Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand

Kong, Young‐Yun; Feige, Ulrich; Sarosi, Iidiko; Bolon, Brad; Tafuri, Agostino; Morony, Sean; Capparelli, Casey; Li, Ji; Elliott, Robin; McCabe, Susan; Wong, Teng-fong; Campagnuolo, Giuseppe; Moran, Erika; Bogoch, Earl R.; Van, Gwyneth; Nguyen, Linh T.; Ohashi, Pamela S.; Lacey, David L.; Fish, Eleanor N.; Boyle, William J.; Penninger, Josef

doi:10.1038/46303

Cited by 1,683 publications

(1,133 citation statements)

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“…The finding of increased T cell activation and proliferation in mice with T cell-specific blockade of TGF␤ signaling is consistent with both the augmented Ag presentation observed in these transgenic mice and the direct repressive action of TGF␤ on T cell proliferation and differentiation. An expected consequence of increased T cell activation is increased production of osteoclastogenic cytokines (12,32,33). Measurements by ELISA of cytokine levels in 72-h culture media revealed that T cells derived from CD4dnTGF␤IIR mice produce significantly higher levels of TNF (Fig.…”

Section: Tgf␤ Represses T Cell Activation and Proliferation In E-replmentioning

confidence: 99%

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

Gao

Qian²,

Dark³

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

159

144

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Estrogen (E) deficiency leads to an expansion of the pool of tumor necrosis factor (TNF)-producing T cells through an IFN-␥-dependent pathway that results in increased levels of the osteoclastogenic cytokine TNF in the bone marrow. Disregulated IFN-␥ 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 ␤ transforming growth factor (TGF␤) signaling are completely insensitive to the bone-sparing effect of E. This phenotype results from a failure of E to repress IFN-␥ production, which, in turn, leads to increased T cell activation and T cell TNF production. Furthermore, ovx blunts TGF␤ levels in the bone marrow, and overexpression of TGF␤ in vivo prevents ovx-induced bone loss. These findings demonstrate that E prevents bone loss through a TGF␤-dependent mechanism, and that TGF␤ signaling in T cells preserves bone homeostasis by blunting T cell activation. Thus, stimulation of TGF␤ production in the bone marrow is a critical ''upstream'' mechanism by which E prevents bone loss, and enhancement of TGF␤ levels in vivo may constitute a previously undescribed therapeutic approach for preventing bone loss.A lthough multiple genotropic and nongenotropic effects contribute to explain how estrogen (E) controls bone remodeling (1, 2), most of the bone-sparing activity exerted by E occurs through modulation of bone cell life span and decreased cytokine-driven osteoclastogenesis (3, 4). Among the factors that up-regulate osteoclast (OC) formation and lead to bone loss in estroprevic humans and rodents is tumor necrosis factor (TNF) ␣ (5). This E-regulated cytokine promotes osteoclastogenesis by augmenting the production of receptor activator of nuclear factor-B ligand (RANKL) (1), the nonredundant cytokine responsible for OC development (6) and by increasing the responsiveness of maturing OCs to this factor (7-9). Furthermore, TNF stimulates the production of other cytokines known to be implicated in the pathogenesis of ovariectomy (ovx)-induced bone loss, such as IL-1, IL-6, IL-7, and macrophage colony-stimulated factor (1, 10).ovx increases TNF levels in the bone marrow (BM) via an expansion of the pool of TNF-producing T cells (7, 11) induced by a complex mechanism driven by IFN-␥ (12). This cytokine augments antigen (Ag) presentation by enhancing MHCII expression on BM macrophages (BMMs), through induction of class II transactivator (CIITA) expression (13). Up-regulation of Ag presentation results, in turn, in increased T cell activation. Thus, upregulation of IFN-␥ production induced by ovx leads to increased T cell proliferation and life span, a phenomenon that results in an increase in both the total number of T cells and the pool of TNF-producing T cells (12). T cell-produced TNF plays a pivotal role in the mechanism of ovx-induced bone loss, as demonstrated by the failure of ovx to induce bone loss in T cell-deficient nude mice and by the ability to reconstitute with WT T cells, but not TNFϪ͞Ϫ ...

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Section: Tgf␤ Represses T Cell Activation and Proliferation In E-replmentioning

confidence: 99%

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

Gao

Qian²,

Dark³

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

159

144

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“…Additionally, although cytokines that contribute to osteoclast differentiation during inflammation, such as TNF␣ and interleukin 1, can activate NF-B and AP-1 (13,14) in osteoclast precursor cells, RANK and RANKL remain essential for osteoclastogenesis in vivo. For instance, administering osteoprotegerin to rats with adjuvant-induced arthritis abrogates osteoclastogenesis and subsequent bone loss without inhibiting inflammation (15). Furthermore, bone erosion induced by overexpression of TNF␣ in transgenic mice can be alleviated by administering RANK-Fc or by crossing TNF␣ transgenic mice into a RANK-null background (16).…”

mentioning

confidence: 97%

Osteoclast Differentiation Is Impaired in the Absence of Inhibitor of κB Kinase α

Chaisson

Branstetter

Derry

et al. 2004

Journal of Biological Chemistry

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Signaling through the receptor activator of nuclear factor B (RANK) is required for both osteoclast differentiation and mammary gland development, yet the extent to which RANK utilizes similar signaling pathways in these tissues remains unclear. Mice expressing a kinase-inactive form of the inhibitor of B kinase ␣ (IKK␣) have mammary gland defects similar to those of RANKnull mice yet have apparently normal osteoclast function. Because mice that completely lack IKK␣ have severe skin and skeletal defects that are not associated with IKK␣-kinase activity, we wished to directly examine osteoclastogenesis in IKK␣ ؊/؊ mice. We found that unlike RANK-null mice, which completely lack osteoclasts, IKK␣ ؊/؊ mice did possess normal numbers of TRAP ؉ osteoclasts. However, only 32% of these cells were multinucleated compared with 57% in wild-type littermates. A more profound defect in osteoclastogenesis was observed in vitro using IKK␣ ؊/؊ hematopoietic cells treated with colony-stimulating factor 1 and RANK ligand (RANKL), as the cells failed to form large, multinucleated osteoclasts. Additionally, overall RANKL-induced global gene expression was significantly blunted in IKK␣ ؊/؊ cells, including osteoclastspecific genes such as TRAP, MMP-9, and c-Src. IKK␣ was not required for RANKL-mediated I B␣ degradation or phosphorylation of mitogen-activated protein kinases but was required for RANKL-induced p100 processing. Treatment of IKK␣ ؊/؊ cells with tumor necrosis factor ␣ (TNF␣) in combination with RANKL led to partial rescue of osteoclastogenesis despite a lack of p100 processing. However, the ability of TNF␣ alone or in combination with transforming growth factor ␤ to induce osteoclast differentiation was dependent on IKK␣, suggesting that synergy between RANKL and TNF␣ can overcome p100 processing defects in IKK␣ ؊/؊ cells.Skeletal mass homeostasis is maintained by the coupled activities of bone-building osteoblasts and bone-resorbing osteoclasts. Dysregulation of osteoclast differentiation or function underlies many diseases affecting the skeletal system, including osteoporosis, joint inflammation, tumor metastasis to bone, and Paget disease (1). Osteoclasts are highly specialized multinucleated cells that differentiate from monocyte/macrophage lineage hematopoietic precursors. The key factors regulating osteoclastogenesis are the TNF 1 receptor family member RANK, its ligand (RANKL), and the RANKL inhibitor, osteoprotegerin. Ablation of RANK or RANKL in mice results in a complete absence of osteoclasts and severe osteopetrosis, whereas lack of osteoprotegerin leads to excessive osteoclast activity and osteoporosis (2-5).Genetic studies in mice, as well as in vitro culture of osteoclasts using CSF-1 and RANKL, have elucidated many key components of RANK signaling during osteoclastogenesis. Binding of RANKL to RANK stimulates recruitment of TRAF2, -5, and -6 (6) followed by activation of mitogenactivated protein kinases and I B kinases, which ultimately lead to activation of the transcription factors AP-1 and NF-B. Osteo...

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“…M-CSF and RANK ligand (RANKL) have been shown to be critical factors for the differentiation of OCL, which are physiologically produced by stromal cells and osteoblasts (Lacey et al, 1998). Kong et al (1999) identified abnormal expression of RANKL on activated T lymphocytes and postulated that this gene is associated with bone loss and joint destruction in inflammatory arthritis. Among the genes associated with hypercalcemia, increased expression of the RANKL gene correlated with hypercalcemia in ATL.…”

Section: Rank Ligandmentioning

confidence: 99%

Human T-cell leukemia virus type I and adult T-cell leukemia

2003

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Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand

Cited by 1,683 publications

References 22 publications

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

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

Osteoclast Differentiation Is Impaired in the Absence of Inhibitor of κB Kinase α

Human T-cell leukemia virus type I and adult T-cell leukemia

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