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Arthritis Research & Therapy
Published in: Arthritis Research & Therapy 1/2016

Open Access 01-12-2016 | Research article

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

Authors: Mohammed Talha Shekhani, Toni S. Forde, Altynai Adilbayeva, Mohamed Ramez, Askhat Myngbay, Yergali Bexeitov, Volkhard Lindner, Vyacheslav A. Adarichev

Published in: Arthritis Research & Therapy | Issue 1/2016

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Abstract

Background

The 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.

Methods

Synovial 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.

Results

Immunohistochemical 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).

Conclusion

CTHRC1 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.
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Literature
1.
Li X, Makarov SS. An essential role of NF-kappaB in the “tumor-like” phenotype of arthritic synoviocytes. Proc Natl Acad Sci USA. 2006;103(46):17432–7.CrossRefPubMedPubMedCentral
2.
3.
Lefevre S, Knedla A, Tennie C, Kampmann A, Wunrau C, Dinser R, et al. Synovial fibroblasts spread rheumatoid arthritis to unaffected joints. Nat Med. 2009;15(12):1414–20.CrossRefPubMedPubMedCentral
4.
Tolboom TC, Mil AH, van der Helm-Van, Nelissen RG, Breedveld FC, Toes RE, Huizinga TW. Invasiveness of fibroblast-like synoviocytes is an individual patient characteristic associated with the rate of joint destruction in patients with rheumatoid arthritis. Arthritis Rheum. 2005;52(7):1999–2002.CrossRefPubMed
5.
Firestein GS, Echeverri F, Yeo M, Zvaifler NJ, Green DR. Somatic mutations in the p53 tumor suppressor gene in rheumatoid arthritis synovium. Proc Natl Acad Sci USA. 1997;94(20):10895–900.CrossRefPubMedPubMedCentral
6.
Chang SK, Gu Z, Brenner MB. Fibroblast-like synoviocytes in inflammatory arthritis pathology: the emerging role of cadherin-11. Immunol Rev. 2010;233(1):256–66.CrossRefPubMed
7.
Huang CF, Lira C, Chu K, Bilen MA, Lee YC, Ye X, et al. Cadherin-11 increases migration and invasion of prostate cancer cells and enhances their interaction with osteoblasts. Cancer Res. 2010;70(11):4580–9.CrossRefPubMedPubMedCentral
8.
Kaur H, Phillips-Mason PJ, Burden-Gulley SM, Kerstetter-Fogle AE, Basilion JP, Sloan AE, Brady-Kalnay SM. Cadherin-11, a Marker of the Mesenchymal Phenotype, Regulates Glioblastoma Cell Migration and Survival In Vivo. Mol Cancer Res. 2012;10(3):293–304.
9.
Kudryavtseva E, Forde TS, Pucker AD, Adarichev VA. Wnt signaling genes of murine chromosome 15 are involved in sex-affected pathways of inflammatory arthritis. Arthritis Rheum. 2012;64(4):1057–68.CrossRefPubMed
10.
Durmus T, LeClair RJ, Park KS, Terzic A, Yoon JK, Lindner V. Expression analysis of the novel gene collagen triple helix repeat containing-1 (Cthrc1). Gene Expr Patterns. 2006;6(8):935–40.CrossRefPubMed
11.
Kimura H, Kwan KM, Zhang Z, Deng JM, Darnay BG, Behringer RR, et al. Cthrc1 is a positive regulator of osteoblastic bone formation. PLoS One. 2008;3(9), e3174.CrossRefPubMedPubMedCentral
12.
LeClair RJ, Durmus T, Wang Q, Pyagay P, Terzic A, Lindner V. Cthrc1 is a novel inhibitor of transforming growth factor-beta signaling and neointimal lesion formation. Circ Res. 2007;100(6):826–33.CrossRefPubMed
13.
Pyagay P, Heroult M, Wang Q, Lehnert W, Belden J, Liaw L, et al. Collagen triple helix repeat containing 1, a novel secreted protein in injured and diseased arteries, inhibits collagen expression and promotes cell migration. Circ Res. 2005;96(2):261–8.CrossRefPubMed
14.
Tang L, Dai DL, Su M, Martinka M, Li G, Zhou Y. Aberrant expression of collagen triple helix repeat containing 1 in human solid cancers. Clin Cancer Res. 2006;12(12):3716–22.CrossRefPubMed
15.
Kharaishvili G1, Cizkova M, Bouchalova K, Mgebrishvili G, Kolar Z, Bouchal J. Collagen Triple Helix Repeat Containing 1 Protein, Periostin and Versican in Primary and Metastatic Breast Cancer: an Immunohistochemical Study. J Clin Pathol. 2011;64(11):977–82.
16.
Duarte CW, Stohn JP, Wang Q, Emery IF, Prueser A, Lindner V. Elevated plasma levels of the pituitary hormone cthrc1 in individuals with red hair but not in patients with solid tumors. PLoS One. 2014;9(6), e100449.CrossRefPubMedPubMedCentral
17.
Magnani DM, Lyons ET, Forde TS, Shekhani MT, Adarichev VA, Splitter GA. Osteoarticular tissue infection and development of skeletal pathology in murine brucellosis. Dis Model Mech. 2013;6(3):811–8.CrossRefPubMedPubMedCentral
18.
Adarichev VA, Vermes C, Hanyecz A, Mikecz K, Bremer EG, Glant TT. Gene expression profiling in murine autoimmune arthritis during the initiation and progression of joint inflammation. Arthritis Res Ther. 2005;7(2):R196–207.CrossRefPubMed
19.
Schneider CA, Rasband WS, Eliceiri KW. NIH Image to ImageJ: 25 years of image analysis. Nat Methods. 2012;9(7):671–5.CrossRefPubMed
20.
21.
Ohsawa K, Imai Y, Kanazawa H, Sasaki Y, Kohsaka S. Involvement of Iba1 in membrane ruffling and phagocytosis of macrophages/microglia. J Cell Sci. 2000;113(Pt 17):3073–84.PubMed
22.
Chung JI1, Barua S, Choi BH, Min BH, Han HC, Baik EJ. Anti-inflammatory Effect of Low Intensity Ultrasound (LIUS) on Complete Freund's Adjuvant-induced Arthritis Synovium. Osteoarthritis Cartilage. 2012;20(4):314–22.
23.
Steenvoorden MM, Tolboom TC, van der Pluijm G, Lowik C, Visser CP, DeGroot J, et al. Transition of healthy to diseased synovial tissue in rheumatoid arthritis is associated with gain of mesenchymal/fibrotic characteristics. Arthritis Res Ther. 2006;8(6):R165.CrossRefPubMedPubMedCentral
24.
Jeong JA, Ko KM, Bae S, Jeon CJ, Koh GY, Kim H. Genome-wide differential gene expression profiling of human bone marrow stromal cells. Stem Cells. 2007;25(4):994–1002.CrossRefPubMed
25.
Kurth TB, Dell’accio F, Crouch V, Augello A, Sharpe PT, De Bari C. Functional mesenchymal stem cell niches in adult mouse knee joint synovium in vivo. Arthritis Rheum. 2011;63(5):1289–300.CrossRefPubMed
26.
Marinova-Mutafchieva L, Williams RO, Funa K, Maini RN, Zvaifler NJ. Inflammation is preceded by tumor necrosis factor-dependent infiltration of mesenchymal cells in experimental arthritis. Arthritis Rheum. 2002;46(2):507–13.CrossRefPubMed
27.
Noss EH, Brenner MB. The role and therapeutic implications of fibroblast-like synoviocytes in inflammation and cartilage erosion in rheumatoid arthritis. Immunol Rev. 2008;223:252–70.CrossRefPubMed
28.
Ochi T, Yoshikawa H, Toyosaki-Maeda T, Lipsky PE. Mesenchymal stromal cells. Nurse-like cells reside in the synovial tissue and bone marrow in rheumatoid arthritis. Arthritis Res Ther. 2007;9(1):201.CrossRefPubMedPubMedCentral
29.
Choi HS, Ryu CJ, Choi HM, Park JS, Lee JH, Kim KI, et al. Effects of the pro-inflammatory milieu on the dedifferentiation of cultured fibroblast-like synoviocytes. Mol Med Rep. 2012;5(4):1023–6.PubMedPubMedCentral
30.
Yamamoto S, Nishimura O, Misaki K, Nishita M, Minami Y, Yonemura S, et al. Cthrc1 selectively activates the planar cell polarity pathway of Wnt signaling by stabilizing the Wnt-receptor complex. Dev Cell. 2008;15(1):23–36.CrossRefPubMed
31.
Liu G, Sengupta PK, Jamal B, Yang HY, Bouchie MP, Lindner V, et al. N-glycosylation induces the CTHRC1 protein and drives oral cancer cell migration. J Biol Chem. 2013;288(28):20217–27.CrossRefPubMedPubMedCentral
32.
Chen YL, Wang TH, Hsu HC, Yuan RH, Jeng YM. Overexpression of CTHRC1 in hepatocellular carcinoma promotes tumor invasion and predicts poor prognosis. PLoS One. 2013;8(7), e70324.CrossRefPubMedPubMedCentral
33.
Yamazaki CM, Kadoya Y, Hozumi K, Okano-Kosugi H, Asada S, Kitagawa K, et al. A collagen-mimetic triple helical supramolecule that evokes integrin-dependent cell responses. Biomaterials. 2010;31(7):1925–34.CrossRefPubMed
34.
Knight CG, Morton LF, Peachey AR, Tuckwell DS, Farndale RW, Barnes MJ. The collagen-binding A-domains of integrins alpha(1)beta(1) and alpha(2)beta(1) recognize the same specific amino acid sequence, GFOGER, in native (triple-helical) collagens. J Biol Chem. 2000;275(1):35–40.CrossRefPubMed
35.
Schäffler A1, Buechler C. CTRP Family: Linking Immunity to Metabolism. Trends Endocrinol Metab. 2012;23(4):194-204.
Metadata
Title
Collagen triple helix repeat containing 1 is a new promigratory marker of arthritic pannus
Authors
Mohammed Talha Shekhani
Toni S. Forde
Altynai Adilbayeva
Mohamed Ramez
Askhat Myngbay
Yergali Bexeitov
Volkhard Lindner
Vyacheslav A. Adarichev
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Arthritis Research & Therapy / Issue 1/2016
Electronic ISSN: 1478-6362
DOI
https://doi.org/10.1186/s13075-016-1067-1

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