OP0036 IL-6 ACTIVATES YES-ASSOCIATED PROTEIN (YAP) IN FIBROBLASTS AND INDUCES YAP-SNAIL COMPLEX FORMATION TO DRIVE SYNOVIAL LINING PATHOLOGY IN INFLAMMATORY ARTHRITIS

Background:In rheumatoid arthritis (RA), the fibroblast-like synoviocytes (FLS) in synovial lining become invasive and cause joint destruction. The molecular mechanisms underpinning this pathogenic FLS phenotype are incompletely understood. The FLS descend from Growth differentiation factor 5 (Gdf5)-expressing joint interzone cells in the embryo, and we showed that conditional ablation of the transcriptional co-activator Yes associated protein (Yap) in Gdf5-lineage cells prevents synovial lining hyperplasia after traumatic cartilage injury in mice [1].Objectives:Here, we investigated a potential role for Yap in pathogenic FLS in immune-mediated inflammatory arthritis.Methods:Immunohistochemistry was used to detect Yap in human RA synovium and Yap, Snail and Ctgf in mouse synovium following antigen-induced arthritis (AIA). To determine the effect of Yap knockout (KO) in synovial stromal cells, AIA was induced in Gdf5-Cre;tdTomato;Yapfl/fl (Yap cKO) and Gdf5-Cre;tdTomato;Yapwt/wt (control) mice, or in Pdgfrα-CreER;Yapfl/fl (Yap ciKO, targeting Pdgfrα-expressing fibroblasts) and Yapfl/fl or YapWT/fl (control) mice after adult tamoxifen induction. Yap KO in both models was confirmed by immunohistochemistry. After nine days, arthritis severity was determined by histological scoring of synovial lining hyperplasia, immune infiltrates, cellular exudate, and marginal erosions. TdTomato+ Gdf5-lineage cells in synovium were quantified. In vitro, Yap reporter cells were treated with inflammatory cytokines to evaluate their ability to stimulate Yap-induced GFP expression by flow cytometry. Snail overexpression, siRNA-mediated Yap knockdown, and IL-6/sIL-6R stimulation were performed on normal mouse FLS, AIA-FLS or human RA-FLS, and cell invasion through a matrigel-coated transwell was quantified. A proximity ligation assay was utilised to detect Yap/Snail complex formation.Results:Average expression levels of Yap (p<0.0001), its transcription factor partner Snail (p=0.002), and their downstream target Ctgf (p=0.0003), were increased in mouse synovium after AIA (n=5), and Yap was highly expressed by FLS in human RA synovium. Yap cKO mice (n=24) showed a significantly decreased arthritis severity (p=0.002) after AIA compared to controls (n=22), with significant reductions in synovial lining hyperplasia (p<0.001), synovial immune cell infiltrates (p=0.026) and marginal erosions (p=0.002). Similarly, Yap ciKO mice (n=6) showed a significant decrease in arthritis score (p=0.039) after AIA compared to controls (n=9). However, both control mice (p<0.001) and Yap cKO mice (p<0.001) showed an extensive expansion of tdTomato+ Gdf5-lineage synovial cells after AIA, with no significant difference between control and Yap cKO mice. In vitro, Yap knockdown prevented IL-6/sIL-6R-induced invasion of normal mouse FLS (p=0.037) and decreased the invasiveness of AIA-FLS (p=0.0057). Using Yap reporter cells, we found that Yap was activated by IL-6/sIL-6R (p=0.016), but not TNFα or IL-1β. Finally, IL-6/sIL-6R treatment of normal mouse FLS (p=0.033) or human RA-FLS (p=0.036) induced Yap-Snail complex formation, and Yap knockdown prevented FLS invasion induced by Snail overexpression (p=0.027).Conclusion:These data demonstrate that via activation by IL-6, and co-operation with the transcription factor Snail, Yap acts as a key modulator of the invasive and destructive phenotype of FLS in inflammatory arthritis. Therapeutic targeting of Yap could reduce joint destruction in RA.References:[1]A. J. Roelofs et al., “Joint morphogenetic cells in the adult mammalian synovium,” Nat. Commun., vol. 8, no. May, p. 15040, 2017. DOI: 10.1136/annrheumdis-2018-213799Acknowledgements:This work was funded by the Medical Research Council (MR/L020211/1 and MR/L022893/1) and Versus Arthritis (20775 and 21156).Disclosure of Interests:None declared

Rheumatoid Arthritis

Chapter 30 discusses rheumatoid arthritis (RA), which is the most common inflammatory arthritis and increases in incidence with age. Radiographs of the hand and feet are the primary imaging modality used for diagnosis and assessing response to treatment. The characteristic marginal erosions of the hands and feet of chronic disease are virtually diagnostic of RA. Ultrasound and MRI are highly sensitive and specific for the articular changes of RA. MRI is the only modality proven to identify bone marrow edema (BME), which is characteristic of early RA and predictive of future erosions. Early RA diagnosis and treatment with disease-modifying antirheumatic drugs (DMARDs) has resulted in a trend toward less severe imaging findings, fewer physical limitations and improved outcomes.

Characteristics of Accelerated Hand Osteoarthritis: Data from the Osteoarthritis Initiative

Objective.We aimed to determine whether hand joints develop an accelerated form of osteoarthritis (OA) and to characterize individuals who develop accelerated hand osteoarthritis (AHOA).Methods.We evaluated 3519 participants in the Osteoarthritis Initiative with complete data for baseline and 48-month radiographic hand osteoarthritis (HOA). One reader scored posteroanterior radiographs of the dominant hand using a modified Kellgren-Lawrence (KL) scale and another reader scored the presence of central or marginal erosions. A third reader read images flagged for signs of diseases other than OA. We defined AHOA as ≥ 1 joints that progressed from a KL grade of 0 or 1 at baseline to KL grade 3 or 4 at 48 months.Results.The definition of AHOA was met by 1% over 4 years: 37 hands had 1 joint affected and 1 hand had 2 joints affected. At baseline, adults who developed AHOA were more likely to have hand pain (37% vs 22%), radiographic HOA (71% vs 36%), as well as central (22% vs 7%) and marginal erosions (11% vs 2%) in other joints compared to those without AHOA. Adults with AHOA were more likely to develop new erosions over 48 months (central 35%, marginal 5%) than those without AHOA (central 5%, marginal 1%). The most common locations of accelerated OA were the second metacarpophalangeal and first carpometacarpal joint.Conclusion.Accelerated OA can occur in the hand, especially among digits commonly used for pinching and fine motor skills.

Monitoring marginal erosion in hydroelectric reservoirs with terrestrial mobile laser scanner

Marginal erosions in reservoirs of hydroelectric plants have caused economic and environmental problems concerning hydroelectric power generation, reduction of productive areas and devaluing land parcels. The real extension and dynamics of these erosion processes are not well known for Brazilian reservoirs. To objectively assess these problems Unesp (Univ Estadual Paulista) and Duke Energy are developing a joint project which aims at the monitoring the progression of some erosive processes and understanding the causes and the dynamics of this phenomenon. Mobile LASER scanning was considered the most suitable alternative for the challenges established in the project requirements. A MDL DynaScan Mobile LASER M150 scanner was selected which uses RTK for real time positioning integrated to an IMU, enabling instantaneous generation of georeferenced point clouds. Two different reservoirs were choose for monitoring: Chavantes (storage plant) and Rosana (run-of-river plant), both in the Paranapanema River, border of São Paulo and Paraná States, Brazil. The monitoring areas are scanned quarterly and analysed with base on the point cloud, meshes, contours and cross sections. Cross sections are used to visualize and compute the rate and the dynamics of erosion. Some examples and quantitative results are presented along with an analysis of the proposed technique. Some recommendations to improve the field work and latter data processing are also introduced.