Abstract
BackgroundSeronegative joint diseases are characterized by a lack of well-defined biomarkers since autoantibodies are not elevated. Calprotectin (S100A8/A9) is a damage-associated molecular pattern (DAMP) which is released by activated phagocytes, and high levels are found in seronegative arthritides. In this study, we investigated the biomarker potential of systemic and local levels of these S100 proteins to assess joint inflammation and joint destruction in an experimental model for seronegative arthritis.MethodsSerum levels of S100A8/A9 and various cytokines were monitored during disease development in interleukin-1 receptor antagonist (IL-1Ra)–/– mice using ELISA and multiplex bead-based immunoassay, and were correlated to macroscopic and microscopic parameters for joint inflammation, bone erosion, and cartilage damage. Local expression of S100A8 and S100A9 and matrix metalloproteinase (MMP)-mediated cartilage damage in the ankle joints were investigated by immunohistochemistry. In addition, local S100A8 and activated MMPs were monitored in vivo by optical imaging using anti-S100A8-Cy7 and AF489-Cy5.5, a specific tracer for activated MMPs.ResultsSerum levels of S100A8/A9 were significantly increased in IL-1Ra–/– mice and correlated with macroscopic joint swelling and histological inflammation, while serum levels of pro-inflammatory cytokines did not correlate with joint swelling. In addition, early serum S100A8/A9 levels were prognostic for disease outcome at a later stage. The increased serum S100A8/A9 levels were reflected by an increased expression of S100A8 and S100A9 within the ankle joint, as visualized by molecular imaging. Next to inflammatory processes, serum S100A8/A9 also correlated with histological parameters for bone erosion and cartilage damage. In addition, arthritic IL-1Ra–/– mice with increased synovial S100A8 and S100A9 expression showed increased cartilage damage that coincided with MMP-mediated neoepitope expression and in vivo imaging of activated MMPs.ConclusionsExpression of S100A8 and S100A9 in IL-1Ra–/– mice strongly correlates with synovial inflammation, bone erosion, and cartilage damage, underlining the potential of S100A8/A9 as a systemic and local biomarker in seronegative arthritis not only for assessing inflammation but also for assessing severity of inflammatory joint destruction.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-016-1121-z) contains supplementary material, which is available to authorized users.
Highlights
Seronegative joint diseases are characterized by a lack of well-defined biomarkers since autoantibodies are not elevated
Serum levels of S100A8/A9 correlate to macroscopic score for swelling in inflamed hind paws of interleukin-1 receptor antagonist (IL-1Ra)–/– mice IL-1Ra–/– mice (n = 26) developed a spontaneous and heterogeneous joint swelling in the hind paws starting at week 6, reaching a combined median joint swelling in both ankle joints of 0.6 on a scale of 0 to 4 with a disease incidence of 70 % at week 15 (Fig. 1a)
Serum levels of S100A8/A9 are prognostic for the development of joint swelling in IL-1Ra–/– mice To investigate whether serum levels of S100A8/A9 are prognostic for disease outcome, serum S100A8/A9 levels were measured in IL-1Ra–/– mice (n = 37) every 2 weeks starting at week 4 when arthritis has not developed yet, and compared to levels in age-matched BALB/c control mice (n = 8)
Summary
Seronegative joint diseases are characterized by a lack of well-defined biomarkers since autoantibodies are not elevated. Calprotectin (S100A8/A9) is a damage-associated molecular pattern (DAMP) which is released by activated phagocytes, and high levels are found in seronegative arthritides. S100A8 (MRP8) and S100A9 (MRP14) are calcium-binding proteins which belong to the group of damage-associated molecular patterns (DAMPs) or alarmins and are selectively expressed in phagocytes, i.e., granulocytes, monocytes, and activated macrophages. Both proteins are co-expressed and form a stable heterodimer S100A8/A9, which is the predominant occurring form and able to activate macrophages via binding and activation of Toll-like receptor (TLR)4-dependent signaling cascades [13]. Human and murine S100A8 and S100A9 show limited sequence similarity, the tertiary structure is very similar and both human and murine S100A8, S100A9, and S100A8/A9 have been shown to bind to TLR4 [14,15,16,17,18]
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