Abstract
Rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS) are inflammatory diseases with different bone remodeling patterns. Fibroblast-like synoviocytes (FLS) are cells involved in the transition from an acute and reparable phase to a chronic and persistent stage in these diseases. The distinction of joint phenotypes involves inflammatory cytokines such as tumor necrosis factor alpha (TNF-α), interleukin (IL)-17, and IL-22 directly or through key signaling pathways such as Wnt. To evaluate the role of FLS as the source of Wnt antagonists (sFRP3/FRZB and Dkk1) in the synovia, levels of TNF- α, IL-17, IL-22, Dkk1, and sFRP3 were measured by ELISA directly in the synovial fluid of patients with RA, PsA, or AS. Dkk1 and sFRP3 were also measured in the FLS culture supernatants after different inflammatory stimulus. sFRP3 and Dkk1 are constitutively expressed by FLS. IL-22 and sFRP3 were positively correlated (r=0.76; P<0.01) in synovial fluid. The stimulation of FLS with IL-22, but not TNF-alpha and IL-17, increased the production of sFRP3. No stimulus altered the basal expression of Dkk1. These results showed, for the first time, the ability of IL-22 to increase the expression of sFRP3/FRZB by human FLS in both in vitro and ex vivo models. This finding linked IL-22 to local inhibition of Wnt signaling and possibly to blockade of osteogenesis. Furthermore, FLS presented as a source of this inhibitor in synovial fluid, assigning to this cell a bone injury mechanism.
Highlights
Rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS) are inflammatory joint diseases (IJD) that exhibit distinct bone remodeling patterns
Different biological systems regulate bone remodeling and should be involved in the distinctiveness of tissue damage in each disease. Inflammatory cytokines such as tumor necrosis factor alpha (TNF-a) and interleukins 17 (IL-17) and 22 (IL-22) act modulating both osteoclast- and osteoblastogenesis, directly or indirectly through other systems as the axis composed by the receptor activator of nuclear factor kappa-B (RANK), its ligand (RANKL), and its decoy receptor osteoprotegerin (OPG), and signaling pathways such as Hedgehog (Hh), bone morphogenetic proteins (BMP), and Wingless/Integrated (Wnt)
This study evaluated the role of Fibroblast-like synoviocytes (FLS) as a source of Wnt antagonists in the synovial environment and the contribution of inflammatory cytokines (IL-17, IL-22, and TNF-a) to this function
Summary
Rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS) are inflammatory joint diseases (IJD) that exhibit distinct bone remodeling patterns. Different biological systems regulate bone remodeling and should be involved in the distinctiveness of tissue damage in each disease Inflammatory cytokines such as tumor necrosis factor alpha (TNF-a) and interleukins 17 (IL-17) and 22 (IL-22) act modulating both osteoclast- and osteoblastogenesis, directly or indirectly through other systems as the axis composed by the receptor activator of nuclear factor kappa-B (RANK), its ligand (RANKL), and its decoy receptor osteoprotegerin (OPG), and signaling pathways such as Hedgehog (Hh), bone morphogenetic proteins (BMP), and Wingless/Integrated (Wnt). The Wnt signaling pathway is a highly conserved group of signal transduction pathways involved in bone formation and bone repair from embryogenesis to adult life It encompasses the soluble Wnt ligands (19 currently described in humans) and its extracellular inhibitors, such as Dickkopf-related protein 1 (Dkk1), secreted Frizzledrelated proteins (sFRP), and sclerostin (SOST). This study evaluated the role of FLS as a source of Wnt antagonists (sFRP3/FRZB and Dkk1) in the synovial environment and the contribution of inflammatory cytokines (IL-17, IL-22, and TNF-a) to this function
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