Single-cell communication patterns and their intracellular information flow in synovial fibroblastic osteoarthritis and rheumatoid arthritis.

BACKGROUND: Synovial fibroblasts are critical for maintaining homeostasis in major autoimmune diseases involving joint inflammation, including osteoarthritis and rheumatoid arthritis. However, little is known about the interactions among different cell subtypes and the specific sets of signaling pathways and activities that they trigger. METHODS: Using social network analysis, pattern recognition, and manifold learning approaches, we identified patterns of single-cell communication in OA (osteoarthritis) and RA (rheumatoid arthritis). RESULTS: Our results suggest that OA and RA have distinct cellular communication patterns and signaling pathways. The LAMININ (Laminin) and COLLAGEN (Collagen) pathways predominate in osteoarthritis, while the EGF (Epidermal growth factor), NT (Neurotrophin) and CDH5 (Cadherin 5) pathways predominate in rheumatoid arthritis, with a central role for THY1 (Thy-1 cell surface antigen) +CDH11 (Cadherin 11) + cells. The OA opens the PDGF (Platelet-derived growth factors) pathway (driver of bone angiogenesis), the RA opens the EGF pathway (bone formation) and the SEMA3 (Semaphorin 3A) pathway (involved in immune regulation). Interestingly, we found that OA no longer has cell types involved in the MHC complex (Major histocompatibility complex) and their activity, whereas the MHC complex functions primarily in RA in the presentation of inflammatory antigens, and that the complement system in OA has the potential to displace the function of the MHC complex. The specific signaling patterns of THY1+CDH11+ cells and their secreted ligand receptors are more conducive to cell migration and lay the foundation for promoting osteoclastogenesis. This subpopulation may also be involved in the accumulation of lymphocytes, affecting the recruitment of immune cells. Members of the collagen family (COL1A1 (Collagen Type I Alpha 1 Chain), COL6A2 (Collagen Type VI Alpha 2 Chain) and COL6A1 (Collagen Type VI Alpha 1 Chain)) and transforming growth factor (TGFB3) maintain the extracellular matrix in osteoarthritis and mediate cell migration and adhesion in rheumatoid arthritis, including the PTN (Pleiotrophin) / THBS1 (Thrombospondin 1) interaction. CONCLUSION: Increased understanding of the interaction networks between synovial fibroblast subtypes, particularly the shared and unique cellular communication features between osteoarthritis and rheumatoid arthritis and their hub cells, should help inform the design of therapeutic agents for inflammatory joint disease.

Atherosclerosis is associated with plasminogen activator inhibitor type-1 in chronic haemodialysis patients.

AIM: The aim of the present report was to investigate the probable association of circulating levels of PAI-1 and expression of PAI-1 in internal iliac artery walls with atherosclerotic disease in chronic haemodialysis (HD) patients. METHODS: Sixty-eight non-diabetic HD patients and 50 age- and sex-matched healthy normotensive controls participated in the study. Atherosclerotic disease in both groups was assessed by measuring intima-media thickness (IMT) and plaque score of the common carotid arteries using an ultrasound scanner. Levels of serum PAI-1, C-reactive protein (CRP), interleukin (IL)-6 and lipids profile were measured. Internal iliac artery samples were obtained at the time of renal transplantation. Quantitative expression of PAI-1 in internal iliac artery walls was assessed by positive unit (pu) value using an immunohistochemical method. In addition, the IMT and carotid plaque score were analyzed in relation to circulating levels of PAI-1 and expression of PAI-1 in internal iliac artery walls. RESULTS: Compared with control subjects, HD patients had significantly increased common carotid artery (CCA)-IMT (P = 0.002). Atherosclerotic plaques were detected in 42 (61.76%) of HD patients and in two (4%) controls. The above ultrasonographic indices were correlated with age in HD patients (P < 0.001). A significant relationship was observed between IMT and systolic blood pressure (BP), low-density lipoprotein in HD patients (P < 0.001 and P < 0.001, respectively). In HD patients, IMT was significantly correlated with CRP and IL-6 (P < 0.001 and P < 0.001, respectively). In HD patients, a close correlation was found between serum PAI-1 level, CRP and IL-6 (P < 0.01 and P < 0.01, respectively). A close correlation was also found between PAI-1 pu value, CRP and IL-6 (P < 0.01 and P < 0.01 respectively). Serum PAI-1 level is highly correlated to PAI-1 pu value (P < 0.01). In HD patients, CCA-IMT and plaque score were correlated significantly with circulating levels of PAI-1(P < 0.01 and P < 0.05, respectively) and expression of PAI-1 in internal iliac artery walls (P < 0.01 and P < 0.05, respectively). Multivariate analysis showed that log CRP values were a strong independent contributor to CCA-IMT and plaque score (P = 0.03 and P = 0.04, respectively). Multivariate analysis showed that serum PAI-1 concentration was a strong independent correlate of CCA-IMT and carotid plaque score (P = 0.004 and P = 0.009, respectively). Multivariate analysis also showed that expression of PAI-1 in internal iliac artery walls was a strong independent correlate of CCA-IMT and carotid plaque score (P = 0.008 and P = 0.005, respectively). CONCLUSION: The circulating levels of PAI-1 and expression of PAI-1 in internal iliac artery walls were statistically associated with CRP, IL-6 and low-density lipoprotein cholesterol. Moreover, in HD patients, CCA-IMT and plaque score were correlated significantly with circulating levels of PAI-1 and expression of PAI-1 in internal iliac artery walls and the circulating levels of PAI-1 and expression of PAI-1 in internal iliac artery walls were independent predictors of carotid atherosclerosis including CCA-IMT and carotid plaque score. The correlations may suggest that increased circulating PAI-1 level and upregulated expression of PAI-1 in the vasculature could indicate a chronic endothelium activated state and PAI-1 may more precisely identify the risk of atherothrombosis and be useful as a target for anti-inflammatory treatment strategies.