Enhanced BMP-2/BMP-4 ratio in patients with peripheral spondyloarthritis and in cytokine- and stretch-stimulated mouse chondrocytes

Anne Briolay,Carole Bougault,Frédéric Blanchard,Alaeddine El Jamal,David Magne,Paul Arnolfo,Benoît Le Goff

doi:10.1186/s13075-020-02330-9

Abstract

BackgroundExcessive 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.MethodsBMP-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.ResultsIn 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.ConclusionsOur 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.

Highlights

Excessive bone formation in the entheses is one of the features of peripheral spondyloarthritis (SpA)
In synovial fluid of SpA patients, bone morphogenetic protein (BMP)-2 content is higher and BMP-4 is lower than in OA samples BMP-2, -4, and -7 concentrations were measured by ELISA in the synovial fluid (SF) of 56 SpA patients (Fig. 1a)
The balance between BMP-2 and -4 was drastically impaired in the SF of SpA patients, as clarified by the calculation of BMP-2/BMP-4 ratio, which is increased by 6.5 folds (Fig. 1b, p < 0.001)

Summary

Introduction

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. Briolay et al Arthritis Research & Therapy (2020) 22:234 antibodies All of these treatments have beneficial effects on inflammatory lesions, and long-term control of inflammation appears critical to limit ectopic ossification [2, 3]. The hierarchy between inflammation, mechanical stress, and ossification mechanisms in SpA pathophysiology seems complex. The process of endochondral ossification is considered prevalent [3, 5, 6]. In this case, within an enthesis, ossification could be initiated by the metaplasia of tendon cells into fibro-chondrocytes and chondrocytes [5]

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