Arthritis & Rheumatism, Volume 63,
November 2011 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Chicago, Illinois November 4-9, 2011.
Collagen Triple Helix Repeat Containing 1 Protein Is a New Synovial Lining Biomarker Overexpressed in Antibody-Mediated Arthritis.
Shekhani1, Mohammed Talha, Forde1, Toni S., Cuttler2, Anne S., Lindner2, Volkhard, Adarichev1, Vyacheslav A.
Hypertrophy of the synovial membrane accompanied by enhanced cell invasiveness and boosted production of cartilage and bone degrading enzymes are a hallmark of rheumatoid arthritis (RA). To find new synovial biomarkers whose expression is affected by sex, and to dissect mechanisms of higher female preponderance in RA, we generated congenic murine strain carrying sex-affected arthritis-protective locus Pgia8a.
To induce arthritis, mice were injected i.p. with cocktail of mAbs to collagen type II followed by LPS stimulation. Differential gene expression analysis of RNA isolated from arthritic paws was performed using Affymetrix GeneChip® Mouse Gene 1.0 ST Array. Collagen Triple Helix Repeat Containing 1 (Cthrc1) transgenic mice FVB-Tg[Cthrc1] were crossed to BALB/c strain to generate mice carrying the discovered sex-affected differentially-expressed Cthrc1 gene in inflammatory-susceptible genetic background. Immunohistochemical staining was performed to identify Cthrc1 in synovial joints and investigate whether the protein expression co-localizes with fibroblast-like and macrophage-like synoviocyte markers.
Using transcriptome analysis, we found that arthritis severity in congenic males is under the control of Cthrc1, Adamts12 and C1qtnf3 locus-specific genes whose expression was tightly correlated with inflammation, r>0.87. Genetic association between Cthrc1 and arthritis was replicated in F1(BALB/c x FVB-Tg[Cthrc1]) mice that showed 30% stronger inflammation than Tg-negative F1 hybrids. Even naïve Tg[Cthrc1] mice exhibited pre-inflammatory phenotype of neutrophilia (30% up, p<0.014) accompanied with peripheral monocytopenia (50% down, p<0.025) and longer blood coagulation time. Immunohistochemical staining of sections of articular joints confirmed a highly inducible pattern of Cthrc1 protein expression, which we observed initially at RNA level using RT-PCR. Importantly, Cthrc1 was localized in synovial lining of arthritic mice, and protein expression was co-localized with pannus development. In synovium of naïve mice, Cthrc1 was almost undetectable. In transgenic mice, protein was expressed in synovial lining even in naïve mice, which might partially explain a stronger arthritis in F1-Tg[Cthrc1] mice when compared to Tg-negative F1 hybrids. Co-localization of Cthrc1 with fibroblast, macrophage and T cell markers is in progress.
Secreted promigratory protein Cthrc1 is a novel biomarker for inflammatory arthritis and hypertrophic synovial lining. When Cthrc1 protein is overexpressed in transgenic mice, it affects multiple systems including blood cell composition, and both normal and inflamed synovium.
To cite this abstract, please use the following information:
Shekhani, Mohammed Talha, Forde, Toni S., Cuttler, Anne S., Lindner, Volkhard, Adarichev, Vyacheslav A.; Collagen Triple Helix Repeat Containing 1 Protein Is a New Synovial Lining Biomarker Overexpressed in Antibody-Mediated Arthritis. [abstract]. Arthritis Rheum 2011;63 Suppl 10 :1637