Activated human T cells express alternative mRNA transcripts encoding a secreted form of RANKL

Walsh, Nicole C.; Alexander, Kylie A.; Manning, Catherine A.; Karmakar, Sougata; Wang, J. F.; Weyand, Cornelia M.; Pettit, Allison R.; Gravallese, Ellen M.

doi:10.1038/gene.2013.29

Cited by 28 publications

(26 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Differ-entiation of mature OCs is triggered by the binding of receptor activator of nuclear factor-B (NF-B) ligand (RANKL) to its signaling receptor RANK, which is expressed on monocytic precursors (9,10). Cells from the osteoblastic lineage and nonosteoblastic cells, such as T cells, NK cells, and synoviocytes, express RANKL in inflammatory arthritis (11)(12)(13)(14)(15)(16)(17). The activity of RANKL can be blocked by its endogenous soluble decoy receptor, osteoprotegerin (OPG) (reviewed in reference 18).…”

mentioning

confidence: 99%

Bindarit, an Inhibitor of Monocyte Chemotactic Protein Synthesis, Protects against Bone Loss Induced by Chikungunya Virus Infection

Chen

Foo

Taylor

et al. 2015

J Virol

101

View full text Add to dashboard Cite

The recent global resurgence of arthritogenic alphaviruses, in particular chikungunya virus (CHIKV), highlights an urgent need for the development of therapeutic intervention strategies. While there has been significant progress in defining the pathophysiology of alphaviral disease, relatively little is known about the mechanisms involved in CHIKV-induced arthritis or potential therapeutic options to treat the severe arthritic symptoms associated with infection. Here, we used microcomputed tomographic (CT) and histomorphometric analyses to provide previously undescribed evidence of reduced bone volume in the proximal tibial epiphysis of CHIKV-infected mice compared to the results for mock controls. This was associated with a significant increase in the receptor activator of nuclear factor-B ligand/osteoprotegerin (RANKL/OPG) ratio in infected murine joints and in the serum of CHIKV patients. The expression levels of the monocyte chemoattractant proteins (MCPs), including MCP-1/CCL2, MCP-2/CCL8, and MCP-3/CCL7, were also highly elevated in joints of CHIKV-infected mice, accompanied by increased cellularity within the bone marrow in tibial epiphysis and ankle joints. Both this effect and CHIKV-induced bone loss were significantly reduced by treatment with the MCP inhibitor bindarit. Collectively, these findings demonstrate a unique role for MCPs in promoting CHIKV-induced osteoclastogenesis and bone loss during disease and suggest that inhibition of MCPs with bindarit may be an effective therapy for patients affected with alphavirus-induced bone loss. IMPORTANCE Arthritogenic alphaviruses, including chikungunya virus (CHIKV) and Ross River virus (RRV), cause worldwide outbreaks of polyarthritis, which can persist in patients for months following infection. Previous studies have shown that host proinflammatory soluble factors are associated with CHIKV disease severity. Furthermore, it is established that chemokine (C-C motif) ligand 2 (CCL2/MCP-1) is important in cellular recruitment and inducing bone-resorbing osteoclast (OC) formation. Here, we show that CHIKV replicates in bone and triggers bone loss by increasing the RANKL/OPG ratio. CHIKV infection results in MCP-induced cellular infiltration in the inflamed joints, and bone loss can be ameliorated by treatment with an MCP-inhibiting drug, bindarit. Taken together, our data reveal a previously undescribed role for MCPs in CHIKV-induced bone loss: one of recruiting monocytes/OC precursors to joint sites and thereby favoring a pro-osteoclastic microenvironment. This suggests that bindarit may be an effective treatment for alphavirus-induced bone loss and arthritis in humans.

show abstract

mentioning

confidence: 99%

Bindarit, an Inhibitor of Monocyte Chemotactic Protein Synthesis, Protects against Bone Loss Induced by Chikungunya Virus Infection

Chen

Foo

Taylor

et al. 2015

J Virol

101

View full text Add to dashboard Cite

show abstract

“…Mammalian RANKL is a type II transmembrane protein that can function as either a membrane-bound or secreted form (Ikeda et al, 2001;Walsh et al, 2013), with no known functional difference between the two (Nakashima et al, 2000). An aa alignment of fulllength chRANKL with those of human and mouse showed high conservation across all species.…”

Section: Discussionmentioning

confidence: 95%

The functions of the avian receptor activator of NF-κB ligand (RANKL) and its receptors, RANK and osteoprotegerin, are evolutionarily conserved

Sutton

et al. 2015

Developmental & Comparative Immunology

View full text Add to dashboard Cite

A new member of the chicken TNF superfamily has recently been identified, namely receptor activator of NF-κB ligand (RANKL), as have its signalling receptor, RANK, and its decoy receptor, osteoprotegerin (OPG). In mammals, RANKL and RANK are transmembrane proteins expressed on the surface of Th1 cells and dendritic cells (DC) respectively, whereas OPG is expressed as a soluble protein from osteoblasts and DC. Recombinant soluble chicken RANKL (chRANKL) forms homotrimers whereas chicken OPG (chOPG) forms homodimers, characteristic of these molecules in mammals. ChRANKL, chRANK and chOPG are expressed at the mRNA level in most tissues and organs. ChRANKL is transcriptionally regulated by Ca(2+) mobilisation and enhances the mRNA expression levels of pro-inflammatory cytokines in bone marrow-derived DC (BMDC); this is inhibited by both chOPG-Fc and soluble chRANK-Fc. However, chRANKL does not enhance the expression of cell surface markers in either BMDC or BM-derived macrophages (BMM). Furthermore, chRANKL enhances the survival of APC similar to its mammalian orthologue.

show abstract

“…RANKL3 plays an inhibitory role when coexpressed with RANKL1 or RANKL2 . Also, new variants of the soluble RANKL form generated by alternative splicing have been described . The expression of the soluble form of RANKL, most probably generated by alternative splicing, has been shown to increase in mouse mammary cells after in vivo treatment with the progesterone derivative medroxiprogesterone (MPA) .…”

Section: The Rank Signaling Pathwaymentioning

confidence: 99%

RANK as a therapeutic target in cancer

González‐Suárez

Sanz-Moreno

2016

The FEBS Journal

View full text Add to dashboard Cite

The RANK signaling pathway has emerged as a new target in breast cancer as receptor activator of nuclear factor jB ligand (RANKL) and its receptor RANK mediate the pro-tumorigenic role of progesterone in the mammary gland. Thousands of cancer patients worldwide are already taking RANKL inhibitors for the management of bone metastasis, given the relevance of this pathway in osteoclastogenesis and bone resorption. RANK signaling also has multiple divergent effects in immunity and inflammation, both in the generation of active immune responses and in the induction of tolerance: it is required for lymph node organogenesis, thymic medullary epithelial development and self-tolerance, and regulates activation of several immune cells and inflammatory processes. The RANK pathway interferes with mammary epithelial differentiation and mediates the major proliferative response of mammary epithelium to progesterone and progesterone-driven expansion of mammary stem cells; it also controls hair follicle and epidermal stem cell homeostasis, pointing to RANK as a key regulator of epithelial stemness. Here we revisit the main functions of RANK signaling in bone remodeling, immune cells and epithelial differentiation. We also discuss the mechanistic evidence that supports its pleiotropic effects on cancer: from bone metastasis to immune and cancercell-dependent effects.

show abstract

Activated human T cells express alternative mRNA transcripts encoding a secreted form of RANKL

Cited by 28 publications

References 51 publications

Bindarit, an Inhibitor of Monocyte Chemotactic Protein Synthesis, Protects against Bone Loss Induced by Chikungunya Virus Infection

Bindarit, an Inhibitor of Monocyte Chemotactic Protein Synthesis, Protects against Bone Loss Induced by Chikungunya Virus Infection

The functions of the avian receptor activator of NF-κB ligand (RANKL) and its receptors, RANK and osteoprotegerin, are evolutionarily conserved

RANK as a therapeutic target in cancer

Contact Info

Product

Resources

About