T Cell Activation Induces Human Osteoclast Formation via Receptor Activator of Nuclear Factor κB Ligand-Dependent and -Independent Mechanisms

Weitzmann, M. Neale; Cenci, Simone; Rifas, Leonard; Haug, Jeffrey S.; DiPersio, John F.; Pacifici, Roberto

doi:10.1359/jbmr.2001.16.2.328

Cited by 150 publications

(113 citation statements)

References 31 publications

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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: 94%

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.

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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: 94%

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.

Self Cite

159

144

View full text Add to dashboard Cite

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“…First-strand cDNA was synthesized from total RNA with oligo(dT) [12][13][14][15][16][17][18] primer and Revertra Ace (Toyobo) and subjected to PCR amplification with Ex Taq polymerase (Takara). The specific primer pairs and temperature conditions were as follows: for mouse RANKL cDNA amplification, forward: 5Ј-CGCTC TGTTCCTGTACTTTCGAGCG-3Ј/reverse: 5Ј-TCGTGCTCCCTCCTTT CATCAGGTT-3; denaturation at 94°C for 2 min followed by 32 …”

Section: Rt-pcr Analysismentioning

confidence: 99%

“…Osteoblasts and T cells express not only metalloproteinases but also tissue inhibitor of metalloproteinases (TIMPs) (9 -11). Osteoblasts in culture hardly release RANKL, but activated T cells in culture release a large amount of RANKL in a soluble form (6,12). Therefore, the soluble RANKL produced by activated T cells is believed to be involved in bone resorption induced by inflammation (13,14).…”

mentioning

confidence: 99%

Osteoprotegerin Reduces the Serum Level of Receptor Activator of NF-κB Ligand Derived from Osteoblasts

Nakamichi

Udagawa

Kobayashi

et al. 2007

The Journal of Immunology

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Osteoprotegerin (OPG) is a decoy receptor for receptor activator of NF-κB ligand (RANKL). We previously reported that OPG deficiency elevated the circulating level of RANKL in mice. Using OPG−/− mice, we investigated whether OPG is involved in the shedding of RANKL by cells expressing RANKL. Osteoblasts and activated T cells in culture released a large amount of RANKL in the absence of OPG. OPG or a soluble form of receptor activator of NF-κB (the receptor of RANKL) suppressed the release of RANKL from those cells. OPG- and T cell-double-deficient mice showed an elevated serum RANKL level equivalent to that of OPG−/− mice, indicating that circulating RANKL is mainly derived from bone. The serum level of RANKL in OPG−/− mice was increased by ovariectomy or administration of 1α,25-dihydroxyvitamin D3. Expression of RANKL mRNA in bone, but not thymus or spleen, was increased in wild-type and OPG−/− mice by 1α,25-dihydroxyvitamin D3. These results suggest that OPG suppresses the shedding of RANKL from osteoblasts and that the serum RANKL in OPG−/− mice exactly reflects the state of bone resorption.

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“…The OVX mice were then treated with OP3-4 for 28 days at a dosage of 2 mg/kg/day, which is less than the optimal dose (6 mg/kg/day) based on IC 50 . In vitro, OP3-4 actively inhibited osteoclast formation at low concentration 2 M (0.015 mg/ml).…”

Section: Op3-4 Protects Mice Against Ovariectomy-associated Bone Lossmentioning

confidence: 99%

Disabling of Receptor Activator of Nuclear Factor-κB (RANK) Receptor Complex by Novel Osteoprotegerin-like Peptidomimetics Restores Bone Loss in Vivo

Cheng

Kinosaki

Miki

et al. 2004

Journal of Biological Chemistry

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The tumor necrosis factor family ligand, tumor necrosis factor-related activation-induced cytokine (TRANCE), and its receptors, receptor activator of nuclear factor-B (RANK) and osteoprotegerin (OPG), are known to be regulators of development and activation of osteoclasts in bone remodeling. Sustained osteoclast activation that occurs through TRANCE-RANK causes osteopenic disorders such as osteoporosis and contributes to osteolytic metastases. Here, we report a rationally designed small molecule mimic of osteoprotegerin to inhibit osteoclast formation in vitro and limit bone loss in an animal model of osteoporosis. One of the mimetics, OP3-4, significantly inhibited osteoclast formation in vitro (IC 50 ‫؍‬ 10 M) and effectively inhibited total bone loss in ovariectomized mice at a dosage of 2 mg/kg/day. Unlike soluble OPG receptors, which preclude TRANCE binding to RANK, OP3-4 shows the ability to modulate RANK-TRANCE signaling pathways and alters the biological functions of the RANK-TRANCE receptor complex by facilitating a defective receptor complex. These features suggest that OPG-derived small molecules can be used as a probe to understand complex biological functions of RANK-TRANCE-OPG receptors and also can be used as a platform to develop more useful therapeutic agents for inflammation and bone disease. TRANCE,1 a TNF family member, also known as OPGL, RANKL, ODF, and OCIF, plays a key role in the development of osteoclasts and in modulating their bone resorbing activity (1-4). Increased osteoclast activity has been reported in many osteopenic disorders, including postmenopausal osteoporosis, Paget's disease, bone metastases, and rheumatoid arthritis (5-7). TRANCE interacts with two receptors: a secreted decoy receptor osteoprotegerin, OPG (8), and a transmembrane receptor, RANK (9 -11). The interaction between TRANCE and RANK is essential for osteoclastogenesis because RANK is activated by TRANCE and then associates with TNF receptorassociated family members to trigger downstream signaling (11) events. OPG, on the other hand, plays an opposite role by preventing TRANCE from binding and activating RANK and thus is considered a "decoy" receptor. In this way, the interaction between TRANCE and OPG or TRANCE and RANK represents a complex network required for normal bone development, and any imbalance in the system potentially leads to bone disorders. Thus it is well recognized that this receptor complex network is an interesting drug development target for the treatment of bone disorders such as osteoporosis (12), and there is considerable interest in developing ways to modulate RANK functions which may prove beneficial for bone-related pathologies.To date there is no three-dimensional structural information available for the RANK receptor complex. However, it is believed that the complex should resemble that of the TNF receptor as a member of TNF superfamily. The TNF-␤⅐TNFR1 co-crystal structure has been solved, thus facilitating rational drug design based on the receptor-ligand interaction sites coupled wi...

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T Cell Activation Induces Human Osteoclast Formation via Receptor Activator of Nuclear Factor κB Ligand-Dependent and -Independent Mechanisms

Cited by 150 publications

References 31 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

Osteoprotegerin Reduces the Serum Level of Receptor Activator of NF-κB Ligand Derived from Osteoblasts

Disabling of Receptor Activator of Nuclear Factor-κB (RANK) Receptor Complex by Novel Osteoprotegerin-like Peptidomimetics Restores Bone Loss in Vivo

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