells. Up-regulation of class II transactivator derives from increased production of IFN-gamma by T helper 1 cells, resulting from enhanced secretion of IL-12 and IL-18 by macrophages. The resulting T cell expansion and bone loss are prevented in vivo by both blockade of antigen presenting cell-induced T cell activation, and silencing of IFN-gamma receptor signaling. Thus, increased IFN-gamma-induced class II transactivator expression and the resulting enhanced T cell proliferation and lifespan are critical to the bone wasting effect of estrogen deficiency.

Animals↗

PubMed2003

Marked decrease in plasma antioxidants in aged osteoporotic women: results of a cross-sectional study.

Although recent epidemiological studies found a positive correlation between dietary vitamin C intake and bone mineral density, data on plasma levels of vitamin C or other antioxidants in osteoporotic subjects are scanty. The aim of this study was to evaluate whether antioxidant defenses are decreased in elderly osteoporotic women and, if this is the case, to understand whether osteoporosis is a condition characterized by increased oxidative stress. To answer these questions, plasma vitamins C, E, and A; uric acid; and the enzymatic activities of superoxide dismutase in plasma and erythrocytes and of glutathione peroxidase in plasma were measured in 75 subjects with osteoporosis and 75 controls. Dietary and endogenous antioxidants were consistently lower in osteoporotic than in control subjects. On the other hand, plasma levels of malondialdehyde, a byproduct of lipid peroxidation, did not differ between groups. Our results reveal that antioxidant defenses are markedly decreased in osteoporotic women. The mechanisms underlying antioxidant depletion and its relevance to the pathogenesis of osteoporosis deserve further investigation.

Activities of Daily Living↗

PubMed2002

IL-7 induces bone loss in vivo by induction of receptor activator of nuclear factor kappa B ligand and tumor necrosis factor alpha from T cells.

IL-7, a powerful lymphopoietic cytokine, is elevated in rheumatoid arthritis (RA) and known to induce bone loss when administered in vivo. IL-7 has been suggested to induce bone loss, in part, by stimulating the proliferation of B220(+) cells, a population capable of acting as early osteoclast (OC) precursors. However, the mechanism by which IL-7 leads to differentiation of precursors into mature OCs remains unknown. We previously reported that, in vitro, IL-7 up-regulated T cell cytokines including receptor activator of nuclear factor kappaB ligand (RANKL). To demonstrate the importance of T cells to the bone-wasting effect of IL-7 in vivo, we have now examined IL-7-induced bone loss in T cell-deficient nude mice. We show that T cell-replete mice undergo significant osteoclastic bone loss after IL-7 administration, concurrent with induction of RANKL and tumor necrosis factor alpha (TNF-alpha) secretion by splenic T cells. In contrast, nude mice were resistant to IL-7-induced bone loss and showed no detectable increase in either RANKL or TNF-alpha, despite an up-regulation of B220(+) cells. Importantly, T cell adoptive transfer into nude mice restored IL-7-induced bone loss, and RANKL and TNF-alpha secretion, demonstrating that T cells are essential mediators of IL-7-induced bone loss in vivo.

Adoptive Transfer↗

PubMed2002

Increased production of IL-7 uncouples bone formation from bone resorption during estrogen deficiency.

Postmenopausal bone loss stems from the inability of osteoblastic activity to match the increase in osteoclastic bone resorption induced by estrogen deficiency. However, the mechanism that uncouples osteoblast from osteoclast activities remains unexplained. We show that ovariectomy enhances the production of the osteoclastogenic cytokine IL-7, and that its neutralization in vivo prevents ovariectomy-induced bone loss. Surprisingly, serum osteocalcin levels, a biochemical marker of bone formation, suggested that the bone-sparing effects of IL-7 neutralization were due not only to inhibition of bone resorption, but also to stimulation of bone formation. Consistent with these data, addition of IL-7 to neonatal calvarial organ cultures blocked new bone formation, and injection of IL-7 into mice in vivo inhibited bone formation as measured by calcein incorporation into long bones. The antianabolic effects of IL-7 were consistent with an observed downregulation of the osteoblast-specific transcription factor core-binding factor alpha1/Runx2. Thus, because it targets both the osteoclast and the osteoblast pathways, IL-7 is central to the altered bone turnover characteristic of estrogen deficiency.

Animals↗