LIGHT/TNFSF14 increases osteoclastogenesis and decreases osteoblastogenesis in multiple myeloma-bone disease

Brunetti, Giacomina; Rizzi, Rita; Oranger, Angela; Gigante, Isabella; Mori, Giorgio; Taurino, Grazia; Mongelli, Teresa; Colaianni, Graziana; Benedetto, Adriana Di; Tamma, Roberto; Ingravallo, Giuseppe; Napoli, Anna; Faienza, Maria Felicia; Mestice, Anna; Curci, Paola; Specchia, Giorgina; Colucci, Silvia; Grano, Maria

doi:10.18632/oncotarget.2633

Cited by 54 publications

(73 citation statements)

References 62 publications

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“…They release the receptor-binding domain into the extracellular space [39,40,42]. It has been recently reported that LIGHT inhibits osteoblastogenesis of MSC co-cultured with monocytes in multiple myeloma-bone disease [43]. There are possibilities that LIGHT signaling might be hampered by various cytokines or factors produced in the environment including soluble LIGHT, soluble HVEM, and its soluble receptor, DcR3.…”

Section: Discussionmentioning

confidence: 99%

LIGHT (TNFSF14) Increases the Survival and Proliferation of Human Bone Marrow-Derived Mesenchymal Stem Cells

et al. 2016

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LIGHT (HVEM-L, TNFSF14, or CD258), an entity homologous to lymphotoxins, with inducible nature and the ability to compete with herpes simplex virus glycoprotein D for herpes virus entry mediator (HVEM)/tumor necrosis factor (TNF)-related 2, is a member of the TNF superfamily. It is expressed as a homotrimer on activated T cells and dendritic cells (DCs), and has three receptors: HVEM, LT-β receptor (LTβR), and decoy receptor 3 (DcR3). So far, three receptors with distinct cellular expression patterns are known to interact with LIGHT. Follicular DCs and stromal cells bind LIGHT through LTβR. We monitored the effects of LIGHT on human bone marrow-derived mesenchymal stem cells (BM-MSCs). At first, we checked the negative and positive differentiation markers of BM-MSCs. And we confirmed the quality of MSCs by staining cells undergoing adipogenesis (Oil Red O staining), chondrogenesis (Alcian blue staining), and osteogenesis (Alizarin red staining). After rhLIGHT treatment, we monitored the count, viability, and proliferation of cells and cell cycle distribution. PDGF and TGFβ production by rhLIGHT was examined by ELISA, and the underlying biological mechanisms were studied by immunoblotting by rhLIGHT treatment. LTβR was constitutively expressed on the surface of human BM-MSCs. Cell number and viability increased after rhLIGHT treatment. BM-MSC proliferation was induced by an increase in the S/G2/M phase. The expression of not only diverse cyclins such as cyclin B1, D1, D3, and E, but also CDK1 and CDK2, increased, while that of p27 decreased, after rhLIGHT treatment. RhLIGHT-induced PDGF and TGFβ production mediated by STAT3 and Smad3 activation accelerated BM-MSC proliferation. Thus, LIGHT and LTβR interaction increases the survival and proliferation of human BM-MSCs, and therefore, LIGHT might play an important role in stem cell therapy.

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Section: Discussionmentioning

confidence: 99%

LIGHT (TNFSF14) Increases the Survival and Proliferation of Human Bone Marrow-Derived Mesenchymal Stem Cells

et al. 2016

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“…52 The description, functional evaluation and validation of this anti-LIGHT antibody opens up many possibilities to study the role of LIGHT and define its therapeutic potential in preclinical murine models of immunerelated diseases (transplantation, tumor immunity and autoimmune diseases), 17,18,26,53,54,55 as well as in other pathologies in which LIGHT has been implicated, such as pulmonary fibrosis subsequent to chronic lung inflammation and idiopathic pulmonary fibrosis diseases, 56,57 skin fibrosis 58 and bone destruction through osteoclastogenesis. 59 This tool offers advantages over the classical approaches of using LTbR.Ig recombinant fusion protein because LTbR.Ig blocks LTab/LTbR in addition to LIGHT/LTbR/HVEM. 51 Administration of anti-LIGHT antibody in the above-mentioned disease models may help to clarify the contribution of LIGHT/LTbR/HVEM to the overall disease protection observed when using LTbR.Ig fusion protein.…”

Section: Discussionmentioning

confidence: 99%

Immunotherapeutic targeting of LIGHT/LTβR/HVEM pathway fully recapitulates the reduced cytotoxic phenotype of LIGHT-deficient T cells

Rio

Fernández-Renedo

Chaloin

et al. 2016

mAbs

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(2016) Immunotherapeutic targeting of LIGHT/LTβR/HVEM pathway fully recapitulates the reduced cytotoxic phenotype of LIGHT-deficient T cells, mAbs, 8:3, 478-490, DOI: 10.1080/19420862.2015 To link to this article: https://doi.org/10. 1080/19420862.2015 ABSTRACTTumor necrosis factor (TNF)/TNF receptor (TNFR) superfamily members play essential roles in the development of the different phases of the immune response. Mouse LIGHT (TNFSF14) is a type II transmembrane protein with a C-terminus extracellular TNF homology domain (THD) that assembles in homotrimers and regulates the course of the immune responses by signaling through 2 receptors, the herpes virus entry mediator (HVEM, TNFSFR14) and the lymphotoxin b receptor (LTbR, TNFSFR3). LIGHT is a membrane-bound protein transiently expressed on activated T cells, natural killer (NK) cells and immature dendritic cells that can be proteolytically cleaved by a metalloprotease and released to the extracellular milieu. The immunotherapeutic potential of LIGHT blockade was evaluated in vivo. Administration of an antagonist of LIGHT interaction with its receptors attenuated the course of graftversus-host reaction and recapitulated the reduced cytotoxic activity of LIGHT-deficient T cells adoptively transferred into non-irradiated semiallogeneic recipients. The lack of LIGHT expression on donor T cells or blockade of LIGHT interaction with its receptors slowed down the rate of T cell proliferation and decreased the frequency of precursor alloreactive T cells, retarding T cell differentiation toward effector T cells. The blockade of LIGHT/LTbR/HVEM pathway was associated with delayed downregulation of interleukin-7Ra and delayed upregulation of inducible costimulatory molecule expression on donor alloreactive CD8 T cells that are typical features of impaired T cell differentiation. These results expose the relevance of LIGHT/LTbR/HVEM interaction for the potential therapeutic control of the allogeneic immune responses mediated by alloreactive CD8 T cells that can contribute to prolong allograft survival.Abbreviations: LIGHT, homologous to lymphotoxin, exhibits inducible expression and competes with HSV glycoprotein D for binding to herpesvirus entry mediator, a receptor expressed on T

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“…LIGHT (homologous to lymphotoxins exhibiting inducible expression and competing with herpes simplex virus glycoprotein D for herpesvirus entry mediator [HVEM], a receptor expressed by T lymphocytes) is elevated in conditions such as RA and multiple myeloma (110,111). In vitro, LIGHT has been reported to induce osteoclastogenesis in RANKL-dependent and –independent manners and indirectly inhibit osteoblastogenesis (110,111).…”

Section: Immune Cytokines and Bonementioning

confidence: 99%

“…In vitro, LIGHT has been reported to induce osteoclastogenesis in RANKL-dependent and –independent manners and indirectly inhibit osteoblastogenesis (110,111). …”

Section: Immune Cytokines and Bonementioning

confidence: 99%

Immunology of Gut-Bone Signaling

Collins

Schepper

Rios‐Arce

et al. 2017

Advances in Experimental Medicine and Biology

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In recent years a link between the gastro-intestinal tract and bone health has started to gain significant attention. Dysbiosis of the intestinal microbiota has been linked to the pathology of a number of diseases which are associated with bone loss. In addition modulation of the intestinal microbiota with probiotic bacteria has revealed to have both beneficial local and systemic effects. In the present chapter we discuss the intestinal and bone immune systems, explore how intestinal disease affects the immune system and examine how these pathologic changes could adversely impact bone health.

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LIGHT/TNFSF14 increases osteoclastogenesis and decreases osteoblastogenesis in multiple myeloma-bone disease

Cited by 54 publications

References 62 publications

LIGHT (TNFSF14) Increases the Survival and Proliferation of Human Bone Marrow-Derived Mesenchymal Stem Cells

LIGHT (TNFSF14) Increases the Survival and Proliferation of Human Bone Marrow-Derived Mesenchymal Stem Cells

Immunotherapeutic targeting of LIGHT/LTβR/HVEM pathway fully recapitulates the reduced cytotoxic phenotype of LIGHT-deficient T cells

Immunology of Gut-Bone Signaling

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