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Abstract Number: 979

Platelet Derived Growth Factor Receptor Alpha (PDGFRα) Blockade Inhibits Arthritis in Mice

Bhanupriya Madarampalli1, Paul Panipinto 1, Erica Chow 1, Kendahl Sugai 1, Fanqi Shi 1 and Erika Noss 1, 1University of Washington, Seattle, WA

Meeting: 2019 ACR/ARP Annual Meeting

Keywords: Arthritis, Fibroblasts, Inflammation, mouse model and joint damage

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Session Information

Date: Monday, November 11, 2019

Session Title: RA – Animal Models Poster

Session Type: Poster Session (Monday)

Session Time: 9:00AM-11:00AM

Background/Purpose: The interplay between infiltrating immune cells and activated joint stromal cells drives inflammation, cartilage destruction, and bone erosion in rheumatoid arthritis (RA). Among joint cells, fibroblasts amplify inflammation and erode cartilage. Identifying anti-fibroblast therapies to combine with approved drugs targeting the systemic immune response has the potential to improve clinical efficacy without substantially increasing immunosuppressive risk. Based on prior studies showing PDGFRα expression is upregulated in RA synovium and stimulates fibroblast proliferation and matrix invasion in vitro, we propose that targeting platelet-derived growth factor receptor-alpha (PDGFRα) will block synovial fibroblast-mediated inflammation and cartilage erosion, promoting translation of a new anti-PDGFRα biologic for sarcoma treatment to autoimmune arthritis.

Methods: PDGFR expression in human primary synovial fibroblasts was determined by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and flow cytometry analysis. Matrix metalloproteinase (MMP)-3 release was quantified by ELISA. Role of PDGFRα in vivo was tested using the serum transfer arthritis model. PDGFRα-expressing cell populations in arthritic KxB/N mice synovium were analyzed by flow cytometry after ex vivo enzymatic digestion. Since PDGFRα genetic silencing is embryonically lethal, PDGFRα conditional knock out (KO) mice were developed by breeding floxed PDGFRα (B6.Cg-PDGFRatm8SorEiJ) mice with a strain expressing tamoxifen-inducible cre-recombinase under control of the ubiquitin promoter (B6.Cg-Tg(UBC-cre/ERT2)1Ejb/1J). Commercially available anti-PDGFRα antibodies were used to prevent arthritis.

Results: In vitro cultured human synovial fibroblasts expressed higher levels of PDGFRα, compared to the related receptor, PDGFRβ, by qPCR analysis. Although both PDGFRα and PDGFRβ activation increased synovial fibroblast proliferation in vitro, only PDGFRα activation through its specific ligand, PDGF-AA, acted synergistically with TNF-α to increase production of MMP-3, a known biomarker of RA joint damage. PDGFRα KO mice developed less arthritis and histologic damage compared to littermate controls in the serum transfer arthritis model. A pilot antibody treatment experiment also showed that antibodies directed against PDGFRα prevented arthritis development. By flow cytometry, most synovial CD45-CD31- mesenchymal (fibroblast) cells in inflamed KxB/N mice synovium strongly expressed PDGFRα and PDGFRβ. However, PDGFRα was more selectively expressed by fibroblasts, with PDGFRβ also expressed on populations of immune and endothelial cells.

Conclusion: These in vitro and in vivo studies support a role of PDGFRα in regulating synovial fibroblast-mediated pathology, indicating that blocking PDGFRα may be a new treatment strategy in inflammatory arthritis. Further investigation of the role of PDGFRα in arthritis development is expected to support translation of a new anti-PDGFRα cancer monoclonal antibody into arthritis treatment. 


Disclosure: B. Madarampalli, None; P. Panipinto, None; E. Chow, None; K. Sugai, None; F. Shi, None; E. Noss, None.

To cite this abstract in AMA style:

Madarampalli B, Panipinto P, Chow E, Sugai K, Shi F, Noss E. Platelet Derived Growth Factor Receptor Alpha (PDGFRα) Blockade Inhibits Arthritis in Mice [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10). https://acrabstracts.org/abstract/platelet-derived-growth-factor-receptor-alpha-pdgfr%ce%b1-blockade-inhibits-arthritis-in-mice/. Accessed January 24, 2021.
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