Proteins involved in the endoplasmic reticulum stress are modulated in synovitis of osteoarthritis, chronic pyrophosphate arthropathy and rheumatoid arthritis, and correlate with the histological inflammatory score

Abstract

2D-nano-UPLC-ESI-Q-Orbitrap 2 Dimensional-nano-ultra performance liquid chromatography-electrospay ionization-Q-Orbitrap CALR Calreticulin CPPA Chronic pyrophosphate arthropathy CRP C-reactive protein DAMPS Damage-associated molecular patterns ER Endoplasmic reticulum ERAD ER-associated degradation FLS Fibroblast-like synoviocytes GRP78 Glucose-regulated protein 78 kDa LC-MS/MS Liquid chromatography-tandem mass spectrometry LFQ Label free quantification MRI Magnetic resonance imaging OA Osteoarthritis PMN Polymorphonuclear cells PSM Peptide spectrum match RA Rheumatoid arthritis TLR Toll-like receptors TXNDC5 Thioredoxin domain-containing protein 5 UPR Unfolded protein response US Ultrasonography Osteoarthritis (OA) was for long considered as a degenerative cartilage disease for which synovitis was only visualized in the late stages and considered as secondary to mechanic aggression of bone and cartilage degradation. However, several observations demonstrated that synovitis could appear even in the early stages of OA. Synovium can also acquire an "inflammatory" phenotype in OA with similar characteristics than those observed in rheumatoid arthritis (RA) for which synovitis is the hallmark: [i.e. synovial lining and villous hyperplasia, infiltration by macrophages and lymphocytes, neo-angiogenesis and fibrosis] 1,2. Using magnetic resonance imaging (MRI), Roemer et al. noted a synovitis in 96.3% of knee joints with effusion and in 70% of knee joint without effusion 3. We previously published by using ultrasonography (US) examination that 53.7% (322/600) of patients with painful knee OA had no sign of inflammation whereas 2.7% (16/600) had synovitis alone, 14.2% (85/600) had both synovitis and effusion and 29.5% (177/600) had joint effusion alone 4. US knee synovitis and US joint effusion were significantly associated with a more severe radiological grade (Kellgren-Lawrence grade ≥ 3) and a moderate-important joint effusion at clinical examination 4. Further, several other studies have confirmed the correlation between synovitis area observed by MRI and specific histologic features of synovitis 5. Two major pathways at least can explain the development of synovitis: activation of toll-like receptors (TLR) and activation of the complement cascade 1. Endogenous "damage-associated molecular patterns" (DAMPS) can activate the innate immune response through TLRs recognition promoting pro-inflammatory mediators secretion 6,7. Activation of the complement cascade induces complement deposits sparsely found in the synovium of OA patients. Deposits of synovial complement components were only observed during acute OA flare but not during chronic OA 8. More recently, proteomic analyses of OA synovial fluids 9,10 and transcriptomic studies of OA synovial membranes 10 confirmed the expression and activation of complement in joints 11. Proteomic analysis of synovial tissue was rarely performed 12,13 and none was compared to the histological pattern of synovium. In this work, we compared protein profiles generated by a proteomic s...

Targeting Soluble Epoxide Hydrolase and Cyclooxygenases Enhance Joint Pain Control, Stimulate Collagen Synthesis, and Protect Chondrocytes From Cytokine-Induced Apoptosis

“…Since synovitis and joint inflammation alters the normal collagen synthesis-degradation coupling and contribute to loss of articular cartilage matrix and OA development (1,4,13), we sought to determine the effect of COX and sEH inhibition on the collagendegradation relationship during synovitis. As shown in Figure 5, CPII concentrations were not significantly different during inhibition of COX, sEH, or both whereas C2C concentrations were significantly lower during sEH inhibition compared to COX inhibition and the lowest dose of combined COX and sEH inhibition.…”

“…In equine and human OA, local and systemic release of cytokines such as tumor necrosis factor (TNF)-α and interleukin (IL)-6 are associated with pain (lameness) as well as greater loss of cartilage volume and joint space narrowing (6)(7)(8)(9). As actively secreting cells, chondrocytes are especially susceptible to endoplasmic reticulum (ER) stress, an important mechanism leading to chondrocyte apoptosis (10)(11)(12) which also correlates with synovitis in OA (13).…”

Bioinformatics analysis for the role of CALR in human cancers

“…DNMT inhibitors can play an anti-tumor role in colon and ovarian cancer by up-regulating B2M and CALR [ 46 ]. GANAB and CANX belong to endoplasmic reticulum protein chaperones, which cooperate with CALR to regulate endoplasmic reticulum stress in osteoarthritis and asthma, respectively [ 47 , 48 ]. In triple-negative breast cancer patients, down-regulation of CALR and TAPBP tend to indicate a poor prognosis [ 49 ].Previous studies have shown that the carcinogenic mechanism of CALR is related to the exposure of malignant primordial cells to CALR, HSP70 and HSP90 on the plasma membrane [ 28 ].…”

Influence of Glucocorticoids on Cellular Senescence Hallmarks in Osteoarthritic Fibroblast-like Synoviocytes

“…Regarding synovial biopsies, as used for immunohistochemistry (Figure 1), samples of synovial biopsies were retrospectively selected from our local cohort of OA patients: the synovial biopsies of OA patients (n = 16) were obtained by needle arthroscopy from affected knees. Samples were extracted and stocked as previously described by de Seny et al [8]. Patients were mostly female, with a median age of 58 years (range 29-89) and a median BMI of 30 kg/m 2 (range 18-42).…”

“…The synovial membrane is no longer considered a bystander in OA: synovial hypertrophy is found in 1/3 of patients with OA [6] and this synovitis is associated with subsequent OA development [7]. Chronic low-grade inflammation is present in the synovial membrane; infiltration by immune cells [8] and the cross-talk between cartilage and synovial cells have a major role in OA pathogenesis [9]. In addition, we identified senescent cells in the synovium of OA mice [10] and Diekman et al demonstrated that cartilage senescence could not be the only driver of the pathology [11].…”