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OBJECTIVE: To examine the involvement of the metastasis-inducing protein S100A4 (Mts-1) in the pathogenesis of rheumatoid arthritis (RA). METHODS: Synovial tissue, synovial fluid, and plasma were obtained from RA and osteoarthritis (OA) patients who were undergoing joint surgery. Immunohistochemical and immunofluorescence analyses and enzyme-linked immunosorbent assays were used to determine the locations and concentrations of S100A4. The conformational structure of S100A4 in plasma and synovial fluid was determined after fractionation by size-exclusion chromatography, protein separation by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and Western blot analysis. Expression of various S100 proteins in RA synovium was determined by immunofluorescence and double-staining using specific anti-S100 antibodies. RESULTS: We found an up-regulation of S100A4 in cells infiltrating RA synovial tissue. Most cell types identified by cell-specific markers (fibroblasts, immune cells, and vascular cells) contributed to the production of S100A4 in RA synovial tissue. The pattern of S100A4 expression differed significantly from that of the proinflammatory proteins S100A9 and S100A12, which were restricted to phagocytes and granulocytes. The up-regulation of S100A4 in RA synovial tissue was consistent with the high concentrations of the protein in RA versus OA plasma (mean 1,100 versus 211 ng/ml) and synovial fluid (mean 1,980 versus 247 ng/ml). Moreover, we found that S100A4 in RA plasma and synovial fluid was present in bioactive multimeric (M-S100A4) conformations, whereas in OA, the majority of extracellular S100A4 was detected as the less active dimeric form. Consistent with our observations in tumor models, extracellular S100A4 stabilized the p53 tumor suppressor in RA synovial fibroblast-like cells and affected the regulation of p53 target genes, including Bcl-2, p21(WAF), and Hdm-2, as well as matrix metalloproteinases. CONCLUSION: Overexpression of S100A4 in RA synovial tissue and its release as M-S100A4 can influence p53 function and modulate the expression of several genes that are potentially implicated in the disease process. Thus, S100A4 might play an important role in the pathogenesis of RA and might represent a new target for the treatment of RA. [ABSTRACT FROM AUTHOR]

In rats, complete Freund's adjuvant (CFA), injected at the base of the tail, induced a hyperactivation of cellular immune functions and triggered the development of adjuvant arthritis (AA). Before onset of arthritis (Days 9-10 upon CFA), the positive control rats showed significant increases of pituitary prolactin (Prl) mRNA accumulation (Days 3-5). On the other hand, production of pituitary growth hormone (GH) mRNA was significantly reduced from Day 3 onwards. During this early latent period, plasma Prl levels were transiently increased (at least on Day 4), while GH levels were reduced within 8 days (and onwards). Pituitary proopiomelanocortin (POMC) mRNA content progressively decreased with a nadir between Days 6 and 8, accompanied by a loss of the adrenocortical ornithine decarboxylase (ODC) circadian rhythm of activity and a transient reduction of plasma corticosterone (CS) levels (Days 3-6. obvious during the dark phase). At onset of arthritis, the POMC mRNA accumulation and adrenocortical ODC activity increased over their respective baselines. Elevation of plasma CS levels (obvious during the light phase) and important CS-induced thymolysis occurred. Further, hypophysectomized rats did not develop AA. However, hypophysectomized male rats carrying pituitary grafts under the kidney capsule had mild hyperprolactinaemia and developed a worsened arthritic response to CFA, compared to sham-operated controls. On the other hand, intact hyperprolactinaemic male rats showed a delay in the onset and a reduction in the severity of AA. This difference might be due to stimulation of the adrenal cortex in intact pituitary-grafted rats. Such rats showed increased baselines of pituitary POMC mRNA production, adrenocortical ODC activity and plasma CS levels. In addition, during the latent period after CFA, POMC mRNA accumulation, adrenocortical ODC activity and plasma CS levels were only partially suppressed, less than in shamoperated rats. Extensive thymolysis occurred after CFA in these animals-as in the sham-operated rats-but not in the hypophysectomized pituitary-implanted rats. This suggested that in the presence of adrenocortical deficiency, Prl released by the pituitary graft can freely act on the immune system, without being counter-regulated by CS. [ABSTRACT FROM AUTHOR]

We investigated the expression of cartilage oligomeric matrix protein (COMP) in normal and rheumatoid arthritis (RA) synovial fibroblasts. In situ hybridization (ISH) was conducted on synovial specimens from five RA patients applying specific probes for COMP of fibroblast collagen type I. ISH was combined with immunohistochemistry, applying antibodies to the macrophage marker CD68. Ribonuclease protection assay (RPA) and rapid amplification of 3'-cDNA ends (3'-RACE) were performed on total RNA from normal and RA synovial fibroblast cultures. Protein extracts from fibroblasts and culture supernatants were compared with synovial fluids and protein extracts from isolated chondrocytes by Western blot utilizing polyclonal and monoclonal antibodies (18-G3 mAb) to COMP. COMP mRNA was detected in fibroblasts of RA synovium by ISH, and in normal and RA synovial fibroblast cultures by RPA. 3'-RACE demonstrated sequence homology of chondrocyte and synovial fibroblast COMP along the coding sequence. COMP protein was detected in synovial fibroblasts and culture supernatants by immunoblot. Using polyclonal antibodies, the major portion of COMP from fibroblasts and culture supernatants was present as low-molecular-weight (LMW) bands, corresponding to those found in synovial fluids. These LMW COMP bands, however, were not detected in any of the cells or tissues tested using 18-G3 mAb. In protein extracts from chondrocytes and in COMP purified from cartilage, these LMW bands could not be detected. In conclusion, the data suggest that certain forms of COMP detected in synovial fluid are secreted from synovial fibroblasts and could be distinguished by specific mAbs from COMP secreted by chondrocytes. [ABSTRACT FROM PUBLISHER]

We determined the tissue distribution of cartilage oligomeric matrix protein (COMP) in man and evaluated COMP in synovial fluid (SF) and serum. COMP was purified from human articular cartilage. Polyclonal antibodies were used to detect COMP in tissue cryosections and protein extracts. COMP was determined quantitatively and qualitatively in SF and serum by competitive enzyme-linked immunosorbent assay and immunoblotting. Knee joint SF was taken from nine cadaveric and six living controls, 52 patients with osteoarthritis (OA), 85 patients with rheumatoid arthritis (RA) and 60 patients with other forms of inflammatory arthritis. The degradative potential of SF on native COMP was tested in vitro. The highest concentrations of COMP were measured in articular cartilage and meniscus, the lowest in rib and trachea. Compared with controls, the concentrations of COMP in SF and serum were elevated in 36 and 50% of the patients. A total of 84% of patients with RA and 60% of patients with other forms of inflammatory arthritis showed significant amounts of low-molecular-weight COMP fragments (50-70 kDa) in SF. In contrast, SF fragments were present in only 21% of the OA patients. Furthermore, 13% of SF taken from patients with RA or other forms of inflammatory arthritis were able to degrade COMP in vitro. Using inhibitors, the involvement of serine proteinases could be demonstrated in only 8% of the cases. Based on these results, the absolute levels of COMP in SF and serum, and its fragmentation pattern in SF, seem to be promising as markers of joint tissue metabolism. [ABSTRACT FROM PUBLISHER]

Paranoia is a common delusion type found in clinical and non-clinical populations. A hierarchical, dimensional model of paranoia in the general population has been proposed, with four categories representing increasing levels of paranoia: interpersonal sensitivity (IP), mistrust (M), ideas of reference (IR), persecutory ideas (PI). What is currently lacking and could provide insights into etiology is a comprehensive clinical characterization of the lower end of the paranoia spectrum, psychological domains that are associated with symptom severity, and how paranoia and its structure fluctuate over time. This study conducted both cross-sectional and longitudinal surveys with 802 participants from the German population assessing paranoia and general psychopathology. Data was collected through Ecological Momentary Assessment (EMA). Several statistical approaches were used including confirmatory factor analysis (CFA), latent class analysis (LCA) and mixed modelling analyses (ME). Paranoid experiences appear to be a common phenomenon that occur in people with and without mental illness. Subjects clustered into four paranoia severity subgroups (IP, M, IR, PI) and showed significant associations in various psychological domains like increased psychiatric symptoms and maladaptive coping. Paranoia fluctuates over time in all four severity subgroups, but the hierarchical subgrouping was stable. Both persecutory ideations and interpersonal sensitivity were significant predictors of paranoia. Findings provide important insights into the architecture of paranoia in the German population by characterizing their hierarchical, dimensional, and dynamic structure and its link to psychopathology., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)