Active involvement of alarmins S100A8 and S100A9 in the regulation of synovial activation and joint destruction during mouse and human osteoarthritis

Abstract

Objective. To investigate whether alarmins S100A8 and S100A9 are involved in mediating cartilage destruction during murine and human osteoarthritis (OA).Methods. Two different murine models of OA that differed in terms of synovial activation were compared. Cartilage destruction was measured histologically. Synovial biopsy and serum samples from OA patients were derived from the Cohort Hip and Cohort Knee (CHECK) patients with symptomatic early OA. Expression of mediators in the synovium was measured by reverse transcription-polymerase chain reaction analysis and immunolocalization.Results. In collagenase-induced OA, which showed marked synovial activation, interleukin-1␤ was expressed at significant levels only during the early stages of disease, whereas S100A8 and S100A9 expression remained high for a prolonged period of time (up to day 21 after induction). In S100A9-knockout mice, we found a major impact of S100A8 and S100A9 on synovial activation (62% inhibition) and OA cartilage destruction (45-73% inhibition) as compared to wild-type controls. In contrast, in the surgically induced destabilized medial meniscus model, in which synovial involvement is scant, we found no role of S100A8 and S100A9 in the focal OA cartilage destruction. Examination of arthroscopic synovial biopsy samples from patients in the early symptomatic OA CHECK cohort revealed substantial levels of S100A8 and S100A9 messenger RNA and protein, which correlated significantly with synovial lining thickness, cellularity in the subintima, and joint destruction. Levels of S100A8/A9 serum protein were significantly enhanced (19%) at baseline in patients who had pronounced progression of joint destruction after 2 years.Conclusion. Our data suggest that the S100A8 and S100A9 proteins are crucially involved in synovial activation and cartilage destruction during OA and that high levels may predict joint destruction in humans with OA.

Calprotectin in rheumatic diseases

“…42 A moderate CLP increase has been observed in the serum of OA patients compared with healthy controls, particularly in early OA. 37,57,113 Notably, in the study by Vogl et al…”

“…24 Furthermore, in synovial biopsies from OA patients, levels of S100A8 and S100A9 correlated with markers of tissue damage, such as synovial lining thickness, sub-intima cellularity, and cartilage destruction. 57 Synovial CLP expression seems to be increased only if synovial inflammation is present. Vogl et al 57 demonstrated that in a murine model of collagenase-induced OA, which is characterized by synovial inflammation, the expression of S100A8 and S100A9 was higher compared with another model of OA, without synovial inflammation.…”

“…57 Synovial CLP expression seems to be increased only if synovial inflammation is present. Vogl et al 57 demonstrated that in a murine model of collagenase-induced OA, which is characterized by synovial inflammation, the expression of S100A8 and S100A9 was higher compared with another model of OA, without synovial inflammation. Also, CLP serum levels were found higher in OA patients with synovial inflammation compared with those without.…”

The role of damage- and pathogen-associated molecular patterns in inflammation-mediated vulnerability of atherosclerotic plaques

“…and S100A9 are the inducers of MMPs (Moz et al 2016;Schelbergen et al 2012;van Lent et al 2012) (Figure 3) …”

Animal Models of Meniscal Injury in Post-Traumatic Arthritis

“…It is important to note that DMM only induces mild synovial infl ammation in mice [ 38 ], while enzymatically induced-OA model such as intra-articular injection of collagenase causes prolonged joint infl ammation [ 39 ]. Similar to OA in humans, wild type mice following DMM also show subchondral bone changes and osteophyte formation [ 33 , 36 , 40 ].…”