EXTENDED REPORT Proof of concept: enthesitis and new bone formation in spondyloarthritis are driven by mechanical strain and stromal cells Peggy Jacques, 1 Stijn Lambrecht, 1 Eveline Verheugen, 1 Elin Pauwels, 2 George Kollias, 3 Maria Armaka, 3 Marleen Verhoye, 4 Annemie Van der Linden, 4 Rik Achten, 5 Rik J Lories, 6 Dirk Elewaut 1 Handling editor Tore K Kvien ▸ Additional material is published online only. To view please visit the journal online (http://dx.doi.org/10.1136/ annrheumdis-2013-203643). For numbered affiliations see end of article. Correspondence to Dr Peggy Jacques or Dr Dirk Elewaut, Laboratory for Molecular Immunology and Inflammation, Ghent University Hospital, Department of Rheumatology, De Pintelaan 185, Ghent 9000, Belgium; Peggy.jacques@ugent.be or dirk.elewaut@ugent.be Received 18 March 2013 Revised 20 June 2013 Accepted 14 July 2013 Published Online First 6 August 2013 ▸ http://dx.doi.org/10.1136/ annrheumdis-2013-203924 To cite: Jacques P, Lambrecht S, Verheugen E, et al. Ann Rheum Dis 2014;73:437–445. ABSTRACT Objectives Spondyloarthritides (SpA) are characterised by both peripheral and axial arthritis. The hallmarks of peripheral SpA are the development of enthesitis, most typically of the Achilles tendon and plantar fascia, and new bone formation. This study was undertaken to unravel the mechanisms leading towards enthesitis and new bone formation in preclinical models of SpA. Results First, we demonstrated that TNF ΔARE mice show typical inflammatory features highly reminiscent of SpA. The first signs of inflammation were found at the entheses. Importantly, enthesitis occurred equally in the presence or absence of mature T and B cells, underscoring the importance of stromal cells. Hind limb unloading in TNF ΔARE mice significantly suppressed inflammation of the Achilles tendon compared with weight bearing controls. Erk1/2 signalling plays a crucial role in mechanotransduction-associated inflammation. Furthermore, new bone formation is strongly promoted at entheseal sites by biomechanical stress and correlates with the degree of inflammation. Conclusions These findings provide a formal proof of the concept that mechanical strain drives both entheseal inflammation and new bone formation in SpA. INTRODUCTION Spondyloarthritides (SpA) are a group of chronic inflammatory disorders characterised by asymmet- rical peripheral arthritis predominantly of lower limbs, and axial inflammation (sacroiliitis and spon- dylitis). The disease is typically accompanied by a variety of extra-articular manifestations, such as intestinal and ocular inflammation. In European countries, the overall incidence is estimated at 0.5%–2% of the Caucasian population, with onset frequently in the early adulthood. 12 Inflammation of attachment sites of ligaments and tendons to bones, enthesitis, is a hallmark of SpA which distin- guishes it from other inflammatory rheumatic dis- orders. 3 In addition, SpA is also characterised by new bone formation evolving into ankylosis, or into the formation of enthesophytes that also appear to originate from these insertion sites. 4 Radiographic progression of disease reflecting structural damage is characterised by new bone for- mation leading to sacroiliac and spinal ankylosis. Both inflammation and progressive structural damage contribute to the burden of disease. 5 The entheses are subjected to repetitive biomech- anical stressing forces that are applied during the course of normal muscle, ligament and tendon action; this suggests a link between biomechanical stress and SpA. McGonagle et al 6 proposed an enthesitis-based model for the pathogenesis of SpA where interactions between biomechanical factors and the innate immune response (eg, to bacterial products) may lead to disease. Nevertheless, the enthesitis concept has remained controversial as synovitis and bone marrow inflammation are also typical signs of active SpA. The anatomical proxim- ity and the ample molecular and cellular communi- cations between these tissues suggest their functional relationship in the pathogenesis of syno- vitis in SpA with the disease processes defined in the context of the synovio–entheseal complex. 7 Within this microenvironment, it has become clear that in SpA patients, new bone formation often occurs in close relationship with the entheses. Spinal syndesmophytes develop along the anterior intervertebral ligaments, and bony spurs are formed at the Achilles tendon and plantar fascia. Interestingly, the process of inflammation and subsequent bone erosion appeared in anatomically distinct sites as compared with new bone formation at the Achilles’ enthesis. 8 Erosions preferentially developed in regions undergoing compression, whereas spur formation occurred in regions prone to tensile forces. These anatomical data further cor- roborate current paradigms that strongly suggest a molecular uncoupling of inflammation and new bone formation in SpA. Despite a proven efficacy on inflammatory signs and symptoms, treatment with tumour necrosis factor (TNF) blocking agents in mouse models and in patients does not substan- tially affect progression of ankylosis. 9–11 Currently, it remains elusive whether inflamma- tion and new bone formation are closely linked or rather uncoupled, and why these processes coloca- lise at entheseal sites. In the current study, we hypothesised that bio- mechanical factors drive inflammation and new bone formation at entheseal sites. This hypothesis was studied in the TNF ΔARE mouse model in which chronic and deregulated TNF production leads to arthritis and a Crohn’s-like ileitis. 12–14 We previ- ously argued that this model, depending on endogenous TNF, involving peripheral and axial Editor’s choice Scan to access more free content Jacques P, et al. Ann Rheum Dis 2014;73:437–445. doi:10.1136/annrheumdis-2013-203643 437 Basic and translational research on May 28, 2020 by guest. Protected by copyright. http://ard.bmj.com/ Ann Rheum Dis: first published as 10.1136/annrheumdis-2013-203643 on 6 August 2013. Downloaded from