Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Arthritis Research & Therapy
Published in: Arthritis Research & Therapy 1/2017

Open Access 01-12-2017 | Research article

Genetic deficiency of Wnt5a diminishes disease severity in a murine model of rheumatoid arthritis

Authors: Susan MacLauchlan, Maria A. Zuriaga, José J. Fuster, Carla M. Cuda, Jennifer Jonason, Fernanda Behzadi, Jennifer Parker Duffen, G. Kenneth Haines III, Tamar Aprahamian, Harris Perlman, Kenneth Walsh

Published in: Arthritis Research & Therapy | Issue 1/2017

Login to get access

Abstract

Background

Rheumatoid arthritis (RA) is a common autoimmune disease characterized by chronic inflammation of the joints, leading to bone erosion and joint dysfunction. Despite the recent successes of disease-modifying anti-rheumatic drugs (DMARDs), there is still clinical need for understanding the development and molecular etiology of RA. Wnts are developmental morphogens whose roles in adult pathology are poorly characterized. Wnt5a is a member of the non-canonical family of Wnts that modulates a wide range of cell processes, including differentiation, migration, and inflammation. Wnt5a has been implicated as a possible contributor to arthritis and it is upregulated in synovial fibroblasts from RA patients.

Methods

We investigated the role of endogenous Wnt5a in RA. Tamoxifen-inducible, Wnt5a knockout (Wnt5a cKO) mice and littermate controls were monitored for arthritis development and joint pathology using the K/BxN serum transfer-induced arthritis (STIA) model. To explore a role of Wnt5a in osteoclast fusion, bone marrow-derived monocytes (BMDMs) were differentiated in vitro.

Results

Wnt5a cKO mice were resistant to arthritis development compared to control littermates as assessed by ankle thickness and histologic measurements. Some parameters of inflammation were reduced in the Wnt5a cKO mice, including the extent of polymononuclear cell infiltration and extra-articular inflammation. Wnt5a cKO mice also exhibited less cartilage destruction and a reduction in osteoclast activity with concomitant reduction in tartrate-resistant acid phosphatase (TRAP), cathepsin K (CTSK), macrophage colony-stimulating factor (MCSF), matrix metalloproteinase (MMP)2 and MMP9 in the arthritic joints. Treatment of BMDMs with Wnt5a enhanced osteoclast fusion and increased the expression of dendrocyte-expressed seven transmembrane protein (DCSTAMP) and MMP9, that are necessary for osteoclast formation and activity.

Conclusions

These data suggest that Wnt5a modulates the development of arthritis by promoting inflammation and osteoclast fusion, and provide the first mouse genetic evidence of a role for endogenous Wnt5a in autoimmune disease.
Appendix
Available only for authorised users
Literature
1.
Koenders MI, van den Berg WB. Novel therapeutic targets in rheumatoid arthritis. Trends Pharmacol Sci. 2015;36(4):189–95.CrossRefPubMed
2.
McInnes IB, O'Dell JR. State-of-the-art: rheumatoid arthritis. Ann Rheum Dis. 2010;69(11):1898–906.CrossRefPubMed
3.
del Rincón ID, Williams K, Stern MP, Freeman GL, Escalante A. High incidence of cardiovascular events in a rheumatoid arthritis cohort not explained by traditional cardiac risk factors. Arthritis Rheum. 2001;44(12):2737–45.CrossRefPubMed
4.
Meune C, Touzé E, Trinquart L, Allanore Y. Trends in cardiovascular mortality in patients with rheumatoid arthritis over 50 years: a systematic review and meta-analysis of cohort studies. Rheumatology (Oxford). 2009;48(10):1309–13.CrossRef
5.
6.
Niehrs C. The complex world of WNT receptor signalling. Nat Rev Mol Cell Biol. 2012;13(12):767–79.CrossRefPubMed
7.
Bretón-Romero R, Feng B, Holbrook M, Farb MG, Fetterman JL, Linder EA, Berk BD, Masaki N, Weisbrod RM, Inagaki E, et al. Endothelial dysfunction in human diabetes is mediated by Wnt5a-JNK signaling. Arterioscler Thromb Vasc Biol. 2016;36(3):561–9.CrossRefPubMedPubMedCentral
8.
Farb MG, Karki S, Park SY, Saggese SM, Carmine B, Hess DT, Apovian C, Fetterman JL, Bretón-Romero R, Hamburg NM, et al. WNT5A-JNK regulation of vascular insulin resistance in human obesity. Vasc Med. 2016;21(6):489-96.
9.
Kikuchi R, Nakamura K, MacLauchlan S, Ngo DT, Shimizu I, Fuster JJ, Katanasaka Y, Yoshida S, Qiu Y, Yamaguchi TP, et al. An antiangiogenic isoform of VEGF-A contributes to impaired vascularization in peripheral artery disease. Nat Med. 2014;20(12):1464–71.CrossRefPubMedPubMedCentral
10.
Fuster JJ, Zuriaga MA, Ngo DT, Farb MG, Aprahamian T, Yamaguchi TP, Gokce N, Walsh K. Noncanonical Wnt signaling promotes obesity-induced adipose tissue inflammation and metabolic dysfunction independent of adipose tissue expansion. Diabetes. 2015;64(4):1235–48.CrossRefPubMed
11.
Nakamura K, Sano S, Fuster JJ, Kikuchi R, Shimizu I, Ohshima K, Katanasaka Y, Ouchi N, Walsh K. Secreted frizzled-related protein 5 diminishes cardiac inflammation and protects the heart from ischemia/reperfusion injury. J Biol Chem. 2016;291(6):2566–75.CrossRefPubMed
12.
Ouchi N, Higuchi A, Ohashi K, Oshima Y, Gokce N, Shibata R, Akasaki Y, Shimono A, Walsh K. Sfrp5 is an anti-inflammatory adipokine that modulates metabolic dysfunction in obesity. Science. 2010;329(5990):454–7.CrossRefPubMedPubMedCentral
13.
Halleskog C, Dijksterhuis JP, Kilander MB, Becerril-Ortega J, Villaescusa JC, Lindgren E, Arenas E, Schulte G. Heterotrimeric G protein-dependent WNT-5A signaling to ERK1/2 mediates distinct aspects of microglia proinflammatory transformation. J Neuroinflammation. 2012;9:111.CrossRefPubMedPubMedCentral
14.
Blumenthal A, Ehlers S, Lauber J, Buer J, Lange C, Goldmann T, Heine H, Brandt E, Reiling N. The Wingless homolog WNT5A and its receptor Frizzled-5 regulate inflammatory responses of human mononuclear cells induced by microbial stimulation. Blood. 2006;108(3):965–73.CrossRefPubMed
15.
Pereira C, Schaer DJ, Bachli EB, Kurrer MO, Schoedon G. Wnt5A/CaMKII signaling contributes to the inflammatory response of macrophages and is a target for the antiinflammatory action of activated protein C and interleukin-10. Arterioscler Thromb Vasc Biol. 2008;28(3):504–10.CrossRefPubMed
16.
Rauner M, Stein N, Winzer M, Goettsch C, Zwerina J, Schett G, Distler JH, Albers J, Schulze J, Schinke T, et al. WNT5A is induced by inflammatory mediators in bone marrow stromal cells and regulates cytokine and chemokine production. J Bone Miner Res. 2012;27(3):575–85.CrossRefPubMed
17.
Yu CH, Nguyen TT, Irvine KM, Sweet MJ, Frazer IH, Blumenthal A. Recombinant Wnt3a and Wnt5a elicit macrophage cytokine production and tolerization to microbial stimulation via Toll-like receptor 4. Eur J Immunol. 2014;44(5):1480–90.CrossRefPubMed
18.
Sen M, Lauterbach K, El-Gabalawy H, Firestein GS, Corr M, Carson DA. Expression and function of wingless and frizzled homologs in rheumatoid arthritis. Proc Natl Acad Sci USA. 2000;97(6):2791–6.CrossRefPubMedPubMedCentral
19.
Sen M, Chamorro M, Reifert J, Corr M, Carson DA. Blockade of Wnt-5A/frizzled 5 signaling inhibits rheumatoid synoviocyte activation. Arthritis Rheum. 2001;44(4):772–81.CrossRefPubMed
20.
Maeda K, Kobayashi Y, Udagawa N, Uehara S, Ishihara A, Mizoguchi T, Kikuchi Y, Takada I, Kato S, Kani S, et al. Wnt5a-Ror2 signaling between osteoblast-lineage cells and osteoclast precursors enhances osteoclastogenesis. Nat Med. 2012;18(3):405–12.CrossRefPubMed
21.
Yamaguchi TP, Bradley A, McMahon AP, Jones S. A Wnt5a pathway underlies outgrowth of multiple structures in the vertebrate embryo. Development. 1999;126(6):1211–23.PubMed
22.
Monach PA, Mathis D, Benoist C. The K/BxN arthritis model. Curr Protoc Immunol. 2008;Chapter 15:Unit 15.22.PubMed
23.
Scatizzi JC, Hutcheson J, Bickel E, Woods JM, Klosowska K, Moore TL, Haines GK, Perlman H. p21Cip1 is required for the development of monocytes and their response to serum transfer-induced arthritis. Am J Pathol. 2006;168(5):1531–41.CrossRefPubMedPubMedCentral
24.
Scatizzi JC, Mavers M, Hutcheson J, Young B, Shi B, Pope RM, Ruderman EM, Samways DS, Corbett JA, Egan TM, et al. The CDK domain of p21 is a suppressor of IL-1beta-mediated inflammation in activated macrophages. Eur J Immunol. 2009;39(3):820–5.CrossRefPubMedPubMedCentral
25.
Misharin AV, Cuda CM, Saber R, Turner JD, Gierut AK, Haines GK, Berdnikovs S, Filer A, Clark AR, Buckley CD, et al. Nonclassical Ly6C(-) monocytes drive the development of inflammatory arthritis in mice. Cell Rep. 2014;9(2):591–604.CrossRefPubMedPubMedCentral
26.
Scatizzi JC, Bickel E, Hutcheson J, Haines GK, Perlman H. Bim deficiency leads to exacerbation and prolongation of joint inflammation in experimental arthritis. Arthritis Rheum. 2006;54(10):3182–93.CrossRefPubMed
27.
Scatizzi JC, Hutcheson J, Bickel E, Haines GK, Perlman H. Pro-apoptotic Bid is required for the resolution of the effector phase of inflammatory arthritis. Arthritis Res Ther. 2007;9(3):R49.CrossRefPubMedPubMedCentral
28.
Perlman H, Georganas C, Pagliari LJ, Koch AE, Haines K, Pope RM. Bcl-2 expression in synovial fibroblasts is essential for maintaining mitochondrial homeostasis and cell viability. J Immunol. 2000;164(10):5227–35.CrossRefPubMed
29.
Chen W, ten Berge D, Brown J, Ahn S, Hu LA, Miller WE, Caron MG, Barak LS, Nusse R, Lefkowitz RJ. Dishevelled 2 recruits beta-arrestin 2 to mediate Wnt5A-stimulated endocytosis of Frizzled 4. Science. 2003;301(5638):1391–4.CrossRefPubMed
30.
Yagi M, Miyamoto T, Sawatani Y, Iwamoto K, Hosogane N, Fujita N, Morita K, Ninomiya K, Suzuki T, Miyamoto K, et al. DC-STAMP is essential for cell-cell fusion in osteoclasts and foreign body giant cells. J Exp Med. 2005;202(3):345–51.CrossRefPubMedPubMedCentral
31.
Wang B, Zinselmeyer BH, Runnels HA, LaBranche TP, Morton PA, Kreisel D, Mack M, Nickerson-Nutter C, Allen PM, Miller MJ. In vivo imaging implicates CCR2(+) monocytes as regulators of neutrophil recruitment during arthritis. Cell Immunol. 2012;278(1-2):103–12.CrossRefPubMedPubMedCentral
32.
Wipke BT, Allen PM. Essential role of neutrophils in the initiation and progression of a murine model of rheumatoid arthritis. J Immunol. 2001;167(3):1601–8.CrossRefPubMed
33.
Duffau P, Menn-Josephy H, Cuda CM, Dominguez S, Aprahamian TR, Watkins AA, Yasuda K, Monach P, Lafyatis R, Rice LM, et al. Promotion of inflammatory arthritis by interferon regulatory factor 5 in a mouse model. Arthritis Rheumatol. 2015;67(12):3146–57.CrossRefPubMedPubMedCentral
34.
Jung YS, Lee HY, Kim SD, Park JS, Kim JK, Suh PG, Bae YS. Wnt5a stimulates chemotactic migration and chemokine production in human neutrophils. Exp Mol Med. 2013;45, e27.CrossRefPubMed
35.
Logan CY, Nusse R. The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol. 2004;20:781–810.CrossRefPubMed
36.
Kurayoshi M, Yamamoto H, Izumi S, Kikuchi A. Post-translational palmitoylation and glycosylation of Wnt-5a are necessary for its signalling. Biochem J. 2007;402(3):515–23.CrossRefPubMedPubMedCentral
37.
Bellon M, Ko NL, Lee MJ, Yao Y, Waldmann TA, Trepel JB, Nicot C. Adult T-cell leukemia cells overexpress Wnt5a and promote osteoclast differentiation. Blood. 2013;121(25):5045–54.CrossRefPubMedPubMedCentral
38.
Bilkovski R, Schulte DM, Oberhauser F, Gomolka M, Udelhoven M, Hettich MM, Roth B, Heidenreich A, Gutschow C, Krone W, et al. Role of WNT-5a in the determination of human mesenchymal stem cells into preadipocytes. J Biol Chem. 2010;285(9):6170–8.CrossRefPubMed
39.
Wang Y, Li YP, Paulson C, Shao JZ, Zhang X, Wu M, Chen W. Wnt and the Wnt signaling pathway in bone development and disease. Front Biosci (Landmark Ed). 2014;19:379–407.CrossRef
40.
Helming L, Gordon S. Molecular mediators of macrophage fusion. Trends Cell Biol. 2009;19(10):514–22.CrossRefPubMed
41.
Long CL, Humphrey MB. Osteoimmunology: the expanding role of immunoreceptors in osteoclasts and bone remodeling. Bonekey Rep. 2012;1:59-65.
42.
43.
MacLauchlan S, Skokos EA, Meznarich N, Zhu DH, Raoof S, Shipley JM, Senior RM, Bornstein P, Kyriakides TR. Macrophage fusion, giant cell formation, and the foreign body response require matrix metalloproteinase 9. J Leukoc Biol. 2009;85(4):617–26.CrossRefPubMedPubMedCentral
44.
Chabot V, Reverdiau P, Iochmann S, Rico A, Sénécal D, Goupille C, Sizaret PY, Sensebé L. CCL5-enhanced human immature dendritic cell migration through the basement membrane in vitro depends on matrix metalloproteinase-9. J Leukoc Biol. 2006;79(4):767–78.CrossRefPubMed
45.
Wucherpfennig AL, Li YP, Stetler-Stevenson WG, Rosenberg AE, Stashenko P. Expression of 92 kD type IV collagenase/gelatinase B in human osteoclasts. J Bone Miner Res. 1994;9(4):549–56.CrossRefPubMed
46.
Kusano K, Miyaura C, Inada M, Tamura T, Ito A, Nagase H, Kamoi K, Suda T. Regulation of matrix metalloproteinases (MMP-2, -3, -9, and -13) by interleukin-1 and interleukin-6 in mouse calvaria: association of MMP induction with bone resorption. Endocrinology. 1998;139(3):1338–45.CrossRefPubMed
47.
Asquith DL, Miller AM, Hueber AJ, Liew FY, Sattar N, McInnes IB. Apolipoprotein E-deficient mice are resistant to the development of collagen-induced arthritis. Arthritis Rheum. 2010;62(2):472–7.PubMed
48.
Postigo J, Genre F, Iglesias M, Fernández-Rey M, Buelta L, Carlos Rodríguez-Rey J, Merino J, Merino R. Exacerbation of type II collagen-induced arthritis in apolipoprotein E-deficient mice in association with the expansion of Th1 and Th17 cells. Arthritis Rheum. 2011;63(4):971–80.CrossRefPubMed
49.
Archer AM, Saber R, Rose S, Shaffer A, Misharin AV, Tsai F, Haines Iii GK, Dominguez S, Eren M, Vaughan DE, et al. ApoE deficiency exacerbates the development and sustainment of a semi-chronic K/BxN serum transfer-induced arthritis model. J Transl Med. 2016;14(1):170.CrossRefPubMedPubMedCentral
50.
Rose S, Eren M, Murphy S, Zhang H, Thaxton CS, Chowaniec J, Waters EA, Meade TJ, Vaughan DE, Perlman H. A novel mouse model that develops spontaneous arthritis and is predisposed towards atherosclerosis. Ann Rheum Dis. 2013;72(1):89–95.CrossRefPubMed
51.
Catalán V, Gómez-Ambrosi J, Rodríguez A, Pérez-Hernández AI, Gurbindo J, Ramírez B, Méndez-Giménez L, Rotellar F, Valentí V, Moncada R, et al. Activation of noncanonical Wnt signaling through WNT5A in visceral adipose tissue of obese subjects is related to inflammation. J Clin Endocrinol Metab. 2014;99(8):E1407–17.CrossRefPubMed
52.
Versini M, Jeandel PY, Rosenthal E, Shoenfeld Y. Obesity in autoimmune diseases: not a passive bystander. Autoimmun Rev. 2014;13(9):981–1000.CrossRefPubMed
53.
Feng J, Chen Q, Yu F, Wang Z, Chen S, Jin Z, Cai Q, Liu Y, He J. Body mass index and risk of rheumatoid arthritis: a meta-analysis of observational studies. Medicine (Baltimore). 2016;95(8), e2859.CrossRef
54.
Del Prete A, Salvi V, Sozzani S. Adipokines as potential biomarkers in rheumatoid arthritis. Mediators Inflamm. 2014;2014:425068.PubMedPubMedCentral
55.
Otero M, Lago R, Gomez R, Lago F, Dieguez C, Gómez-Reino JJ, Gualillo O. Changes in plasma levels of fat-derived hormones adiponectin, leptin, resistin and visfatin in patients with rheumatoid arthritis. Ann Rheum Dis. 2006;65(9):1198–201.CrossRefPubMedPubMedCentral
56.
Yoshino T, Kusunoki N, Tanaka N, Kaneko K, Kusunoki Y, Endo H, Hasunuma T, Kawai S. Elevated serum levels of resistin, leptin, and adiponectin are associated with C-reactive protein and also other clinical conditions in rheumatoid arthritis. Intern Med. 2011;50(4):269–75.CrossRefPubMed
57.
Olama SM, Senna MK, Elarman M. Synovial/serum leptin ratio in rheumatoid arthritis: the association with activity and erosion. Rheumatol Int. 2012;32(3):683–90.CrossRefPubMed
58.
Giles JT, van der Heijde DM, Bathon JM. Association of circulating adiponectin levels with progression of radiographic joint destruction in rheumatoid arthritis. Ann Rheum Dis. 2011;70(9):1562–8.CrossRefPubMedPubMedCentral
59.
Bokarewa M, Nagaev I, Dahlberg L, Smith U, Tarkowski A. Resistin, an adipokine with potent proinflammatory properties. J Immunol. 2005;174(9):5789–95.CrossRefPubMed
Metadata
Title
Genetic deficiency of Wnt5a diminishes disease severity in a murine model of rheumatoid arthritis
Authors
Susan MacLauchlan
Maria A. Zuriaga
José J. Fuster
Carla M. Cuda
Jennifer Jonason
Fernanda Behzadi
Jennifer Parker Duffen
G. Kenneth Haines III
Tamar Aprahamian
Harris Perlman
Kenneth Walsh
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Arthritis Research & Therapy / Issue 1/2017
Electronic ISSN: 1478-6362
DOI
https://doi.org/10.1186/s13075-017-1375-0

Other articles of this Issue 1/2017

Arthritis Research & Therapy 1/2017 Go to the issue

Research article

Blood chemokine profile in untreated early rheumatoid arthritis: CXCL10 as a disease activity marker

Research article

Multiplex serum protein analysis reveals potential mechanisms and markers of response to hyperimmune caprine serum in systemic sclerosis

Research article

Treatment of mucocutaneous manifestations in Behçet’s disease with anakinra: a pilot open-label study

Research article

Early changes in gene expression and inflammatory proteins in systemic juvenile idiopathic arthritis patients on canakinumab therapy

Research article

Chromatin landscapes and genetic risk for juvenile idiopathic arthritis

Research article

Phase 1b randomized, double-blind study of namilumab, an anti-granulocyte macrophage colony-stimulating factor monoclonal antibody, in mild-to-moderate rheumatoid arthritis

ACC 2024 Congress Coverage

Heart Failure Video

Year in Review: Heart failure and cardiomyopathies

Watch now

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits