Site‐specific absence of microfibrillar‐associated protein 4 (MFAP4) from the internal elastic membrane of arterioles in the rheumatoid arthritis synovial membrane: an immunohistochemical study in patients with advanced rheumatoid arthritis versus osteoarthritis

Abstract

Sorensen FB. Site-specific absence of microfibrillar-associated protein 4 (MFAP4) from the internal elastic membrane of arterioles in the rheumatoid arthritis synovial membrane: an immunohistochemical study in patients with advanced rheumatoid arthritis versus osteoarthritis. APMIS 2019;127:588-593.Microfibrillar-associated protein 4 (MFAP4) is a non-structural matrix protein with cell regulatory activities and a potential as seromarker for fibrosis. We aimed to study the occurrence of MFAP4 in the synovial membrane from patients with rheumatoid arthritis (RA) vs osteoarthritis (OA). Formaldehyde-fixed synovial tissue sections, from patients with RA (N = 6) and OA (N = 6) undergoing total hip arthroplasty, were deparaffinized and immunostained with monoclonal antibodies against MFAP4. Elastin was detected using ElastiKit. MFAP4 in serum (sMFAP4) and synovial fluid was measured by an immunoassay. MFAP4 was present in synovial biopsies from both RA and OA patients, particularly prominent in deep arterioles where it colocalized with elastin. Notably however, MFAP4 was absent from the internal elastic lamina in RA arterioles irrespective of disease duration and synovitis activity, while present although with irregular staining patterns in OA specimens. sMFAP4 was increased in RA and OA serum vs healthy controls: median (interquartile range) 29.8 (25.3-39.1) and 25.5 U/L (18.1-43.3) vs 17.7 U/L (13.7-21.2), p = 0.006 and p = 0.02, respectively The concentration of synovial fluid was lower than in serum in both RA and OA. These findings may suggest that MFAP4 is involved in adaptive vessel wall remodeling associated with chronic joint disease.

Location, location, location: how the tissue microenvironment affects inflammation in RA

“…In the tissue, it is detected in synovial sub-lining arteriole vessel walls and in adventitial tissue at sites of immune cell infiltration. However, it is absent from the internal elastic membrane of vessels in RA synovia, whilst present at high levels at this site in OA synovia 125 . The consequences of differential distribution of MFAP4 in OA and RA synovia are not yet clear, but these data highlight that alterations in local tissue architecture are not always reflected in 'bulk' serum or tissue analysis.…”

MFAP4 deficiency alleviates renal fibrosis through inhibition of NF‐κB and TGF‐β/Smad signaling pathways

“…MFAP4 is reported to be involved in ECM remodeling-associated diseases, such as vascular stenosis, 13 hepatic fibrosis, 25 and rheumatoid arthritis. 31 The pathophysiological characteristics of renal fibrosis and other fibrotic diseases are similar. Thus, we investigated the regulatory role of MFAP4 in renal fibrosis using MFAP4-deficient mice and TGF-β-treated HK-2 cells.…”

Pathological Investigations And Correlation Research of Microfibrillar-Associated Protein 4 And Tropoelastin In Oral Submucous Fibrosis

“…Current research has shown that MFAP4 expression is correlated with numbers of functions, including coagulation, angiogenesis, tissue growth and remodeling and innate immunity [28][29][30]. Furthermore, increased MFAP4 protein play an extremely significant role in the development of fibrotic diseases, including heart, liver, joint and kidney fibrosis [10,13,14,16,25,31,32]. However, whether MFAP4 is related to OSF procedure has not been intensively investigated.…”