Synovial inflammation in knee osteoarthritis : histological and imaging studies

Although osteoarthritis is a common disease, there are currently no disease-modifying availible. For a long time osteoarthritis was considered a purely degenerative disease without inflammation of the synovium (synovitis). However, recent research has shown that synovitis is of importance in patients with osteoarthritis. Therefore, this thesis aimed to understand the role synovitis in ossteoarthritis. In the first part of this thesis, we investigated the nature of synovitis by examining the synovium of osteoarthritis patients using differnt laboratory techniques. Furthermore, we validated a new synovitis scoring system on MRI with contrast. In the second part of this thesis, we investigated role of synovitis in relation to clinical characteristics such as pain and structural damage. This thesis shows that synovial inflammation in osteoarthritis is not only frequently present, but may also play a role in the pathophysiology of osteoarthritis and development of clinical features. Results presented in this thesis provide insight into different aspects of synovial inflammation aimed at increasing our understanding of the pathophysiology of OA and aiding to the development of disease-modifying drugs in OA.ABN-AMRO, Abbvie B.V., Pfizer, TI-PharmaUBL - phd migration 201

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

Lack of high BMI-related features in adipocytes and inflammatory cells in the infrapatellar fat pad (IFP)

BACKGROUND: Obesity is associated with the development and progression of osteoarthritis (OA). Although the infrapatellar fat pad (IFP) could be involved in this association, due to its intracapsular localization in the knee joint, there is currently little known about the effect of obesity on the IFP. Therefore, we investigated cellular and molecular body mass index (BMI)-related features in the IFP of OA patients. METHODS: Patients with knee OA (N = 155, 68% women, mean age 65 years, mean (SD) BMI 29.9 kg/m2 (5.7)) were recruited: IFP volume was determined by magnetic resonance imaging in 79 patients with knee OA, while IFPs and subcutaneous adipose tissue (SCAT) were obtained from 106 patients undergoing arthroplasty. Crown-like structures (CLS) were determined using immunohistochemical analysis. Adipocyte size was determined by light microscopy and histological analysis. Stromal vascular fraction (SVF) cells were characterized by flow cytometry. RESULTS: IFP volume (mean (SD) 23.6 (5.4) mm(3)) was associated with height, but not with BMI or other obesity-related features. Likewise, volume and size of IFP adipocytes (mean 271 pl, mean 1933 μm) was not correlated with BMI. Few CLS were observed in the IFP, with no differences between overweight/obese and lean individuals. Moreover, high BMI was not associated with higher SVF immune cell numbers in the IFP, nor with changes in their phenotype. No BMI-associated molecular differences were observed, besides an increase in TNFα expression with high BMI. Macrophages in the IFP were mostly pro-inflammatory, producing IL-6 and TNFα, but little IL-10. Interestingly, however, CD206 and CD163 were associated with an anti-inflammatory phenotype, were the most abundantly expressed surface markers on macrophages (81% and 41%, respectively) and CD163(+) macrophages had a more activated and pro-inflammatory phenotype than their CD163(-) counterparts. CONCLUSIONS: BMI-related features usually observed in SCAT and visceral adipose tissue could not be detected in the IFP of OA patients, a fat depot implicated in OA pathogenesis

Synovial pathology detected on ultrasound correlates with the severity of radiographic knee osteoarthritis more than with symptoms

OBJECTIVE: To [1] compare the frequency and severity of ultrasound (US) features in people with normal knees (controls), knee pain (KP), asymptomatic radiographic OA (ROA), and symptomatic OA (SROA), [2] examine relationships between US features, pain and radiographic severity, [3] explore the relationship between change in pain and US features over a 3-month period. METHOD: Community participants were recruited into a multiple group case-control study. All underwent assessment for pain, knee radiographs and US examination for effusion, synovial hypertrophy, popliteal cysts and power Doppler (PD) signal within the synovium. A 3-month follow-up was undertaken in over half of control and SROA participants. RESULTS: 243 participants were recruited (90 controls; 59 KP; 32 ROA; 62 SROA). Effusion and synovial hypertrophy were more common in ROA and SROA participants. Severity of effusion and synovial hypertrophy were greater in SROA compared to ROA (P < 0.05). Severity of US effusion and synovial hypertrophy were correlated with radiographic severity (r = 0.6 and r = 0.7, P < 0.01) but the relationship between pain severity and US features was weak (r = 0.3, P < 0.01). In SROA participants, pain severity did not change in tandem with a change in synovial hypertrophy over time. CONCLUSION: US abnormalities are common in OA. Effusion and synovial hypertrophy were moderately correlated with radiographic severity but the relationship with pain is less strong. The degree to which these features reflect "active inflammation" is questionable and they may be better considered as part of the total organ pathology in OA. Further studies are warranted to confirm these findings

Differential contributions of peripheral and central mechanisms to pain in a rodent model of osteoarthritis

The mechanisms underlying the transition from acute nociceptive pain to centrally maintained chronic pain are not clear. We have studied the contributions of the peripheral and central nervous systems during the development of osteoarthritis (OA) pain. Male Sprague-Dawley rats received unilateral intra-articular injections of monosodium iodoacetate (MIA 1mg) or saline, and weight bearing (WB) asymmetry and distal allodynia measured. Subgroups of rats received intra-articular injections of, QX-314 (membrane impermeable local anaesthetic)+capsaicin, QX-314, capsaicin or vehicle on days 7, 14 or 28 post-MIA and WB and PWT remeasured. On days 7&14 post-MIA, but not day 28, QX-314+capsaicin signfcantly attenuated changes in WB induced by MIA, illustrating a crucial role for TRPV1 expressing nociceptors in early OA pain. The role of top-down control of spinal excitability was investigated. The mu-opioid receptor agonist DAMGO was microinjected into the rostroventral medulla, to activate endogenous pain modulatory systems, in MIA and control rats and refex excitability measured using electromyography. DAMGO (3ng) had a signifcantly larger inhibitory effect in MIA treated rats than in controls. These data show distinct temporal contribtuions of TRPV1 expressing nociceptors and opioidergic pain control systems at later timepoints

Characterization of multinucleated giant cells in synovium and subchondral bone in knee osteoarthritis and rheumatoid arthritis

Background: Multinucleated giant cells have been noticed in diverse arthritic conditions since their first description in rheumatoid synovium. However, their role in the pathogenesis of osteoarthritis (OA) or rheumatoid arthritis (RA) still remains broadly unknown. We aimed to study the presence and characteristics of multinucleated giant cells (MGC) both in synovium and in subchondral bone tissues of patients with OA or RA. Methods: Knee synovial and subchondral bone samples were from age-matched patients undergoing total joint replacement for OA or RA, or non-arthritic post mortem (PM) controls. OA synovium was stratified by histological inflammation grade using index tissue sections. Synovitis was assessed by Krenn score. Histological studies employed specific antibodies against macrophage markers or cathepsin K, or TRAP enzymatic assay. Results: Inflamed OA and RA synovia displayed more multinucleated giant cells than did non-inflamed OA and PM synovia. There was a significant association between MGC numbers and synovitis severity. A TRAP negative/cathepsin K negative Langhans-like subtype was predominant in OA, whereas both Langhans-like and TRAP-positive/ cathepsin K negative foreign-body-like subtypes were most commonly detected in RA. Plasma-like and foam-like subtypes also were observed in OA and RA synovia, and the latter was found surrounding adipocytes. TRAP positive/ cathepsin K positive osteoclasts were only identified adjacent to subchondral bone surfaces. TRAP positive osteoclasts were significantly increased in subchondral bone in OA and RA compared to PM controls. Conclusions: Multinucleated giant cells are associated with synovitis severity, and subchondral osteoclast numbers are increased in OA, as well as in RA. Further research targeting multinucleated giant cells is warranted to elucidate their contributions to the symptoms and joint damage associated with arthritis

Osteoarthritis-related nociceptive behaviour following mechanical joint loading correlates with cartilage damage

In osteoarthritis (OA), the pain-structure relationship remains complex and poorly understood. Here, we used the mechanical joint loading (MJL) model of OA to investigate both knee pathology and nociceptive behaviour

Transglutaminase 2 in cartilage homoeostasis: novel links with inflammatory osteoarthritis.

Transglutaminase 2 (TG2) is highly expressed during chondrocyte maturation and contributes to the formation of a mineralised scaffold by introducing crosslinks between extracellular matrix (ECM) proteins. In healthy cartilage, TG2 stabilises integrity of ECM and likely influences cartilage stiffness and mechanistic properties. At the same time, the abnormal accumulation of TG2 in the ECM promotes chondrocyte hypertrophy and cartilage calcification, which might be an important aspect of osteoarthritis (OA) initiation. Although excessive joint loading and injuries are one of the main causes leading to OA development, it is now being recognised that the presence of inflammatory mediators accelerates OA progression. Inflammatory signalling is known to stimulate the extracellular TG2 activity in cartilage and promote TG2-catalysed crosslinking of molecules that promote chondrocyte osteoarthritic differentiation. It is, however, unclear whether TG2 activity aims to resolve or aggravate damages within the arthritic joint. Better understanding of the complex signalling pathways linking inflammation with TG2 activities is needed to identify the role of TG2 in OA and to define possible avenues for therapeutic interventions