TNFSF14

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Bente Halvorsen - One of the best experts on this subject based on the ideXlab platform.

Giacomina Brunetti - One of the best experts on this subject based on the ideXlab platform.

  • LIGHT/TNFSF14 affects basal bone remodeling
    Italian journal of anatomy and embryology, 2020
    Co-Authors: Giacomina Brunetti, Graziana Colaianni, Isabella Gigante, Angela Oranger, Paolo Pignataro, Adriana Di Benedetto, Mariasevera Di Comite, Roberto Tamma, Luciana Lippo, Giorgio Mori
    Abstract:

    LIGHT (TNFSF14), expressed by different cells of the immune system, binds two trans-membrane receptors: HVEM and LTβR. It is over-expressed in erosive rheumatoid arthritis and lytic myeloma-bone disease and controversial data have been published on its role in osteoclast (OC) formation in vitro. Here, we investigated the role of LIGHT on in vitro murine osteoclastogenesis model and bone phenotype in LIGHT-/- mice. Firstly, we showed that murine macrophages stimulated with LIGHT alone did not differentiate into OCs. Interestingly, the presence of LIGHT and sub-optimal RANKL concentration displayed synergic effects on OC formation through the early and sustained activation of Akt, NFκB and JNK pathways. Secondly, by microCT we found that the femurs of LIGHT-KO mice exhibited a 30% (p

  • light TNFSF14 promotes osteolytic bone metastases in non small cell lung cancer patients
    Journal of Bone and Mineral Research, 2020
    Co-Authors: Giacomina Brunetti, Maria Felicia Faienza, Graziana Colaianni, Sara Bortolotti, Giuseppina Storlino, Dimas Carolina Belisario, Lorenzo Sanesi, Valentina Alliod, Lucio Buffoni, Elisa Centini
    Abstract:

    : Tumor necrosis factor superfamily member 14 (TNFSF14), LIGHT, is a component of the cytokine network that regulates innate and adaptive immune responses, which promote homeostasis of lymphoid organs, liver, and bone. Metastatic tumors often disrupt the tissue microenvironment, thus altering the homeostasis of the invaded organ; however, the underlying mechanisms required further studies. We investigated the role of LIGHT in osteolytic bone disease induced by metastatic non-small cell lung cancer (NSCLC). Patients diagnosed with NSCLC bone metastasis show significantly higher levels of LIGHT expressed in monocytes compared with non-bone metastatic tumors and healthy controls. Serum LIGHT levels were also higher in patients with bone metastases than in controls, suggesting a role for LIGHT in stimulating osteoclast precursors. In bone metastatic patients, we also detected increased RNA expression and serum RANKL levels, thus by adding anti-LIGHT or RANK-Fc in PBMC cultures, a significant inhibition of osteoclastogenesis was observed. To model in mice this observation, we used the mouse lung cancer cell line LLC-1. After intratibial implantation, wild-type mice showed an increased number of osteoclasts but reduced numbers of osteoblasts and decreased osteoid formation. In contrast, TNFSF14-/- mice showed no significant bone loss or other changes in bone homeostasis associated with this model. These data indicate LIGHT as a key control mechanism for regulating bone homeostasis during metastatic invasion. Thus, LIGHT may be a novel therapeutic target in osteolytic bone metastases. This article is protected by copyright. All rights reserved.

  • LIGHT/TNFSF14 regulates estrogen deficiency-induced bone loss.
    The Journal of Pathology, 2020
    Co-Authors: Giacomina Brunetti, Maria Felicia Faienza, Graziana Colaianni, Angela Oranger, Giuseppe Ingravallo, Mariasevera Di Comite, Giuseppina Storlino, Janne E Reseland, Monica Celi, Umberto Tarantino
    Abstract:

    : Bone loss induced by ovariectomy is due to the direct activity on bone cells and mesenchymal cells and to the dysregulated activity of bone marrow cells, including immune cells and stromal cells, but the underlying mechanisms are not completely known. Here, we demonstrate that ovariectomy induces the T-cell co-stimulatory cytokine LIGHT, which stimulates both osteoblastogenesis and osteoclastogenesis by modulating osteoclastogenic cytokine expression, including TNF, osteoprotegerin, and the receptor activator of nuclear factor-κB ligand (RANKL). Predictably, LIGHT-deficient (TNFSF14-/- ) mice are protected from ovariectomy-dependent bone loss, whereas trabecular bone mass increases in mice deficient in both LIGHT and T and B lymphocytes (Rag -/- TNFSF14 -/- ) and is associated with an inversion of the TNF and RANKL/OPG ratio. Furthermore, women with postmenopausal osteoporosis display high levels of LIGHT in circulating T cells and monocytes. Taken together, these results indicate that LIGHT mediates bone loss induced by ovariectomy, suggesting that patients with postmenopausal osteoporosis may benefit from LIGHT antagonism. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  • light TNFSF14 regulates estrogen deficiency induced bone loss
    The Journal of Pathology, 2020
    Co-Authors: Giacomina Brunetti, Maria Felicia Faienza, Graziana Colaianni, Angela Oranger, Giuseppe Ingravallo, Mariasevera Di Comite, Giuseppina Storlino, Janne E Reseland, Monica Celi, Umberto Tarantino
    Abstract:

    : Bone loss induced by ovariectomy is due to the direct activity on bone cells and mesenchymal cells and to the dysregulated activity of bone marrow cells, including immune cells and stromal cells, but the underlying mechanisms are not completely known. Here, we demonstrate that ovariectomy induces the T-cell co-stimulatory cytokine LIGHT, which stimulates both osteoblastogenesis and osteoclastogenesis by modulating osteoclastogenic cytokine expression, including TNF, osteoprotegerin, and the receptor activator of nuclear factor-κB ligand (RANKL). Predictably, LIGHT-deficient (TNFSF14-/- ) mice are protected from ovariectomy-dependent bone loss, whereas trabecular bone mass increases in mice deficient in both LIGHT and T and B lymphocytes (Rag -/- TNFSF14 -/- ) and is associated with an inversion of the TNF and RANKL/OPG ratio. Furthermore, women with postmenopausal osteoporosis display high levels of LIGHT in circulating T cells and monocytes. Taken together, these results indicate that LIGHT mediates bone loss induced by ovariectomy, suggesting that patients with postmenopausal osteoporosis may benefit from LIGHT antagonism. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  • LIGHT/TNFSF14 Promotes Osteolytic Bone Metastases in Non‐small Cell Lung Cancer Patients
    Journal of Bone and Mineral Research, 2020
    Co-Authors: Giacomina Brunetti, Maria Felicia Faienza, Graziana Colaianni, Sara Bortolotti, Giuseppina Storlino, Dimas Carolina Belisario, Lorenzo Sanesi, Valentina Alliod, Lucio Buffoni, Elisa Centini
    Abstract:

    : Tumor necrosis factor superfamily member 14 (TNFSF14), LIGHT, is a component of the cytokine network that regulates innate and adaptive immune responses, which promote homeostasis of lymphoid organs, liver, and bone. Metastatic tumors often disrupt the tissue microenvironment, thus altering the homeostasis of the invaded organ; however, the underlying mechanisms required further studies. We investigated the role of LIGHT in osteolytic bone disease induced by metastatic non-small cell lung cancer (NSCLC). Patients diagnosed with NSCLC bone metastasis show significantly higher levels of LIGHT expressed in monocytes compared with non-bone metastatic tumors and healthy controls. Serum LIGHT levels were also higher in patients with bone metastases than in controls, suggesting a role for LIGHT in stimulating osteoclast precursors. In bone metastatic patients, we also detected increased RNA expression and serum RANKL levels, thus by adding anti-LIGHT or RANK-Fc in PBMC cultures, a significant inhibition of osteoclastogenesis was observed. To model in mice this observation, we used the mouse lung cancer cell line LLC-1. After intratibial implantation, wild-type mice showed an increased number of osteoclasts but reduced numbers of osteoblasts and decreased osteoid formation. In contrast, TNFSF14-/- mice showed no significant bone loss or other changes in bone homeostasis associated with this model. These data indicate LIGHT as a key control mechanism for regulating bone homeostasis during metastatic invasion. Thus, LIGHT may be a novel therapeutic target in osteolytic bone metastases. This article is protected by copyright. All rights reserved.

Takashi Matsuo - One of the best experts on this subject based on the ideXlab platform.

  • Tea polyphenols inhibit IL-6 production in tumor necrosis factor superfamily 14-stimulated human gingival fibroblasts.
    Molecular nutrition & food research, 2020
    Co-Authors: Yoshitaka Hosokawa, Ikuko Hosokawa, Kazumi Ozaki, Hideaki Nakae, Tadashi Nakanishi, Takashi Matsuo
    Abstract:

    IL-6 is well recognized to be a potent bone resorptive agent and thus in the development of periodontal disease. Epigallocatechin gallate (EGCG) and epicatechin gallate (ECG), the major catechins in green tea, and theaflavin-3,3'-digallate (TFDG), polyphenol in black tea, have multiple beneficial effects, but the effects of catechins and theaflavins on IL-6 production in human gingival fibroblasts (HGFs) are not known. In this study, we investigated the mechanisms by which EGCG, ECG, and TFDG inhibit tumor necrosis factor superfamily 14 (TNFSF14)-induced IL-6 production in HGFs. We detected TNFSF14 mRNA expression in human diseased periodontal tissues. TNFSF14 increased IL-6 production in HGFs in a concentration-dependent manner. EGCG, ECG, and TFDG prevented TNFSF14-mediated IL-6 production in HGFs. EGCG, ECG, and TFDG prevented TNFSF14-induced extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and nuclear factor-kappaB activation in HGFs. Inhibitors of ERK, JNK, and nuclear factor-kappaB decreased TNFSF14-induced IL-6 production. In addition, EGCG, ECG, and TFDG attenuated TNFSF14 receptor expression on HGFs. These data provide a novel mechanism through which the green tea and black tea polyphenols could be used to provide direct benefits in periodontal disease.

  • Tea polyphenols inhibit IL‐6 production in tumor necrosis factor superfamily 14‐stimulated human gingival fibroblasts
    Molecular Nutrition & Food Research, 2010
    Co-Authors: Yoshitaka Hosokawa, Ikuko Hosokawa, Kazumi Ozaki, Hideaki Nakae, Tadashi Nakanishi, Takashi Matsuo
    Abstract:

    : IL-6 is well recognized to be a potent bone resorptive agent and thus in the development of periodontal disease. Epigallocatechin gallate (EGCG) and epicatechin gallate (ECG), the major catechins in green tea, and theaflavin-3,3'-digallate (TFDG), polyphenol in black tea, have multiple beneficial effects, but the effects of catechins and theaflavins on IL-6 production in human gingival fibroblasts (HGFs) are not known. In this study, we investigated the mechanisms by which EGCG, ECG, and TFDG inhibit tumor necrosis factor superfamily 14 (TNFSF14)-induced IL-6 production in HGFs. We detected TNFSF14 mRNA expression in human diseased periodontal tissues. TNFSF14 increased IL-6 production in HGFs in a concentration-dependent manner. EGCG, ECG, and TFDG prevented TNFSF14-mediated IL-6 production in HGFs. EGCG, ECG, and TFDG prevented TNFSF14-induced extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and nuclear factor-kappaB activation in HGFs. Inhibitors of ERK, JNK, and nuclear factor-kappaB decreased TNFSF14-induced IL-6 production. In addition, EGCG, ECG, and TFDG attenuated TNFSF14 receptor expression on HGFs. These data provide a novel mechanism through which the green tea and black tea polyphenols could be used to provide direct benefits in periodontal disease.

  • TNFSF14 coordinately enhances cxcl10 and cxcl11 productions from ifn γ stimulated human gingival fibroblasts
    Molecular Immunology, 2010
    Co-Authors: Yoshitaka Hosokawa, Ikuko Hosokawa, Kazumi Ozaki, Hideaki Nakae, Takashi Matsuo
    Abstract:

    Abstract TNFSF14 is involved in the pathogenesis of some inflammatory diseases such as arthritis. CXCL10 and CXCL11 recruit Th1 cells, and the productions of these chemokines are related to the exacerbation of some inflammatory diseases including arthritis and periodontal disease. We examined in vitro effects of TNFSF14 on IFN-γ-induced CXCL10 and CXCL11 production in human gingival fibroblasts (HGFs). HGFs constitutively expressed TNFSF14 receptors, LTβR and HVEM. TNFSF14 enhanced IFN-γ-induced secretion of CXCL10 and CXCL11 from HGFs. IFN-γ treatment increased HVEM expression on HGFs. TNFSF14 in combination with IFN-γ resulted in increased activation of p38 MAPK, ERK and IκB-α compared with TNFSF14 or IFN-γ alone. Moreover, inhibitors of p38 MAPK, ERK and NF-κB abolished the CXCL10 and CXCL11 productions from TNFSF14 with IFN-γ-stimulated HGFs. These effects of TNFSF14 may promote the infiltration of Th1 cells into lesions with inflammatory diseases. TNFSF14 might act as a proinflammatory cytokine in some inflammatory diseases thus is a candidate therapeutic target.

H Hauner - One of the best experts on this subject based on the ideXlab platform.

  • LIGHT (TNFSF14) inhibits adipose differentiation without affecting adipocyte metabolism
    International Journal of Obesity, 2011
    Co-Authors: G Tiller, H Laumen, P Fischer-posovszky, A Finck, T Skurk, M Keuper, U Brinkmann, M Wabitsch, D Link, H Hauner
    Abstract:

    Objective: The member of the tumor necrosis factor family LIGHT (lymphotoxin-like inducible protein that competes with glycoprotein D for herpesvirus entry on T cells; TNFSF14 (tumor necrosis factor super family protein 14) is primarily expressed in lymphocytes, in which it induces the expression of pro-inflammatory cytokines and alterations of lipid homeostasis. Recently, the protein was shown to be upregulated in obesity and to induce cytokine secretion from adipocytes. Research Methods and Procedures: Using an automated complementary DNA (cDNA) screen, LIGHT was identified to inhibit adipose differentiation. As cellular models for adipogenesis mouse 3T3-L1, human SGBS (Simpson-Golabi-Behmel syndrome) and primary human preadipocytes differentiated in vitro were used as well as primary human adipocytes to study adipocyte functions. Analysis of lipid deposition by Oil Red O staining, mRNA expression by quantitative reverse transcriptase-PCR, nuclear factor (NF)-κB activation as well as protein secretion by enzyme linked immunosorbent assay and Luminex technology was performed. Results: LIGHT was found to inhibit lipid accumulation in the three models of preadipocytes in a dose-dependent manner without cytotoxic effects. This inhibition of differentiation was probably because of interference at early steps of adipogenesis, as early exposure during differentiation showed the strongest effect, as assessed by decreased peroxisome proliferator-activated receptor-γ (PPARγ) and CCAAT/enhancer-binding protein-α (C/EBPα) mRNA expression. In contrast to TNFα, basal and insulin-stimulated glucose uptake and lipolysis of terminally differentiated mature adipocytes were not altered in the presence of LIGHT. At a concentration sufficient to inhibit differentiation, secretion of proinflammatory cytokines was not significantly induced and NF-κB activity was only modestly induced compared with TNFα. Conclusion: LIGHT is a novel inhibitor of human adipocyte differentiation without adversely influencing central metabolic pathways in adipocytes.

  • light TNFSF14 inhibits adipose differentiation without affecting adipocyte metabolism
    International Journal of Obesity, 2011
    Co-Authors: G Tiller, H Laumen, A Finck, T Skurk, M Keuper, U Brinkmann, M Wabitsch, D Link, Pamela Fischerposovszky, H Hauner
    Abstract:

    The member of the tumor necrosis factor family LIGHT (lymphotoxin-like inducible protein that competes with glycoprotein D for herpesvirus entry on T cells; TNFSF14 (tumor necrosis factor super family protein 14) is primarily expressed in lymphocytes, in which it induces the expression of pro-inflammatory cytokines and alterations of lipid homeostasis. Recently, the protein was shown to be upregulated in obesity and to induce cytokine secretion from adipocytes. Using an automated complementary DNA (cDNA) screen, LIGHT was identified to inhibit adipose differentiation. As cellular models for adipogenesis mouse 3T3-L1, human SGBS (Simpson-Golabi-Behmel syndrome) and primary human preadipocytes differentiated in vitro were used as well as primary human adipocytes to study adipocyte functions. Analysis of lipid deposition by Oil Red O staining, mRNA expression by quantitative reverse transcriptase-PCR, nuclear factor (NF)-κB activation as well as protein secretion by enzyme linked immunosorbent assay and Luminex technology was performed. LIGHT was found to inhibit lipid accumulation in the three models of preadipocytes in a dose-dependent manner without cytotoxic effects. This inhibition of differentiation was probably because of interference at early steps of adipogenesis, as early exposure during differentiation showed the strongest effect, as assessed by decreased peroxisome proliferator-activated receptor-γ (PPARγ) and CCAAT/enhancer-binding protein-α (C/EBPα) mRNA expression. In contrast to TNFα, basal and insulin-stimulated glucose uptake and lipolysis of terminally differentiated mature adipocytes were not altered in the presence of LIGHT. At a concentration sufficient to inhibit differentiation, secretion of proinflammatory cytokines was not significantly induced and NF-κB activity was only modestly induced compared with TNFα. LIGHT is a novel inhibitor of human adipocyte differentiation without adversely influencing central metabolic pathways in adipocytes.

Graziana Colaianni - One of the best experts on this subject based on the ideXlab platform.

  • LIGHT/TNFSF14 affects basal bone remodeling
    Italian journal of anatomy and embryology, 2020
    Co-Authors: Giacomina Brunetti, Graziana Colaianni, Isabella Gigante, Angela Oranger, Paolo Pignataro, Adriana Di Benedetto, Mariasevera Di Comite, Roberto Tamma, Luciana Lippo, Giorgio Mori
    Abstract:

    LIGHT (TNFSF14), expressed by different cells of the immune system, binds two trans-membrane receptors: HVEM and LTβR. It is over-expressed in erosive rheumatoid arthritis and lytic myeloma-bone disease and controversial data have been published on its role in osteoclast (OC) formation in vitro. Here, we investigated the role of LIGHT on in vitro murine osteoclastogenesis model and bone phenotype in LIGHT-/- mice. Firstly, we showed that murine macrophages stimulated with LIGHT alone did not differentiate into OCs. Interestingly, the presence of LIGHT and sub-optimal RANKL concentration displayed synergic effects on OC formation through the early and sustained activation of Akt, NFκB and JNK pathways. Secondly, by microCT we found that the femurs of LIGHT-KO mice exhibited a 30% (p

  • light TNFSF14 promotes osteolytic bone metastases in non small cell lung cancer patients
    Journal of Bone and Mineral Research, 2020
    Co-Authors: Giacomina Brunetti, Maria Felicia Faienza, Graziana Colaianni, Sara Bortolotti, Giuseppina Storlino, Dimas Carolina Belisario, Lorenzo Sanesi, Valentina Alliod, Lucio Buffoni, Elisa Centini
    Abstract:

    : Tumor necrosis factor superfamily member 14 (TNFSF14), LIGHT, is a component of the cytokine network that regulates innate and adaptive immune responses, which promote homeostasis of lymphoid organs, liver, and bone. Metastatic tumors often disrupt the tissue microenvironment, thus altering the homeostasis of the invaded organ; however, the underlying mechanisms required further studies. We investigated the role of LIGHT in osteolytic bone disease induced by metastatic non-small cell lung cancer (NSCLC). Patients diagnosed with NSCLC bone metastasis show significantly higher levels of LIGHT expressed in monocytes compared with non-bone metastatic tumors and healthy controls. Serum LIGHT levels were also higher in patients with bone metastases than in controls, suggesting a role for LIGHT in stimulating osteoclast precursors. In bone metastatic patients, we also detected increased RNA expression and serum RANKL levels, thus by adding anti-LIGHT or RANK-Fc in PBMC cultures, a significant inhibition of osteoclastogenesis was observed. To model in mice this observation, we used the mouse lung cancer cell line LLC-1. After intratibial implantation, wild-type mice showed an increased number of osteoclasts but reduced numbers of osteoblasts and decreased osteoid formation. In contrast, TNFSF14-/- mice showed no significant bone loss or other changes in bone homeostasis associated with this model. These data indicate LIGHT as a key control mechanism for regulating bone homeostasis during metastatic invasion. Thus, LIGHT may be a novel therapeutic target in osteolytic bone metastases. This article is protected by copyright. All rights reserved.

  • LIGHT/TNFSF14 regulates estrogen deficiency-induced bone loss.
    The Journal of Pathology, 2020
    Co-Authors: Giacomina Brunetti, Maria Felicia Faienza, Graziana Colaianni, Angela Oranger, Giuseppe Ingravallo, Mariasevera Di Comite, Giuseppina Storlino, Janne E Reseland, Monica Celi, Umberto Tarantino
    Abstract:

    : Bone loss induced by ovariectomy is due to the direct activity on bone cells and mesenchymal cells and to the dysregulated activity of bone marrow cells, including immune cells and stromal cells, but the underlying mechanisms are not completely known. Here, we demonstrate that ovariectomy induces the T-cell co-stimulatory cytokine LIGHT, which stimulates both osteoblastogenesis and osteoclastogenesis by modulating osteoclastogenic cytokine expression, including TNF, osteoprotegerin, and the receptor activator of nuclear factor-κB ligand (RANKL). Predictably, LIGHT-deficient (TNFSF14-/- ) mice are protected from ovariectomy-dependent bone loss, whereas trabecular bone mass increases in mice deficient in both LIGHT and T and B lymphocytes (Rag -/- TNFSF14 -/- ) and is associated with an inversion of the TNF and RANKL/OPG ratio. Furthermore, women with postmenopausal osteoporosis display high levels of LIGHT in circulating T cells and monocytes. Taken together, these results indicate that LIGHT mediates bone loss induced by ovariectomy, suggesting that patients with postmenopausal osteoporosis may benefit from LIGHT antagonism. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  • light TNFSF14 regulates estrogen deficiency induced bone loss
    The Journal of Pathology, 2020
    Co-Authors: Giacomina Brunetti, Maria Felicia Faienza, Graziana Colaianni, Angela Oranger, Giuseppe Ingravallo, Mariasevera Di Comite, Giuseppina Storlino, Janne E Reseland, Monica Celi, Umberto Tarantino
    Abstract:

    : Bone loss induced by ovariectomy is due to the direct activity on bone cells and mesenchymal cells and to the dysregulated activity of bone marrow cells, including immune cells and stromal cells, but the underlying mechanisms are not completely known. Here, we demonstrate that ovariectomy induces the T-cell co-stimulatory cytokine LIGHT, which stimulates both osteoblastogenesis and osteoclastogenesis by modulating osteoclastogenic cytokine expression, including TNF, osteoprotegerin, and the receptor activator of nuclear factor-κB ligand (RANKL). Predictably, LIGHT-deficient (TNFSF14-/- ) mice are protected from ovariectomy-dependent bone loss, whereas trabecular bone mass increases in mice deficient in both LIGHT and T and B lymphocytes (Rag -/- TNFSF14 -/- ) and is associated with an inversion of the TNF and RANKL/OPG ratio. Furthermore, women with postmenopausal osteoporosis display high levels of LIGHT in circulating T cells and monocytes. Taken together, these results indicate that LIGHT mediates bone loss induced by ovariectomy, suggesting that patients with postmenopausal osteoporosis may benefit from LIGHT antagonism. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  • LIGHT/TNFSF14 Promotes Osteolytic Bone Metastases in Non‐small Cell Lung Cancer Patients
    Journal of Bone and Mineral Research, 2020
    Co-Authors: Giacomina Brunetti, Maria Felicia Faienza, Graziana Colaianni, Sara Bortolotti, Giuseppina Storlino, Dimas Carolina Belisario, Lorenzo Sanesi, Valentina Alliod, Lucio Buffoni, Elisa Centini
    Abstract:

    : Tumor necrosis factor superfamily member 14 (TNFSF14), LIGHT, is a component of the cytokine network that regulates innate and adaptive immune responses, which promote homeostasis of lymphoid organs, liver, and bone. Metastatic tumors often disrupt the tissue microenvironment, thus altering the homeostasis of the invaded organ; however, the underlying mechanisms required further studies. We investigated the role of LIGHT in osteolytic bone disease induced by metastatic non-small cell lung cancer (NSCLC). Patients diagnosed with NSCLC bone metastasis show significantly higher levels of LIGHT expressed in monocytes compared with non-bone metastatic tumors and healthy controls. Serum LIGHT levels were also higher in patients with bone metastases than in controls, suggesting a role for LIGHT in stimulating osteoclast precursors. In bone metastatic patients, we also detected increased RNA expression and serum RANKL levels, thus by adding anti-LIGHT or RANK-Fc in PBMC cultures, a significant inhibition of osteoclastogenesis was observed. To model in mice this observation, we used the mouse lung cancer cell line LLC-1. After intratibial implantation, wild-type mice showed an increased number of osteoclasts but reduced numbers of osteoblasts and decreased osteoid formation. In contrast, TNFSF14-/- mice showed no significant bone loss or other changes in bone homeostasis associated with this model. These data indicate LIGHT as a key control mechanism for regulating bone homeostasis during metastatic invasion. Thus, LIGHT may be a novel therapeutic target in osteolytic bone metastases. This article is protected by copyright. All rights reserved.

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