Inhibition of Synovial Macrophage Pyroptosis Alleviates Synovitis and Fibrosis in Knee Osteoarthritis

Abstract

Increasing evidence has shown that macrophage pyroptosis in different tissues participates in chronic aseptic inflammation and is related to tissue fibrosis. Our last studies also revealed the vital role of synovial fibroblast pyroptosis in the onset and development of knee osteoarthritis (KOA). In this study, we aimed to investigate whether synovial macrophage pyroptosis did occur and whether this form of cell death should be related to synovitis and fibrosis of KOA. In the synovial tissue of KOA model rats, we observed a decrease of caspase1, NLRP3, ASC, and GSDMD caused by macrophage depletion in both the mRNA and protein expressions. Besides, rats treated with the specific caspase1 inhibitor Ac-YVAD-CMK showed less inflammatory reaction and fibrosis, not only in the expression of proinflammatory factors IL-1β, IL-18, and HMGB1 and fibrosis markers TGF-β, PLOD2, COL1A1, and TIMP1 but also in the observation of HE staining, Sirius Red staining, and the transverse diameters of the right knees. Subsequently, we established an LPS+ATP-induced model in macrophages mimicking the inflammatory environment of KOA and inducing macrophage pyroptosis. Macrophages transfected with caspase1 siRNA showed reduced cell death; meanwhile, the relative expression of pyroptosis-related proteins were also downregulated. In addition, the level of fibrotic markers in synovial fibroblasts were significantly decreased after coculture with siRNA GSDMD-transfected macrophages. To conclude, synovial macrophage pyroptosis may occur in the pathological processes of KOA and inhibition of synovial macrophage pyroptosis alleviates synovitis and fibrosis in KOA model rats.

The potential roles of high mobility group box 1 (HMGB1) in musculoskeletal disease: A systematic review

“…A total of 4376 abstracts were screened, and 168 articles were selected for full‐text article screening (Figure 1). After full‐text article screening, 66 articles were included in the systematic review as they fulfilled all selection criteria 13,15,23‐27,32‐91 . Although most studies focused on either human musculoskeletal disease (n = 31) or animal models of musculoskeletal disease (n = 31), four studies investigated HMGB1 in both human and animal models of musculoskeletal disease (Tables 1 and 2).…”

“…HMGB1 expression was increased in animal models of musculoskeletal disease in 22 of 23 studies (Table 3). 13,37,40,44,45,47‐52,54‐56,60,61,63,67,70,83,84,87 …”

“…Twenty‐six studies investigated the role of HMGB1 in animal models of arthritis, including OA and RA 13,15,27,34,35,37,40,44,45,47‐56,59‐61,63,65,67,70‐74,78,83,84,86,87 . In all 18 studies, HMGB1 expression was increased in diseased tissues compared to control tissues 35,37,40,44,45,47,49‐52,56,60,61,63,67,70,84,87 . In control tissues, HMGB1 was mainly localized in the nuclei, whereas arthritic tissues showed more cytoplasmic and extracellular HMGB1 expression as the severity increased.…”

“…In general, HMGB1 expression is increased in tissues of both human and animal models of musculoskeletal disease compared to control tissues, as well as in early (acute) disease compared to late (chronic) disease 13,24‐26,32,33,35‐52,54‐58,60‐64,66‐71,75‐77,80‐85,87‐89,91 . HMGB1 is expressed by both tissue‐resident stromal cells and infiltrating immune cells 24‐26,32,33,42‐48,50‐52,56‐58,60‐64,66,67,69‐71,75,76,80‐82,85,88 .…”

<p>Chrysin Attenuates the NLRP3 Inflammasome Cascade to Reduce Synovitis and Pain in KOA Rats</p>

“…Researches confirmed that the studies of NLRP3-mediated chronic aseptic inflammation are becoming increasingly popular, and evidence of NLRP3 activation has also been found in KOA. 41 The downstream IL-1β and IL-18 have been highly correlated with OA pain. Our research have indicated that NLRP3 may be the effect target of Chrysin, which can effectively attenuate the NLRP3 inflammasome cascade, which is consistent with the various antiinflammatory effects of Chrysin confirmed by other scholars.…”