Enhanced BMP-2/BMP-4 ratio in patients with peripheral spondyloarthritis and in cytokine- and stretch-stimulated mouse c
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RESEARCH ARTICLE
Open Access
Enhanced BMP-2/BMP-4 ratio in patients with peripheral spondyloarthritis and in cytokine- and stretch-stimulated mouse chondrocytes Anne Briolay1, Alaeddine El Jamal1, Paul Arnolfo2,3, Benoît Le Goff2,3, Frédéric Blanchard2, David Magne1 and Carole Bougault1*
Abstract Background: Excessive bone formation in the entheses is one of the features of peripheral spondyloarthritis (SpA). Complex pathological mechanisms connecting inflammation, mechanical stress, and ossification are probably involved. We focused on bone morphogenetic protein (BMP)-2, -4, and -7 as possible mediators of this process. Methods: BMP-2, -4, and -7 concentration was measured by ELISA in synovial fluids (SFs) of SpA (n = 56) and osteoarthritic (n = 21) patients. Mouse organotypic ankle cultures were challenged by a pro-inflammatory cocktail. Mouse primary chondrocytes, osteoblasts, or tenocytes were treated with TNF-α, interleukin (IL)-17, or IL-22 and/or subjected to cyclic stretch, or with recombinant BMP-2 or -4. Results: In SpA SFs, if BMP-7 was barely detectable, BMP-2 concentration was higher and BMP-4 was lower than in osteoarthritic samples, so that BMP-2/BMP-4 ratio augmented 6.5 folds (p < 0.001). In SpA patients, TNF-α, IL-6, and IL-17 levels correlated this ratio (n = 21). Bmp-2/Bmp-4 ratio was similarly enhanced by cytokine treatment in explant and cell cultures, at mRNA level. In particular, simultaneous application of TNF-α and cyclical stretch induced a 30-fold increase of the Bmp-2/Bmp-4 ratio in chondrocytes (p = 0.027). Blockade of prostaglandin E2 and IL-6 production had almost no effect on the stretch-induced regulation of Bmp-2 or -4. Osteoinductive effects of BMP-4, and to a lesser extend BMP-2, were identified on cultured chondrocytes and tenocytes. Conclusions: Our results first settle that BMP factors are locally deregulated in the SpA joint. An unexpected decrease in BMP-4 could be associated to an increase in BMP-2, possibly in response to mechanical and/or cytokine stimulations. Keywords: Spondyloarthritis, BMPs, Ossification, Stretch, Cytokine, Enthesis
Background Spondyloarthropathy is a common rheumatic disease, with a worldwide prevalence estimated at between 0.2 and 1.6% [1]. Patients whose symptoms are principally peripheral rather than axial are grouped under the term * Correspondence: [email protected] 1 Univ Lyon, Univ Claude Bernard Lyon 1, CNRS UMR 5246, ICBMS, F-69622 Lyon, France Full list of author information is available at the end of the article
peripheral spondyloarthritis (SpA), which includes psoriatic arthritis, reactive arthritis, and enteropathic arthritis, among others. Frequently involved joints include the hands, wrists, elbows, shoulders, knees, ankles, and feet. Excessive bone formation is observed in the entheses, the bony insertions of the tendons and ligaments, which can lead in advanced stages to ankylosis. The pain is typically relieved by nonsteroidal anti-inflammatory drugs (NSAIDs), anti-TNF agents, or anti-interleukin (IL)-17
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