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Featured researches published by Toni Forde.


Arthritis & Rheumatism | 2012

Wnt signaling genes of murine chromosome 15 are involved in sex-affected pathways of inflammatory arthritis.

Elena Kudryavtseva; Toni Forde; Andrew D. Pucker; Vyacheslav A. Adarichev

OBJECTIVE Sex disparities in rheumatoid arthritis (RA) are well documented despite the lack of any known major RA susceptibility genes mapped to sex chromosomes. Murine chromosome 15 carries the sex-affected Pgia8 locus that mediates proteoglycan-induced arthritis, and homologous human loci are associated with RA. This study was undertaken to identify genes/mechanisms implicated in sex disparities in arthritis. METHODS Gene expression analysis was performed using RNA isolated from the paws of male and female Pgia8-congenic mice with collagen antibody-induced arthritis. Results were corroborated by reverse transcription-polymerase chain reaction, and mice were also studied prior to disease onset. Ingenuity Pathways Analysis of the expression patterns and gene functions was used to discover locus-specific and sex-affected signature transcripts. RESULTS We found that the Pgia8 locus regulates antibody-mediated inflammatory arthritis differently in males and females. In Pgia8-congenic males, arthritis severity was 30% less (P < 0.005) than in wild-type males, but the antiinflammatory effect was similar in wild-type and congenic females. Transcriptome analysis indicated that 12 genes within the locus were significantly dysregulated in arthritic joints of congenic mice; expression of these genes was also sex specific. The genes that correlated most highly with arthritis severity included those for collagen triple-helix repeat-containing 1 (Cthrc1), metalloproteinase (Adamts12), R-spondin (Rspo2), and syndecan (Sdc2) (r = 0.87-0.91). The level of Cthrc1 message also correlated with that of the genes for the proinflammatory cytokines interleukin-1β and interleukin-6. CONCLUSION These results indicate that sex-specific disparities in RA are linked to transcriptional regulation of genes involved in cartilage degradation (Adamts12) and canonical and noncanonical Wnt signaling (Cthrc1, Rspo2, Sdc2).


Disease Models & Mechanisms | 2013

Osteoarticular tissue infection and development of skeletal pathology in murine brucellosis

Diogo Magnani; Elizabeth Lyons; Toni Forde; Mohammed Talha Shekhani; Vyacheslav A. Adarichev; Gary A. Splitter

SUMMARY Brucellosis, a frequent bacterial zoonosis, can produce debilitating chronic disease with involvement of multiple organs in human patients. Whereas acute brucellosis is well studied using the murine animal model, long-term complications of host-pathogen interaction remain largely elusive. Human brucellosis frequently results in persistent, chronic osteoarticular system involvement, with complications such as arthritis, spondylitis and sacroiliitis. Here, we focused on identifying infectious sites in the mouse that parallel Brucella melitensis foci observed in patients. In vivo imaging showed rapid bacterial dispersal to multiple sites of the murine axial skeleton. In agreement with these findings, immunohistochemistry revealed the presence of bacteria in bones and limbs, and in the lower spine vertebrae of the axial skeleton where they were preferentially located in the bone marrow. Surprisingly, some animals developed arthritis in paws and spine after infection, but without obvious bacteria in these sites. The identification of Brucella in the bones of mice corroborates the findings in humans that these osteoarticular sites are important niches for the persistence of Brucella in the host, but the mechanisms that mediate pathological manifestations in these sites remain unclear. Future studies addressing the immune responses within osteoarticular tissue foci could elucidate important tissue injury mediators and Brucella survival strategies.


Arthritis Research & Therapy | 2016

Collagen triple helix repeat containing 1 is a new promigratory marker of arthritic pannus.

Mohammed Talha Shekhani; Toni Forde; Altynai Adilbayeva; Mohamed Ramez; Askhat Myngbay; Yergali Bexeitov; Volkhard Lindner; Vyacheslav A. Adarichev

BackgroundThe formation of destructive hypercellular pannus is critical to joint damage in rheumatoid arthritis (RA). The collagen triple helix repeat containing 1 (CTHRC1) protein expressed by activated stromal cells of diverse origin has previously been implicated in tissue remodeling and carcinogenesis. We recently discovered that the synovial Cthrc1 mRNA directly correlates with arthritis severity in mice. This study characterizes the role of CTHRC1 in arthritic pannus formation.MethodsSynovial joints of mice with collagen antibody-induced arthritis (CAIA) and human RA-fibroblast-like synoviocytes (FLS) were immunostained for CTHRC1, FLS and macrophage-specific markers. CTHRC1 levels in plasma from patients with RA were measured using sandwich ELISA. The migratory response of fibroblasts was studied with a transwell migration assay and time-lapse microscopy. Velocity and directness of cell migration was analyzed by recording the trajectories of cells treated with rhCTHRC1.ResultsImmunohistochemical analysis of normal and inflamed synovium revealed highly inducible expression of CTHRC1 in arthritis (10.9-fold). At the tissue level, CTHRC1-expressing cells occupied the same niche as large fibroblast-like cells positive for α-smooth muscle actin (α-SMA) and cadherin 11 (CDH11). CTHRC1 was produced by activated FLS predominantly located at the synovial intimal lining and at the bone-pannus interface. Cultured RA-FLS expressed CDH11, α-SMA, and CTHRC1. Upon treatment with exogenous rhCTHRC1, embryonic fibroblasts and RA-FLS significantly increased migration velocity, directness, and cell length along the front-tail axis (1.4-fold, p < 0.01).ConclusionCTHRC1 was established as a novel marker of activated synoviocytes in murine experimental arthritis and RA. The pro-migratory effect of CTHRC1 on synoviocytes is considered one of the mechanisms promoting hypercellularity of the arthritic pannus.


Cancer Research | 2017

SGK1 is a critical component of an AKT-independent pathway essential for PI3K-mediated tumor development and maintenance

Arturo Orlacchio; Michela Ranieri; Martina Brave; Valeria G. Antico Arciuch; Toni Forde; Daniela De Martino; Karen E. Anderson; Phillip T. Hawkins; Antonio Di Cristofano

Activation of the PI3K-AKT signaling cascade is a common critical event during malignant transformation. In this study, we used thyroid gland epithelial cells and a series of genetically engineered mouse strains as model systems to demonstrate that, although necessary, AKT activation is not sufficient for PI3K-driven transformation. Instead, transformation requires the activity of the PDK1-regulated AGC family of protein kinases. In particular, SGK1 was found to be essential for proliferation and survival of thyroid cancer cells harboring PI3K-activating mutations. Notably, cotargeting SGK1 and AKT resulted in significantly higher growth suppression than inhibiting either PI3K or AKT alone. Overall, these findings underscore the clinical relevance of AKT-independent pathways in tumors driven by genetic lesions targeting the PI3K cascade. Cancer Res; 77(24); 6914-26. ©2017 AACR.


Annals of the Rheumatic Diseases | 2013

SAT0256 Osteophytosis is associated with low-grade spondylitis and disconnected from peripheral arthritis in mice immunized with human aggrecan G1 domain

Vyacheslav A. Adarichev; Mohamed Ramez; Toni Forde

Background The balance between inflammation-driven cartilage and bone erosion and new bone formation is set at different levels in rheumatoid arthritis and in ankylosing spondylitis (AS). Inflammation and tissue damage usually prepare the stage for the later repair process of new tissue formation like osteophytosis and bone fusions in AS 1,2. Objectives We were aiming to better characterize the mechanisms of bones remodeling in spine in inflammatory conditions through the development of a murine model for spondylitis induced with heterologous aggrecan immunizations. Methods Human aggrecan G1 domain (1-235 aa of ACAN-201) tagged with 6xHis was cloned using a baculovirus system, and the fusion protein was isolated using Ni-NTA resin. Protein identity and purity was characterized with SDS-PAGE and immunodetection. BALB/c females were immunized intraperitoneally with rhAG1 emulsified either in Complete Freund’s adjuvant (CFA) or in dimethyldioctadecylammonium bromide (DDA) adjuvant 3,4. Mice were scored for visual signs of peripheral arthritis. Histopathology sections of paws and spines were stained with hematoxylin & eosin, alcian blue, and for macrophage markers. Results In mice immunized with rhAG1-DDA or rhAG1-CFA, slowly progressing arthritis reached maximum after four immunizations. Histopathological examination of paw sections confirmed the presence of inflammatory cells, but severity of arthritis was rather mild. Despite the weak peripheral inflammation, histopathological assessment of spine sections revealed massive ventral chondroplasia and osteophytosis of fibrocartilaginous annulus fibrosus-like cells that has been displacing anterior longitudinal ligament. Ventral aspects of enthesis, annulus fibrosus, and growth plate were mainly affected. One to three osteophytes per every spine were observed in approximately 20% of all examined mice. Immense osteophytes were easily detectable using micro-CT and routine X-ray analysis. The most affected regions were the junction of sacrum with lumbar and caudal parts of axial skeleton: S1-L6 and S4-Ca1. We observed consistent but low grade inflammation around afflicted skeletal regions that strongly correlated with spine osteophytosis, r=0.81. Correlation between peripheral joints inflammation and osteophytes formation was much weaker, r=0.29. Surrounding osteophytes fibrous tissue contained IBA-1-positive macrophages. Conclusions A new murine model for osteophytosis disconnected from peripheral joints inflammation is developed. The balance between peripheral arthritis, spondylitis and osteophytosis appears to be dependent on the biochemical properties and immunogenicity of the immunizing aggrecan antigen. References Lories, R. The balance of tissue repair and remodeling in chronic arthritis. Nat Rev Rheumatol 7, 700-707, (2011). Uderhardt, S. et al. Blockade of Dickkopf (DKK)-1 induces fusion of sacroiliac joints. Ann Rheum Dis 69, 592-597, (2010). Vegvari, A. et al. Two major interacting chromosome loci control disease susceptibility in murine model of spondyloarthropathy. J Immunol 175, 2475-2483, (2005). Adarichev, V. A. & Glant, T. T. Experimental spondyloarthropathies: animal models of ankylosing spondylitis. Curr Rheumatol Rep 8, 267-274, (2006). Disclosure of Interest None Declared


Annals of the Rheumatic Diseases | 2013

SAT0045 In inflammatory arthritis, chemokine CCL19/21 expression is regulated by nuclear factor of activated T cells (NFATC4) pathways

Vyacheslav A. Adarichev; Mohamed Ramez; P.A. Kenny; Toni Forde

Background Nuclear factors of activated T cells (NFAT) is a family of transcription factors critical in regulating genes expression in development and disease. The pathway is an important target for cyclosporine immunosuppression in transplant rejection and in autoimmune diseases such as rheumatoid arthritis (RA). Objectives To validate the in silico finding of the NFATc4 encoding gene within the major peak controlling antibody (Ab)-mediated arthritis, and to investigate a functional significance and mechanisms implicated in NFATc4-driven regulation of inflammatory arthritis. Methods In genome-wide association study (GWAS), we correlated susceptibility to antibody-mediated arthritis (serum transfer-induced arthritis 1 and collagen Ab-induced arthritis, CAIA 2) of inbred murine strains with all available SNPs 3. CAIA was induced in Nfatc4-ko gene deficient 4 and in wild-type (WT) C57BL/6J mice with a cocktail of mAbs to collagen type II and LPS injection. Differential gene expression analysis of RNA isolated from arthritic paws of Nfatc4-ko and WT mice was performed using Affymetrix GeneChip® Mouse Gene 1.0 ST Array. Statistical analysis, functional and unsupervised hierarchical clustering was performed using Ingenuity Pathway Analysis and Partek software. Significantly dysregulated genes were replicated using TaqMan RT-PCR with independent RNA samples. Immunohistochemical staining of tissue sections and chemokine production in isolated macrophages were studied. Results Using GWAS, Nfatc4 gene was discovered to be significantly associated with arthritis severity, p<0.000003. Biological effect was confirmed in Nfatc4-ko gene-deficient mice that exhibited significantly weaker CAIA (55% downregulation, p<0.01) when were compared to wild-type. The most significantly downregulated genes in paws of Nfatc4-ko mice were chemokines Ccl19 and Ccl21 (11.55-fold, p<0.00006). Using RT-PCR and ELISA, we showed that production of CCL19/21 was basically blocked in LPS-stimulated peritoneal macrophages from Nfatc4-ko mice. Cells isolated from articular cartilage of these gene-deficient mice also showed significantly lower production of collagen type I and aggrecan (2-fold, p<0.01). Conclusions Transcriptome and proteome analyses confirmed in silico genetic association between severity of inflammatory arthritis and polymorphisms within the Nfatc4 gene. We showed that activation of macrophages is under the strong control of NFATc4 regulatory pathways. References Ji, H. et al. Genetic influences on the end-stage effector phase of arthritis. Journal of Experimental Medicine 194, 321-330, (2001). Nandakumar, K. S. & Holmdahl, R. Collagen antibody induced arthritis. Methods Mol Med 136, 215-223, (2007). Grubb, S. C., Maddatu, T. P., Bult, C. J. & Bogue, M. A. Mouse phenome database. Nucleic Acids Res 37, D720-730, (2009). Wilkins, B. J. et al. Targeted disruption of NFATc3, but not NFATc4, reveals an intrinsic defect in calcineurin-mediated cardiac hypertrophic growth. Mol Cell Biol 22, 7603-7613, (2002). Disclosure of Interest None Declared


Annals of the Rheumatic Diseases | 2013

SAT0249 Novel cytotoxic T cell epitope in brucellosis-induced murine spondyloarthropathy

Vyacheslav A. Adarichev; Elizabeth Lyons; Diogo Magnani; Toni Forde; Gary A. Splitter

Background Brucellosis is one of the most common bacterial zoonosis and causes significant human morbidity worldwide1. Osteoarticular complications are the most frequent clinical manifestations in patients2,3. However, pathophysiological and immune mechanisms of brucellosis remain poorly characterized. Objectives The goal of the study was to establish a murine model for human Brucellosis to better understanding the immune mechanisms of association between Brucellosis and spondyloarthropathy (SpA). Methods BALB/c mice were infected intraperitoneally with 106–108 CFU of the virulent bioluminescent B. melitensis strain GR023 or B. abortus vaccine strain S194,5. Bacterial dissemination was monitored using biophotonic imaging and immunohistochemistry (IHC). Histopathology slides of axial skeleton, paws, spleen, and liver were IHC stained for IBA-1 marker and Brucella. Results In vivo biophotonic imaging showed accumulation of B.melitensis in paws and knees, while the strongest signal was detected in the tail that reproduce the distribution of vertebrae. Upon IHC staining, bacteria were found in the spleen, liver, and in bone marrow. Three weeks post-infection, bacteria-infected cells were not found in the peridiscal space or in the joint cavity, but were located in the subchondral bone of peripheral joints and vertebrae. At 26 weeks post-infection, spleen and bone marrow were negative for IHC staining, and liver showed a weak rare staining. Despite the general absence of infection at this time point, mice developed arthritis in ankle joints and spondylolisthesis. We found that immunodominant Brucella-derived peptide from methionine sulfoxide reductase is presented to cytotoxic T cells by murine macrophages in the context of MHC class I molecule. Homologous mouse/host protein carries a sequence that is 100% identical to Brucella epitope. In silico prediction analysis indicates that the epitope is able to bind to human HLA-B*2705 class I molecule that is strongly associated with human SpA. Conclusions Arthritis was not associated with acute Brucella infection in this murine model. Inflammation in joints and changes in skeleton were found weeks after the bacteria were cleared from tissues. Murine Brucellosis demonstrated features that are typical to reactive arthritis. Our data provide support for brucellosis-induced SpA as a reactive arthritis-type disease with a potential involvement of cytotoxic T cells. References Pappas G, Papadimitriou P, Akritidis N, Christou L, Tsianos EV. The new global map of human brucellosis. Lancet Infect Dis 6, 91-99, (2006). Turan H, Serefhanoglu K, Karadeli E, Togan T, Arslan H. Osteoarticular involvement among 202 brucellosis cases identified in Central Anatolia region of Turkey. Intern Med 50, 421-428, (2011). Lifeso RM, Harder E, McCorkell SJ. Spinal brucellosis. J Bone Joint Surg Br 67, 345-351, (1985). Magnani DM, Harms JS, Durward MA, Splitter GA. Nondividing but metabolically active gamma-irradiated Brucella melitensis is protective against virulent B. melitensis challenge in mice. Infect Immun 77, 5181-5189, (2009). Ko J, Gendron-Fitzpatrick A, Splitter GA. Susceptibility of IFN regulatory factor-1 and IFN consensus sequence binding protein-deficient mice to brucellosis. J Immunol 168, 2433-2440, (2002). Disclosure of Interest None Declared


Cancer Research | 2015

Abstract 2023: MYC amplification and overexpression in metastatic anaplastic thyroid cancer dictates response to therapy

Emrullah Yilmaz; Marika A. Russo; Arturo Orlacchio; Toni Forde; Antonio Di Cristofano


Journal of Immunology | 2012

Cytotoxic T cell epitope in Brucellosis-induced murine spondyloarthropathy shows 100% homology with the host mouse peptide

Vyacheslav A. Adarichev; Elizabeth Lyons; Diogo M. Magnani; Toni Forde; Gary A. Splitter


Journal of Immunology | 2011

Promigratory secreted protein Collagen triple helix repeat containing 1 is involved in sex-biased regulation of inflammatory arthritis

Mohammed Talha Shekhani; Mohamed Ramez; Toni Forde; Elizabeth Lyons; Volkhard Lindner; Vyacheslav A. Adarichev

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Vyacheslav A. Adarichev

Rush University Medical Center

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Mohamed Ramez

Albert Einstein College of Medicine

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Elizabeth Lyons

Albert Einstein College of Medicine

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Gary A. Splitter

University of Wisconsin-Madison

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Mohammed Talha Shekhani

Albert Einstein College of Medicine

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Arturo Orlacchio

Albert Einstein College of Medicine

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Diogo Magnani

University of Wisconsin-Madison

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Andrew D. Pucker

Albert Einstein College of Medicine

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