Synovitis in osteoarthritis: current understanding with therapeutic implications

Modern concepts of osteoarthritis (OA) have been forever changed by modern imaging phenotypes demonstrating complex and multi-tissue pathologies involving cartilage, subchondral bone and (increasingly recognized) inflammation of the synovium. The synovium may show significant changes, even before visible cartilage degeneration has occurred, with infiltration of mononuclear cells, thickening of the synovial lining layer and production of inflammatory cytokines. The combination of sensitive imaging modalities and tissue examination has confirmed a high prevalence of synovial inflammation in all stages of OA, with a number of studies demonstrating that synovitis is related to pain, poor function and may even be an independent driver of radiographic OA onset and structural progression. Treating key aspects of synovial inflammation therefore holds great promise for analgesia and also for structure modification. This article will review current knowledge on the prevalence of synovitis in OA and its role in symptoms and structural progression, and explore lessons learnt from targeting synovitis therapeutically

Radiographs and low field MRI (0.2T) as predictors of efficacy in a weight loss trial in obese women with knee osteoarthritis

<p>Abstract</p> <p>Background</p> <p>To study the predictive value of baseline radiographs and low-field (0.2T) MRI scans for the symptomatic outcome of clinically significant weight loss in obese patients with knee osteoarthritis.</p> <p>Methods</p> <p>In this study we hypothesize that imaging variables assessed with radiographs and MRI scans pre-treatment can predict the symptomatic changes following a recommended clinically significant weight reduction Patients were recruited from the Department of Rheumatology, Frederiksberg Hospital, Denmark. Eligibility criteria were: age >18 years; primary osteoarthritis according to ACR; BMI > 28 kg/m2; motivation for weight loss. Subjects were randomly assigned to either intervention by low-energy diet (LED) for 8 weeks followed by another 24 weeks of dietary instruction or control-group. MRI scans and radiographs were scored for structural changes and these parameters were examined as independent predictors of changes in osteoarthritis symptoms after 32 weeks. The outcome assessor and statistician were blinded to group allocation.</p> <p>Results</p> <p>No significant correlations were found between imaging variables and changes in Western Ontario and McMaster Universities Index of Osteoarthritis (Spearman's test, r < 0.33 and P > 0.07).</p> <p>Only the LED group achieved a weight loss, with a mean difference of 16.3 kg (95%CI: 13.4-19.2;P < 0.0001) compared to the control group. The total WOMAC index showed a significant difference favouring LED, with a group mean difference of - 321.3 mm (95%CI: -577.5 to -65.1 mm; P = 0.01). No significant adverse events were reported.</p> <p>Conclusion</p> <p>Stage of joint destruction, assessed on either radiographs or low-field MRI (0.2T), does not preclude a symptoms relief following a clinically relevant weight loss in elderly obese female patients with knee osteoarthritis.</p

With a biomechanical treatment in knee osteoarthritis, less knee pain did not correlate with synovitis reduction

© 2017 The Author(s). Background: Braces are used to treat pain in patellofemoral joint osteoarthritis (PFJOA). In a trial, we previously reported pain improvement after 6-weeks brace use. The pain reduction did not correlate with changes in Magnetic Resonance Imaging (MRI) assessed Bone Marrow Lesion volume or static synovial volume. Studies show that changes in the synovium on dynamic contrast enhanced (DCE) MRI are more closely associated with symptom change than static synovial volume changes. We hypothesised change in synovitis assessed using dynamic imaging could explain the reduction in pain. Method: One hundred twenty-six men and women aged 40-70 years with painful radiographically confirmed PFJOA were randomised to either brace wearing or no brace for 6-weeks. Pain assessment and DCE-MRI were performed at baseline and 6 weeks. DCE data was analysed using Tofts's equation. Pain measures included a VAS of pain on nominated aggravating activity (VAS NA ), and the KOOS pain subscale. Paired t-tests were used to determine within person change in outcome measures and Spearman's correlation coefficients were used to determine the correlation between change in pain and change in the DCE parameters. Results: Mean age of subjects was 55.5 years (SD = 7.5) and 57% were female. There was clear pain improvement in the brace users compared to controls (VAS NA - 16.87 mm, p = < 0.001). There was no significant change to the dynamic synovitis parameters among brace users nor was pain change correlated with change in dynamic synovitis parameters. Conclusion: The reduction in knee pain following brace wearing in patients with PFJOA is not explained by changes in synovitis. Trial registration: Trial registration number UK. ISRCTN50380458 /Registered 21.5.2010

Proteoglycan-4 Regulates Fibroblast to Myofibroblast Transition and Expression of Fibrotic Genes in the Synovium

Background: Synovial tissue fibrosis is common in advanced OA with features including the presence of stress fiber-positive myofibroblasts and deposition of cross-linked collagen type-I. Proteoglycan-4 (PRG4) is a mucinous glycoprotein secreted by synovial fibroblasts and is a major component of synovial fluid. PRG4 is a ligand of the CD44 receptor. Our objective was to examine the role of PRG4-CD44 interaction in regulating synovial tissue fibrosis in vitro and in vivo. Methods: OA synoviocytes were treated with TGF-β ± PRG4 for 24h and α-SMA content was determined using immunofluorescence. Rhodamine-labeled rhPRG4 was incubated with OA synoviocytes ± anti-CD44 or isotype control antibodies and cellular uptake of rhPRG4 was determined following a 30-min incubation and α-SMA expression following a 24-h incubation. HEK-TGF-β cells were treated with TGF-β ± rhPRG4 and Smad3 phosphorylation was determined using immunofluorescence and TGF-β/Smad pathway activation was determined colorimetrically. We probed for stress fibers and focal adhesions (FAs) in TGF-β-treated murine fibroblasts and fibroblast migration was quantified ± rhPRG4. Synovial expression of fibrotic markers: α-SMA, collagen type-I, and PLOD2 in Prg4 gene-trap (Prg4GT) and recombined Prg4GTR animals were studied at 2 and 9 months of age. Synovial expression of α-SMA and PLOD2 was determined in 2-month-old Prg4GT/GT&Cd44−/− and Prg4GTR/GTR&Cd44−/− animals. Results: PRG4 reduced α-SMA content in OA synoviocytes (p \u3c 0.001). rhPRG4 was internalized by OA synoviocytes via CD44 and CD44 neutralization attenuated rhPRG4’s antifibrotic effect (p \u3c 0.05). rhPRG4 reduced pSmad3 signal in HEKTGF- β cells (p \u3c 0.001) and TGF-β/Smad pathway activation (p \u3c 0.001). rhPRG4 reduced the number of stress fiberpositive myofibroblasts, FAs mean size, and cell migration in TGF-β-treated NIH3T3 fibroblasts (p \u3c 0.05). rhPRG4 inhibited fibroblast migration in a macrophage and fibroblast co-culture model without altering active or total TGF-β levels. Synovial tissues of 9-month-old Prg4GT/GT animals had higher α-SMA, collagen type-I, and PLOD2 (p \u3c 0.001) content and Prg4 re-expression reduced these markers (p \u3c 0.01). Prg4 re-expression also reduced α-SMA and PLOD2 staining in CD44-deficient mice. Conclusion: PRG4 is an endogenous antifibrotic modulator in the joint and its effect on myofibroblast formation is partially mediated by CD44, but CD44 is not required to demonstrate an antifibrotic effect in vivo