Abstract
A strong crosstalk exists between endoplasmic reticulum (ER) stress and synovitis. Several ER chaperone proteins, besides their function in protein folding, can enhance inflammation and immunogenicity when secreted. This research aims at localizing and quantifying by immunohistochemistry (IHC) ER stress proteins (BiP, HYOU1, MANF, PDIA4, GANAB, HSP90B1, TXNDC5, DNAJB11, LMAN1, ERP29 and CALR) in synovial membranes provided from patients with osteoarthritis (OA; n = 9), chronic pyrophosphate arthropathy (CPPA; n = 7) and rheumatoid arthritis (RA; n = 8) and exhibiting continuous degree of inflammation. It also investigates ER protein expressions in fibroblast-like synoviocytes (FLS) under ER stress, pro-inflammatory and pro-fibrotic conditions. This study demonstrates the restricted localization of these proteins to the lining layer when inflammation was mild and in the whole synovium when the inflammation was severe. Differential expression of some ER stress proteins in synovitis was confirmed by using the CIOA mouse model. Tunicamycin-induced ER stress enhanced the intracellular protein expression of BiP, HYOU1, MANF, PDIA4, HSP90B1, LMAN1 and CALR in FLS and their extracellular secretion (except for HYOU1, MANF and LMAN1). Induction of inflammation with TNF-a upregulated BiP, HYOU1, MANF and PDIA4 expression, whereas exposure to the pro-fibrotic mediator TGF-b elevated expression of BiP, HYOU1, MANF and DNAJB11 in FLS.