Scavenger receptor class A type I/II determines matrix metalloproteinase–mediated cartilage destruction and chondrocyte death in antigen‐induced arthritis

Abstract

Objective. Scavenger receptor class A type I (SR-AI) and SR-AII are expressed by macrophages in particular and bind and internalize a broad range of molecules (including endotoxins, apoptotic bodies, and oxidized low-density lipoprotein). This study was undertaken to investigate the role of SR-AI/II in mediating severe cartilage destruction in antigen-induced arthritis (AIA).Methods. AIA was induced in the knee joints of SR-AI/II ؊/؊ mice and wild-type (WT) controls. Joint inflammation and cartilage destruction (chondrocyte death) were measured by examining the histology of total knee joints. Matrix metalloproteinase (MMP)-mediated neoepitopes were measured by immunolocalization using anti-VDIPEN antibodies and chondrocyte activation with anti-S100A8 antibodies. Messenger RNA (mRNA) levels were determined in inflamed synovium using microarray analysis and quantitative reverse transcriptase-polymerase chain reaction. In synovial washouts, cytokines (interleukin-1␤ [IL-1␤], IL-10, and tumor necrosis factor ␣) and S100A8/S100A9 were measured using Luminex and enzyme-linked immunosorbent assay.Results. Levels of SR-AI/II mRNA were strongly elevated in inflamed synovium in AIA. On days 2, 8, and 14 after AIA induction, joint inflammation (exudates/ infiltrate) was similar between the 2 groups. In WT mice, severe cartilage destruction was found in multiple cartilage surfaces of the inflamed knee joint on day 14 after AIA induction. MMP-mediated matrix destruction ranged between 40% and 60%, and chondrocyte death was prominent in 40-75% of the cartilage surfaces. In striking contrast, in SR-AI/II ؊/؊ mice, despite comparable joint inflammation, pronounced cartilage destruction was almost completely absent. Levels of IL-1␤ and S100A8/S100A9 were significantly lower on days 7 and 14 after AIA induction, but levels of mRNA for various MMPs (MMP-2, MMP-3, MMP-9, and MMP-13) were comparable.Conclusion. Our findings indicate that SR-AI and SR-AII are crucial receptors involved in mediating severe cartilage destruction in AIA.

High LDL levels lead to increased synovial inflammation and accelerated ectopic bone formation during experimental osteoarthritis

“…Synovial tissue was weighed and put in Roswell Park Memorial Institute medium (Gibco, Invitrogen), enriched with penicillin/ streptomycin (100 units/mL potassium penicillin and 100 mg/mL streptomycin sulfate; Lonza, Walkersville, MD, USA) and 0.1 % bovine serum albumin (SigmaeAldrich) for 1 h at room temperature. S100A8/A9-complexes were measured in the wash-outs using sandwich enzyme-linked immunosorbent assay (ELISA), as described previously 32,33 . Keratinocyte chemoattractant (KC)-protein levels were measured with Luminex-technology (Biorad, Hercules, CA, USA), using magnetic milliplex beads (Millipore, Billerica, MA, USA) according to the manufacture's protocol.…”

The Conserved Scavenger Receptor Cysteine-Rich Superfamily in Therapy and Diagnosis

“…Moreover, they imply that SR-AI/II could be involved in the development of autoimmunity. Indeed, it has been shown that induction of arthritis in SR-A-deficient mice resulted in decreased severity of disease compared with wild-type mice (van Lent et al, 2009).…”

S100A8-S100A9 Protein Complex Mediates Psoriasis by Regulating the Expression of Complement Factor C3

“…The extracellular function of S100A8-S100A9 is well documented as being a potent chemoattractant in mice and antimicrobial in humans (Nakatsuji and Gallo, 2011). S100A8 and S100A9 bind to several receptors including RAGE and CD36 (Gebhardt et al, 2008;van Lent et al, 2009), thereby affecting downstream signaling through NF-kB and AP-1 (Gebhardt et al, 2006;Grivennikov et al, 2010). These proteins were also identified as downstream targets of NF-kB in carcinogenesis (Né meth et al, 2009).…”