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• W2054757511 abstract "More than a decade has passed since the publication of the first report implicating T cells in the bone loss induced by ovariectomy (ovx).1 Since then there has been extraordinary progress in the understanding of the regulatory network that links the hemopoietic and the mesenchymal compartments of the bone marrow (BM), the interactions between the immune system and bone, and the role of lymphocytes as mediators of the effects of calciotrophic hormones in bone. Collectively this body of knowledge has led to the firm establishment of “osteoimmunology” as a novel discipline and a promising area of investigation. The objective of this perspective is to revisit the exciting hypothesis that T cells play a pivotal role in the mechanism of ovx-induced bone loss. The bone-sparing activity of estrogens is due to a repression of bone remodeling coupled with a balancing effect on bone formation and resorption.2 The dominant acute effect of estrogen is the blockade of new osteoclast formation, cells which arise by cytokine-driven proliferation and differentiation of monocyte precursors that circulate within the hematopoietic cell.3 This process is facilitated by BM stromal cells (SCs), which provide physical support for nascent osteoclasts and produce soluble and membrane-associated factors essential for the proliferation and differentiation of osteoclast precursors. This inhibitory effect on osteoclastogenesis is associated with a repressive effect on osteoblastogenesis.4 Another critical effect of estrogen is that of increasing osteoclast apoptosis5-7 while blocking the apoptosis of osteoblasts and osteocytes.2, 8 It has been proposed that the effects of estrogens on the generation of osteoblasts and the lifespan of osteoblasts and osteoclasts result from extranuclear actions of the endoplasmic reticulum (ER) and activation of cytoplasmic kinases.2, 7 The decline of ovarian function at menopause results in decreased production of estrogen and a parallel increase in pituitary follicle-stimulating hormone (FSH) levels. The combined effects of estrogen deprivation and elevated FSH production cause a marked stimulation of bone resorption9 and a period of rapid bone loss that is central to the pathogenesis of postmenopausal osteoporosis. In mice the acute effects of menopause are modeled by ovx, a procedure that stimulates bone resorption by increasing osteoclast formation3 and lifespan.5-7 This initial phase of bone loss is followed by a slower but more prolonged loss of mainly cortical bone due to incomplete refilling of the resorption cavities due to insufficient osteoblast (OB) activity and lifespan.10 An expansion of the osteoclastic pool is therefore the key mechanism responsible for the bone loss that occurs early after ovx. The net bone loss caused by ovx is limited, in part, by an increase in bone formation resulting from stimulated osteoblastogenesis.11 This compensation is fueled by an expansion of the pool of BM–SCs, increased commitment of such pluripotent precursors toward the osteoblastic lineage,11 and enhanced proliferation of early OB precursors.4 Subsequent escalations in OB apoptosis12, 13 extensions of osteoclast lifespan5, 6 and increased secretion of cytokines that suppress bone formation, such as interleukin 7 (IL-7) and tumor necrosis factor (TNF), are the likely reasons for why bone formation does not increase as much as resorption after ovx. The stimulatory effect of ovx on SCs is equally relevant for osteoclastogenesis as one of the consequences of estrogen deprivation is the formation of osteoblastic cells with an increased osteoclastogenic activity14; ie, the capacity to support osteoclast formation. Evidence now suggests that T cells play a pivotal role in the mechanism of ovx-induced bone loss. Core observations include reports showing that ovx fails to induce trabecular and cortical bone loss in: T-cell–deficient nude mice,1, 15-17, wild-type (WT) mice deleted of T cells by injection of anti–T cell antibodies,18 mice treated with Abatacept19 (an agent that blocks T cell costimulation and induces T cell anergy and apoptosis)20, 21 and mice lacking the T cell costimulatory molecule CD40 ligand (CD40L).18 The fact that nude mice are protected against ovx-induced bone loss has been confirmed independently.22 By contrast, Lee and colleagues23 showed that nude mice are protected against the loss of cortical, but not trabecular bone induced by ovx. In another study, T-cell–deficient and B-cell–deficient mice were found to lose bone after ovx.24 The discrepancy between our reports1, 15-19, 25 and those of others23, 24 is likely explained by differences in the experimental design, the lack of B cells in some models, and compensatory mechanisms such as an increase in natural killer (NK) cells producing the osteoclastogenic factor IL-17.26 Both CD4+ and CD8+ cells have been found to play a role in ovx-induced bone loss. CD4+ cells include the TH1, Th2, and Th17 subsets. Th17 are regarded as the most osteoclastogenic subset of T CD4+ cells because they produce high levels of IL-17, receptor activator of NF-κB ligand (RANKL), and TNF, and low levels of interferon gamma (IFNγ).27, 28 The differentiation of Th17 is inhibited by estrogen via a direct effect mediated by estrogen receptor alpha (ERα).29 The role of Th17 in ovx-induced bone loss remains to be determined because one study reported that IL-17R–null mice are more susceptible to ovx-induced bone loss than controls,30 while another group found these mice to be protected from ovx-induced bone loss.26 More abundant information is available about regulatory T cells (Tregs), a population capable of suppressing the effector function of TH1, Th2, and Th17 T cells. Tregs are defined by the expression of the transcription factor FoxP3. Tregs inhibit monocyte differentiation into osteoclasts in vitro and in vivo, and blunt bone resorption31, 32 through the secretion of IL-4, IL-10, and transforming growth factor beta 1 (TGFβ1).33 Attesting to the relevance of Tregs, studies have shown that estrogen increases the relative number of Tregs.27, 34 Moreover, transgenic mice overexpressing Tregs develop progressive high bone mass due to inhibition of bone resorption, and are protected against ovx-induced bone loss.35 Moreover, adoptive transfer of Tregs into T cell–deficient mice increases bone mass, indicating that Tregs directly affect bone homeostasis without the need to engage other T cell lineages.35 Two mechanisms have been described to explain how T cells contribute to ovx-induced bone loss (Fig. 1). The first involves an increase in T cell activation, leading to enhanced production of TNF by BM T cells. The second is a regulatory crosstalk between T cells and SCs, resulting in enhanced production of osteoclastogenic cytokines by SCs. Schematic representation of the role of T cells in the mechanism by which ovx promotes osteoclastogenesis, osteoblastogenesis, and hemopoiesis. Estrogen deficiency promotes T cell activation by increasing the interaction of antigen (Ag)-loaded MHC molecules with bone marrow macrophages (BMM) and dendritic cells (DC) with the T cell receptor (TCR). The Ags are likely to be non-self peptides derived from the intestinal macrobiota. T cell activation also requires at least two costimulatory signals provided by the binding of BMM and DC-expressed CD40 and CD80 to the T cell surface molecules CD40L and CD28, respectively. A critical upstream event is the increased production of reactive oxygen species (ROS) that activate DCs by increasing their expression of CD80. The expansion of T cells in the BM is partially driven by an ovx-induced increase in the thymic output of naïve T cells. Activated T cells secrete TNF that stimulates osteoclast formation primarily by potentiating the response to RANKL. In addition, T cell–expressed CD40L and DLK1/FA-1 increase the osteoclastogenic activity of SC by blunting their secretion of OPG and augmenting their production of RANKL, M-CSF, and other proinflammatory factors. The survival of naïve T cells and some memory T cells requires the low-affinity engagement of the T cell receptor (TCR) by a diverse repertoire of self-antigens (Ags) bound to major histocompatibility complex (MHC) molecules expressed on Ag-presenting cells.36, 37 By contrast, binding of foreign Ags such as bacterial Ags with MHC molecules is followed by high-affinity interactions with TCRs that drive T cell activation. Both low-affinity interactions with self-Ags and high-affinity foreign Ag/MHC/TCR interactions are referred to as “Ag presentation.” Ovx induces T cell expression of activation markers and promotes T cell proliferation, expansion, and acquisition of effector functions. These are all features of T cells exposed to foreign Ags.36 The gastrointestinal tract is colonized for life with 100 trillion indigenous bacteria, creating a diverse ecosystem known as the microbiota, whose contributions to human health are profound.38 The macrobiota is likely to represent the source of foreign Ag that drives the expansion of T cells induced by ovx. Although direct verification of a role for macrobiota in T cell expansion is still lacking, compelling supportive data are available. For example, adoptive transfer of T cells into T cell–deficient mice is followed by rapid engraftment and expansion of donor T cells into the host. This process is driven by foreign Ags.36 Attesting to a role of the macrobiota, the expansion of transferred T cells into T cell–deficient mice is greatly reduced in host mice raised in a germ-free environment.36 Moreover, mice maintained in germ-free conditions display increased bone mass due to the lack of immune cell activation.39 T cells are key inducers of bone-wasting because ovx increases T cell TNF production to a level sufficient to augment RANKL-induced osteoclastogenesis.1 This effect is due to an increased number of TNF-producing T cells15 and enhanced production of TNF per cell.18, 40 Ovx also increases the population of premature senescent CD4 + CD28–T cells,40 a lineage that produces high levels of TNF. The presence of increased levels of T cell–produced TNF in the BM of ovx animals is well documented.15, 19, 40, 41 Studies have also shown that menopause increases T cell activation and T cell production of TNF and RANKL in humans.42, 43 The role of TNF in ovx-induced bone loss has been demonstrated in multiple models. For example, ovx fails to induce bone loss in TNF-null mice and in animals lacking the p55 TNF receptor.15 Likewise, transgenic mice insensitive to TNF due to the overexpression of a soluble TNF receptor,44 and mice treated with the TNF inhibitor TNF binding protein45 are protected from ovx-induced bone loss. The specific relevance of T cell TNF production in vivo was demonstrated by the finding that although reconstitution of nude recipient mice with T cells from WT mice restores the capacity of ovx to induce bone loss, reconstitution with T cells from TNF-deficient mice does not.15 The mechanism by which estrogen deficiency expands the pool of TNF-producing T cells is summarized in Figure 1 and involves reactivation of thymic function and induction of T cell activation in the BM. T cell activation is driven by enhanced Ag presentation by macrophages and dendritic cells (DCs).46, 47 The thymus undergoes progressive structural and functional decline with age, coinciding with increased circulating sex-steroid levels at puberty.48 By middle age most parenchymal tissue is replaced by fat, and in both mice and humans fewer T cells are produced and exported to secondary lymphoid organs. However, the thymus continues to generate new T cells even into old age.49, 50 In fact, active lymphocytic thymic tissue has been documented in adults up to 107 years of age.51 Under severe T cell depletion secondary to human immunodeficiency virus (HIV) infection, chemotherapy, or bone marrow transplant, an increase in thymic output (known as thymic rebound) becomes critical for long-term restoration of T cell homeostasis. For example, middle-aged women treated with autologous bone marrow transplants develop thymic hypertrophy and a resurgence of thymic T cell output, which contributes to the restoration of a wide T cell repertoire,52 although the intensity of thymic rebound declines with age. The mechanism driving thymic rebound is not completely understood, but one factor involved is IL-7.53 Both androgens and estrogen suppress thymic function.54, 55 Accordingly, castration reverses thymic atrophy and increases export of recent thymic emigrants to the periphery,56 whereas sex steroids inhibit thymic regeneration by promoting thymocyte apoptosis and arresting thymocyte/prelymphocyte differentiation.57 Restoration of thymic function after castration occurs in young58 as well as in very old rodents.59, 60 In accordance with the notion that estrogen deficiency induces a rebound in thymic function, ovx increases the thymic export of naïve T cells.61 Indeed, stimulated thymic T cell output accounts for ∼50% of the increase in the number of T cells in the periphery. Moreover, thymectomy decreases the bone loss induced by ovx by ∼50%, thus demonstrating that the thymus plays a previously unrecognized role in the pathogenesis of ovx-induced bone loss in mice.61 The remaining bone loss is a consequence of the peripheral expansion of naïve and memory T cells. This finding suggests the tantalizing hypothesis that estrogen deficiency–induced thymic rebound may be responsible for the exaggerated bone loss in young women undergoing surgical menopause62 or for the rapid bone loss characteristic of women in their first 5 to 7 years after natural menopause.63 Indeed, an age-related decrease in estrogen deficiency–induced thymic rebound could mitigate the stimulatory effects of sex steroid deprivation and explain why the rate of bone loss in postmenopausal women diminishes as aging progresses.63 The most upstream effects of ovx in the BM are to stimulate the production of reactive oxygen species (ROS) and to impair the generation of antioxidants.10, 19, 64, 65 In response to ovx, ROS are produced by most BM cells, including T cells.41 ROS play an important role in postmenopausal bone loss by generating a more oxidized bone microenvironment.66, 67 Multiple enzymatic pathways regulate the intracellular redox state through modulation of ROS levels.68 Ovx blunts the BM levels of glutathione (GSH), a critical ROS scavenger, and reduces expression of APE1/Ref-1 and Prx-1 proteins, which collectively limit the production of intracellular ROS.69 ROS have important direct effects on osteoblasts and osteoclasts; these effects have been addressed elsewhere.7, 70, 71 However, additional pivotal effects of ROS include expanding the pool of mature DCs that express the costimulatory molecule CD80, and increasing DC-mediated Ag presentation.19 Antioxidants potently inhibit DC differentiation and their ability to activate T cells,72, 73 in part by suppressing expression of MHC class II and costimulatory molecules in response to Ag.74 N-acetyl-cysteine (NAC), which acts as an intracellular scavenger of ROS by restoring intracellular concentrations of GSM, can block DC maturation75 and DC-mediated T cell activation.76 In vivo support for a role of ROS is provided by experiments demonstrating that administration of antioxidants prevents ovx-induced bone loss,19, 64, 70 while depletion of glutathione by buthionine sulfoximine (BSO), which inhibits glutathione synthesis, enhances bone loss.64 Bone loss caused by BSO has significant similarities to bone loss induced by estrogen deficiency, as both processes are TNF-dependent.77 A second, direct upstream effect of estrogen deficiency is to blunt BM levels of TGFβ,78 a powerful repressor of T cell activation. TGFβ acts as an immunosuppressant by inhibiting T cell activation and T cell production of inflammatory cytokines, including IFNγ. Demonstrating the relevance of the repressive effects of TGFβ on T cell function, mice with T cell–specific blockade of TGFβ signaling were found to be completely resistant to the bone-sparing effects of estrogen.16 Gain of function experiments confirmed that elevation of the systemic levels of TGFβ prevents ovx-induced bone loss and bone turnover.16 The key downstream mechanism by which ovx increases Ag presentation by macrophages is a stimulatory effect on the expression of the gene encoding Class II Transactivator (CIITA). The product of CIITA is a non-DNA binding factor induced by IFNγ that functions as a transcriptional coactivator at the MHC II promoter.79 Increased CIITA expression in macrophages results from ovx-mediated increases in IFNγ production by CD4+ T cells and the responsiveness of CIITA to IFNγ.46 This cytokine was initially described as an anti-osteoclastogenic cytokine because it is a potent inhibitor of osteoclastogenesis in vitro.80 The notion that IFNγ is an inhibitor of bone resorption was reinforced by the finding that silencing of IFNγR−/− signaling leads to a more rapid onset of collagen-induced arthritis and bone resorption81 as compared to WT controls, and by the report that IFNγ decreases serum calcium and osteoclastic bone resorption in nude mice.82, 83 Several mechanisms have been proposed to explain the anti-osteoclastogenic activity of IFNγ, including inhibition of RANKL signaling through the degradation of TNF receptor–associated factor 6 (TRAF6),80 stimulation of apoptosis mediated by Fas/FasL signals,84 and inhibition of RANK and c-Fms gene expression.85 However, the finding that IFNγ is an effective treatment for osteopetrosis both in humans86 and rodents87 demonstrates that the net effect of IFNγ in vivo is to stimulate osteoclastic bone resorption. In keeping with a net pro-resorptive effect of IFNγ in vivo are reports demonstrating that IFNγ−/− and IFNγR−/− mice are protected against ovx-induced bone loss.17, 46 Mice lacking IFNγ production are also protected against infection-induced alveolar bone loss,88 whereas in erosive tuberculoid leprosy and psoriatic arthritis IFNγ production correlates positively with tissue destruction.89 In addition, randomized controlled trials have shown that IFNγ does not prevent bone loss in patients with rheumatoid arthritis (RA),90 nor the bone-wasting effect of cyclosporine A.91 Finally, disruption of IFNγ signaling in vivo results in a strong and sustained inhibition of markers of osteoclastic activity.92 These opposing in vitro and in vivo effects of IFNγ are explained by the fact that IFNγ influences osteoclast formation via both direct and indirect effects.17 IFNγ directly blocks osteoclast formation through targeting of maturing osteoclast.93 However, IFNγ is also a potent inducer of antigen presentation and thus of T cell activation. Therefore, when IFNγ levels are increased in vivo, activated T cells secrete pro-osteoclastogenic factors and this activity offsets the anti-osteoclastogenic effects of IFNγ.17 It should also be mentioned that it is now recognized that IFNγ affects bone turnover by promoting the commitment of BM–SCs into the osteoblastic lineage and their differentiation into mature osteoblasts.94 Accordingly, treatment with IFNγ reverses ovx-induced bone loss by promoting bone formation.92 Another mechanism by which estrogen regulates T cell TNF production is by repressing the production of IL-7, a potent lymphopoietic cytokine and an inducer of bone destruction in vivo.95 Attesting to the relevance of this factor, IL-7 levels are significantly elevated following ovx,61, 96 and in vivo IL-7 blockade is effective in preventing ovx-induced bone destruction.96 The elevated BM levels of IL-7 contribute to the expansion of the T cell population in peripheral lymphoid organs through several mechanisms. First, IL-7 directly stimulates T cell proliferation.61 Second, IL-7 increases antigen presentation by upregulating the production of IFNγ. Third, IL-7 and TGFβ inversely regulate each other's production.97, 98 The reduction in TGFβ signaling characteristic of estrogen deficiency may serve to further stimulate IL-7 production, thus driving the cycle of osteoclastogenic cytokine production and bone wasting. In estrogen deficiency, IL-7 compounds bone loss by suppressing bone formation and thus uncoupling bone formation from resorption. A clue that the crosstalk between T cells and SCs is relevant for ovx-induced bone loss was provided by the finding that activated T cells induce SC apoptosis via the Fas/Fas ligand pathway, a phenomenon which blunts the compensatory increase in bone formation that limits bone loss in ovx mice.22 More abundant information is available about the T cell/SC crosstalk driven by the CD40L/CD40 system. CD40L, also known as CD154, is a key surface ligand expressed on T cells.99 CD40L binds to CD40100 and several integrins.101, 102 CD40 is expressed on antigen-presenting cells, hemopoietic progenitors, and cells of the osteoblastic lineage.103 CD40L has been linked to postnatal skeletal maturation because T cells, through the CD40L/CD40 system, promote production of the anti-osteoclastogenic factor osteoprotegerin (OPG) by B cells.104 Consequently, CD40L-deficient mice attain a reduced peak bone volume due to exaggerated bone resorption.104 Low bone density has also been found in children affected by X-linked hyper–immunoglobulin M (IgM) syndrome, a condition in which CD40L production is impaired due to a mutation in the CD40L gene.105 However, mice lacking T cell–expressed CD40L are protected against parathyroid hormone (PTH)-induced bone loss,106 raising the possibility that CD40L may exert antiresorptive activities in unstimulated conditions, while promoting bone resorption under conditions of bone stress. Studies with CD40L-null mice and with WT mice treated with the anti CD40L Ab MR-1 have revealed that silencing of CD40L completely prevents ovx-induced bone loss.18 A dual mechanism was shown to be involved. First, silencing of CD40L blocks the activation of T cells and the resulting production of TNF. Second, CD40L is required for ovx to increase the proliferation and the differentiation of SCs and their capacity to support osteoclast formation through enhanced production of macrophage colony-stimulating factor (M-CSF) and RANKL, and diminished secretion of OPG. Thus, a critical additional mechanism by which T cells dysregulate bone homeostasis in ovx mice is through a CD40L-mediated crosstalk between T cells and SCs that results in enhanced osteoclastogenesis and, to a lesser degree, enhanced osteoblastogenesis. In summary, ovx increases the number of activated CD40L-expressing T cells that promote the expression of M-CSF and RANKL by SCs, and ovx downregulates the SC production of OPG. The net result is a significant increase in the rate of osteoclastogenesis. The interaction of CD40L with CD40 on SCs in the context of estrogen deficiency appears to override the protective effects of CD40/CD40L costimulation on basal B cell OPG production,104 distorting the balance of osteoclast formation in favor of bone loss. An additional mechanism of T cells/SC crosstalk involving the novel regulator of bone mass delta-like 1/fetal antigen 1(DLK1/FA-1)107, 108 has recently been described.109 DLK1 encodes for a membrane-bound protein known as DLK1. This factor can be cleaved to generate a soluble protein known as FA-1. In physiologic conditions DLK1/FA-1 are produced by SCs, B cells, and T cells. These factors stimulate osteoclastogenesis and block osteoblastogenesis by inducing the production of TNF, IL-7, and other inflammatory cytokines by SCs. Ovx markedly increases the production of DLK1/FA-1 by activated CD4+ and CD8+ T cells, resulting in a further stimulation of the production of osteoclastogenic cytokines by SCs. Attesting to the relevance of DLK1/FA-1, DLK1 null mice are significantly protected against ovx-induced bone loss.109 The hypothesis that the immune system is pivotal for the bone loss brought about by menopause remains to be demonstrated in humans. Meanwhile, it remains interesting to entertain the question of why the immune system in mice, and possibly women, is involved in the mechanism of ovx-induced bone loss. Clues may emerge by regarding postmenopausal bone loss as an unintended recapitulation of an event critical for reproduction, namely the need to stimulate bone resorption in the immediate postpartum period. This process is essential to meeting the markedly increased maternal demand for calcium brought about by lactation. The signal for this event is the acute drop in estrogen levels immediately postpartum. A second adaptation to the postpartum period is changes in breast physiology associated with lactation. Pregnancy is characterized by massive proliferation of the mammary epithelium and formation of lobulo-alveolar structures. These changes are orchestrated by progesterone and prolactin. There is now ample evidence that progesterone regulates breast development and breast adaptation to pregnancy by modulating the local production of RANKL and RANK.110-112 Thus, a system that is absolutely required for bone homeostasis is also a key regulator of lactation.112 The precipitous drop in progesterone levels in the postpartum period results in reduced breast tissue levels of RANK and RANKL, with the effect of finalizing the breasts for lactation. The concomitant increase in the RANKL/OPG ratio and TNF levels in the BM induced by declining estrogen levels accomplishes the goal of transferring calcium from the maternal skeleton to the breast milk, and then to the newborn. During pregnancy, a state of maternal tolerance to the fetus is induced by an estrogen-driven increase in the number of Tregs.113 A third adaptation to the end of pregnancy is the loss of such immune tolerance and the restoration of a normal immune reactivity. This goal is achieved through a decrease in the Treg population, resulting from the acute drop in placental steroid levels. However, a link between immune tolerance to the fetus and bone is provided by the observation that OPG is expressed by human gestational membranes.114 Thus, it is tempting to speculate that cessation of ovarian function induces bone loss through an adaptive immune response because natural selection has integrated these three key adaptations within the immune system to fulfill postpartum requirements (Fig. 2). Schematic representation of events taking place in the immediate postpartum period and of the involved cells and cytokines. The figure shows that estrogen and progesterone withdrawal are followed by a stimulation of bone resorption, breast adaptation to lactation, and termination of immune tolerance to the fetus. Activated T cells drive bone resorption by secreting TNF. A decrease in the number of Tregs induces the termination of the immune tolerance developed during pregnancy. The loss of placental OPG may contribute to the tolerance reversal and the increased bone resorption. A decrease in breast levels of RANKL and RANK induce the terminal preparation of the breast for lactation. Together with increased released of calcium from the skeleton, the morphological changes in the breast contribute to successful lactation, an event critical for reproduction. The data suggest the untested hypothesis that cessation of ovarian function induces bone loss through an adaptive immune response because natural selection has centralized key adaptations within the immune system to fulfill postpartum requirements. The data reviewed above strongly support the hypothesis that the bone loss induced by estrogen deficiency is due to a complex interplay of hormones and cytokines that converge to disrupt the process of bone remodeling. Ovx upregulates T cell TNF production by increasing T cell activity in the BM, thymus, and the peripheral lymphoid organs. T cell precursors leave the BM and migrate to the thymus, where T cell differentiation, selection, and expansion take place, in large measure under the control of IL-7. Following release from the thymus, these new T cells home to peripheral lymphoid organs, including the BM itself. Ovx induces T cell activation in the BM in part by directly promoting antigen presentation, and in part via stimulation of IL-7 and IFNγ production and downregulation of TGFβ production. The net result of these actions is an increase in the number of TNF-producing T cells. The elevated levels of TNF increase RANKL-induced osteoclast formation. Estrogen deficiency also amplifies T cell activation and osteoclastogenesis by downregulating antioxidant pathways, leading to an upswing in ROS. The combined effect of IFNγ and ROS markedly enhances Ag presentation, amplifying T cell activation. T cells further stimulate RANKL and M-CSF production by SCs, through CD40L and DLK1/FA-1. The author states that he has no conflicts of interest." @default.
• W2054757511 created "2016-06-24" @default.
• W2054757511 creator A5077283095 @default.
• W2054757511 date "2012-01-23" @default.
• W2054757511 modified "2023-10-10" @default.
• W2054757511 title "Role of T cells in ovariectomy induced bone loss-revisited" @default.
• W2054757511 cites W1527213249 @default.
• W2054757511 cites W1639854378 @default.
• W2054757511 cites W1666294246 @default.
• W2054757511 cites W1963138732 @default.
• W2054757511 cites W1964077677 @default.
• W2054757511 cites W1965566942 @default.
• W2054757511 cites W1965921683 @default.
• W2054757511 cites W1966432380 @default.
• W2054757511 cites W1968078709 @default.
• W2054757511 cites W1970078194 @default.
• W2054757511 cites W1974220279 @default.
• W2054757511 cites W1976267670 @default.
• W2054757511 cites W1983738273 @default.
• W2054757511 cites W1984387425 @default.
• W2054757511 cites W1984821835 @default.
• W2054757511 cites W1986712404 @default.
• W2054757511 cites W1986714785 @default.
• W2054757511 cites W1987373756 @default.
• W2054757511 cites W1989048614 @default.
• W2054757511 cites W1989372485 @default.
• W2054757511 cites W1989601297 @default.
• W2054757511 cites W1991163950 @default.
• W2054757511 cites W1992418528 @default.
• W2054757511 cites W1994058707 @default.
• W2054757511 cites W1997722036 @default.
• W2054757511 cites W2001009931 @default.
• W2054757511 cites W2003524040 @default.
• W2054757511 cites W2003762301 @default.
• W2054757511 cites W2006045837 @default.
• W2054757511 cites W2007703889 @default.
• W2054757511 cites W2009170813 @default.
• W2054757511 cites W2013632991 @default.
• W2054757511 cites W2015686826 @default.
• W2054757511 cites W2016511163 @default.
• W2054757511 cites W2017335158 @default.
• W2054757511 cites W2018020394 @default.
• W2054757511 cites W2020049891 @default.
• W2054757511 cites W2024609097 @default.
• W2054757511 cites W2024932182 @default.
• W2054757511 cites W2026729290 @default.
• W2054757511 cites W2032449149 @default.
• W2054757511 cites W2037333519 @default.
• W2054757511 cites W2041672277 @default.
• W2054757511 cites W2044147730 @default.
• W2054757511 cites W2051320963 @default.
• W2054757511 cites W2053516334 @default.
• W2054757511 cites W2054540030 @default.
• W2054757511 cites W2057400917 @default.
• W2054757511 cites W2058146698 @default.
• W2054757511 cites W2062028959 @default.
• W2054757511 cites W2064282853 @default.
• W2054757511 cites W2064797437 @default.
• W2054757511 cites W2068408311 @default.
• W2054757511 cites W2074080709 @default.
• W2054757511 cites W2074187899 @default.
• W2054757511 cites W2075786281 @default.
• W2054757511 cites W2077208664 @default.
• W2054757511 cites W2077305316 @default.
• W2054757511 cites W2078659852 @default.
• W2054757511 cites W2079059381 @default.
• W2054757511 cites W2079431443 @default.
• W2054757511 cites W2081243825 @default.
• W2054757511 cites W2081379880 @default.
• W2054757511 cites W2082709457 @default.
• W2054757511 cites W2087726670 @default.
• W2054757511 cites W2088864696 @default.
• W2054757511 cites W2092099741 @default.
• W2054757511 cites W2092505499 @default.
• W2054757511 cites W2094911966 @default.
• W2054757511 cites W2096234941 @default.
• W2054757511 cites W2096584806 @default.
• W2054757511 cites W2097642599 @default.
• W2054757511 cites W2101051981 @default.
• W2054757511 cites W2102041100 @default.
• W2054757511 cites W2102477325 @default.
• W2054757511 cites W2103333716 @default.
• W2054757511 cites W2104879998 @default.
• W2054757511 cites W2108463345 @default.
• W2054757511 cites W2109044040 @default.
• W2054757511 cites W2110289042 @default.
• W2054757511 cites W2114319533 @default.
• W2054757511 cites W2114982159 @default.
• W2054757511 cites W2117025246 @default.
• W2054757511 cites W2119049249 @default.
• W2054757511 cites W2122724238 @default.
• W2054757511 cites W2123434358 @default.
• W2054757511 cites W2131958114 @default.
• W2054757511 cites W2132932119 @default.
• W2054757511 cites W2133281510 @default.
• W2054757511 cites W2135202875 @default.
• W2054757511 cites W2137512902 @default.
• W2054757511 cites W2153101639 @default.

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