Morphological characterization of intra-articular HMGB1 expression during the course of collagen-induced arthritis

Abstract

High-mobility group chromosomal box protein 1 (HMGB1) is a structural nuclear protein that promotes inflammation when present extracellularly. Aberrant, extracellular HMGB1 expression has been demonstrated in human and experimental synovitis. The aim of the present study was to elucidate the temporal and spatial expression of HMGB1 compared to that of the central mediators tumor necrosis factor (TNF) and interleukin-1-beta (IL-1β) during the course of collagen-induced arthritis. Thus, Dark Agouti rats were immunized with homologous type II collagen and synovial tissue specimens were obtained at various time points prior to and during the course of clinical arthritis. Local cytokine responses were assessed by immunohistochemistry and by in situ hybridization. We demonstrate a distinct nuclear expression of HMGB1 at early disease-preceding time points. Preceding clinical onset by a few days, cytoplasmic HMGB1 expression was evident in synoviocytes within the non-proliferative lining layer. Pronounced cytoplasmic and additional extracellular HMGB1 expression coincided with the progression of clinical disease. In advanced arthritis, the number of cells with cytoplasmic HMGB1 expression was quantitatively comparable to that of cells expressing TNF and IL-1β. Interestingly, although HMGB1 was abundantly expressed throughout the inflamed synovium at a protein level, upregulation of HMGB1 mRNA was restricted mainly to areas of cartilage and bone destruction. In conclusion, these new findings implicate a role for HMGB1 in both inducing and perpetuating inflammatory events of significant importance in the destructive processes in chronic arthritis.

Genomic Analysis and Differential Expression of HMG and S100A Family in Human Arthritis: Upregulated Expression of Chemokines, IL-8 and Nitric Oxide by HMGB1

“…AMIN AND ISLAM preferentially localized to DNAase I hypersensitive sites, promoters, functional enhancers, and transcription factor binding sites (Cuddapah et al, 2011). The present study shows the simultaneous increase of TSP2, OGN, FGF-18, and S100 and decrease in VEGF, which are relevant to the pathophysiology of OA-affected cartilage and repair (Palmblad et al, 2007;Sparvero et al, 2009;Li et al, 2013). For example, TSP2 regulated the ratio of cartilage to bone during fracture healing (Taylor et al, 2009), and TSP2 -/ -mice showed abnormalities in collagen fibrils (Kyriakides et al, 1999).…”

“…(8) HMGB1 induces MMP-3 and -13 in murine (Liu-Bryan and Terkeltaub, 2010) and human chondrocytes (Unpublished data); (9) HMGB1 or HMGB2 gene deletion (or decreased expression) showed decreased chondrogenesis, reduced superficial zone cellularity, and early onset of OA similar to human OA-affected cartilage (Taniguchi et al, 2009(Taniguchi et al, , 2011. (10) Activated human and mice synovial cells show increased levels of HMGB1 (García-Arnandis et al, 2001, Palmblad et al, 2007.…”

“…One of the key characteristics of OA-affected cartilage was chondrocyte hypertrophy and increased synthesis of type X collagen, which could be driven in vitro by RAGE receptor of HMGB1 (Cecil et al, 2005). Animal models of OA (STR/ort mice) and collagen-induced arthritis showed increased levels of HMGB1 in the synovial membrane, cartilage, meniscus, and ligaments (Palmblad et al, 2007;Kyostio-Moore et al, 2011). The multifunctional activity of HMGs and its functions in tissue injury in other systems prompted us to analyze their expression in one of the target tissues in human OA.…”

Monoclonal Anti-HMGB1 (High Mobility Group Box Chromosomal Protein 1) Antibody Protection in Two Experimental Arthritis Models

“…Differences in histopathology score between studied groups were analyzed by twotailed, nonparametric Mann-Whitney test. (17,19,32). It is thus of particular interest that administration of anti-HMGB1 mAb managed to counteract tissue destruction and cartilage proteoglycan depletion.…”

“…Furthermore, the 2G7 mAb performs excellently in vitro to detect natural HMGB1 in the HMGB1-specific Elispot assay developed by our group (31), in immunohistochemistry studies (32) and to neutralize rHMGB1-induced TNF production in cultured macrophages (11).…”