Abstract
IntroductionWe aimed to investigate the expression and therapeutic modulation of the receptor activator of the NF-κB ligand (RANKL) system in early-untreated rheumatoid arthritis (RA).MethodsIn this study, 15 patients with newly diagnosed RA (median symptom duration 7 months) were started on methotrexate (MTX) 20 mg weekly. Synovial biopsies were obtained by needle arthroscopy at baseline and 8 weeks after initiation of therapy. X-rays of the hands and feet were obtained at baseline and 1 year after diagnosis. Immunohistochemistry was performed to detect RANKL, receptor activator of nuclear factor-κB (RANK) and osteoprotegerin (OPG) in the synovial biopsies. The in vitro effect of MTX was tested on RA-derived primary fibroblasts and the osteoblasts-like osteosarcoma cell line (rtPCR, Western blot and ELISA) and in osteoclasts (tartrate-resistant acid phosphatase staining and dentine pit formation assay).ResultsMTX decreased synovial cellularity as well as RANK expression and the RANKL/OPG ratio. We confirmed this effect by a decrease of the mRNA and protein RANKL/OPG ratio in synovial-derived fibroblasts and osteoblasts-like tumoral cells exposed in vitro to methotrexate. Supernatants from MTX treated osteoblasts-like tumoral cells prevented pre-osteoclast formation in the absence of exogenous RANKL. Furthermore, MTX blocked osteoclastogenesis from peripheral blood mononuclear cells despite the presence of macrophage colony stimulating factor and RANKL, which indicates that MTX directly inhibits osteoclastogenesis.ConclusionsThe synovial membrane of early-untreated RA is characterized by a high RANKL/OPG ratio that can be reversed by methotrexate.
Highlights
We aimed to investigate the expression and therapeutic modulation of the receptor activator of the Nuclear factor-kappa B (NF-κB) ligand (RANKL) system in early-untreated rheumatoid arthritis (RA)
Bone destruction is controlled by the complex interplay between three molecules essential for bone biology: a receptor (receptor activator of NF-κB (RANK)), a ligand (receptor activator of the NF-κB ligand (RANKL)) and a soluble decoy receptor (osteoprotegerin (OPG)) [2]
We have previously shown that anti-tumor necrosis factor (TNF) agents and glucocorticoids directly modulate the Receptor activator of the NF-κB ligand (RANKL) system in human RA [7,8]
Summary
We aimed to investigate the expression and therapeutic modulation of the receptor activator of the NF-κB ligand (RANKL) system in early-untreated rheumatoid arthritis (RA). In RA it has been postulated that bone destruction occurs as a direct consequence of inflammation This has been challenged recently by the observation that bone destruction can occur in RA despite clinical remission [3,4], while specific anti-rheumatic drugs might protect against destruction even in the absence of clinical remission [5,6]. We aimed to characterize RANKL, RANK and OPG expression in the synovial membrane of early-untreated RA in relation to local inflammation and disease activity and to investigate how expression of these molecules might change following MTX treatment
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