Selective Deletion of a Pathogenic Subset Synovial Fibroblasts Attenuates Synovial Inflammation

Adam Paul Croft, Joana Campos, Andrew Filer, Francesca Barone and Chris Buckley, Institute of Inflammation and Ageing (IIA), University of Birmingham, Birmingham, United Kingdom

Meeting: 2016 ACR/ARHP Annual Meeting

Date of first publication: September 28, 2016

Keywords: Animal models, Arthritis, Fibroblasts, inflammation and joint damage

Session Information

Date: Wednesday, November 16, 2016

Title: Rheumatoid Arthritis – Animal Models II

Session Type: ACR Concurrent Abstract Session

Session Time: 9:00AM-10:30AM

Background/Purpose: Despite their role as key effector cells driving synovial inflammation and joint damage, fibroblast like synoviocytes (FLS) have yet to be targeted therapeutically. Fibroblast activation protein (FAP) is a cell surface serine protease, known to be expressed at a low level in resting FLS but up-regulated during inflammation (1). Genetic deletion of FAP has been shown to protect against cartilage damage despite no protective effect on inflammation or bone erosion (2). The pathogenic role of FLS expressing FAP is currently unknown. To determine the pathogenic role of FAP expressing FLS in inflammatory arthritis we selectively deleted these cells using a conditional cell deletion stratergy during the effector phase of inflammatory arthritis.

Methods: We utilized a transgenic mouse in which FAP expressing cells were conditionally ablated (FAP-DTR³) by administration of diphtheria toxin in either in a prophylactic or therapeutic regime. Inflammatory polyarthritis was induced by the passive transfer of K/BxN serum into naïve mice. Mice were scored for clinical signs of arthritis and flow cytometry of digested synovial tissue was performed to determine the expression of fibroblast subsets .

Results: We found that FAP expression in the human synovium predicts disease persistence in patients with early synovitis .FAP was dynamically expressed by FLS during inflammatory arthritis and defined a population of activated fibroblasts that co-express the lining layer marker Podoplanin (gp38). Therapeutic deletion of FAP+ cells during either the induction or peak phases of inflammatory arthritis significantly attenuated synovial inflammation leading to a reduction in the clinical severity of arthritis, reduced inflammatory cell infiltration and protection against inflammatory bone changes as measured by micro CT. In contrast, prophylactic deletion of FAP expressing cells led to a delayed onset of inflammatory arthritis, but did not impact on subsequent clinical severity.

Conclusion: These data support a pathogenic role for a subset of FAP expressing FLS in inflammatory arthritis and provide a rationale for the selective targeting of FAP+ fibroblasts as a novel therapeutic approach.

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Disclosure: A. P. Croft, None; J. Campos, None; A. Filer, None; F. Barone, None; C. Buckley, None.

To cite this abstract in AMA style:

Croft AP, Campos J, Filer A, Barone F, Buckley C. Selective Deletion of a Pathogenic Subset Synovial Fibroblasts Attenuates Synovial Inflammation [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/selective-deletion-of-a-pathogenic-subset-synovial-fibroblasts-attenuates-synovial-inflammation/. Accessed .

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