Spondyloarthritis: may the force be with you? Dennis McGonagle, 1,2 Rebecca C Thomas, 1 Georg Schett 3 Jacques et al 1 provide proof of concept that experimental spondyloarthritis (SpA) may be a biomechanically triggered process. The implication is that an aberrant mesenchymal tissue response to physiological mechanical forces that occur during joint movement may trigger inflammation associated with SpA. Given the long-known genetic associ- ation of human SpA with human leukocyte antigen (HLA)-B27, 2 which governs initi- ation of adaptive immune responses, the concept that SpA resembles a biomechanic- ally driven rather than autoimmune disease may come as a great surprise. The en face argument that mechanically driven animal models bear no resemblance to human SpA, however, has to be taken with caution, given that the role of mechanics in human SpA has several supporting strands of evi- dence that date back over 50 years. Jacques and colleagues show that the earliest lesions in their model are localised at the Achilles tendon. As far back as 1959, La Cava, in his prophetic commen- tary on enthesitis, but not specifically in relationship to SpA, recognised that “the continually recurring concentration of muscle stress at these points provokes a reaction of inflammation with a strong tendency to the formation of fibrosis and calcification”. 3 He also stated that inser- tions appeared to show ‘a peculiar reac- tion to irritative stimuli’ and that such stimuli were most frequently ‘microtrau- matic in origin’. Since that time evidence has accumulated that supports all aspects of these suppositions. In the 1970s, Moll and Wright deduced the clinical concept of SpA. 4–6 Although they did not pinpoint the ‘invisible unify- ing concept’, which appears to be mech- anical stress, they recognised that physical trauma to joints appeared to trigger psori- atic arthritis and speculated that psoriatic arthritis (PsA) represented a ‘Deep Koebner response’. However, they did not specifically recognise the importance of the entheseal organ as the link between biomechanics and inflammation. Likewise, nail disease in psoriasis shows a propen- sity for the thumbs and index fingers com- pared with adjacent nails, 7 pointing to the importance of mechanical factors and resi- dent tissue responses in the initiation and clinical gestalt of disease. The differing clinical patterns of SpA with the propensity for large joints in the lower limbs in adult disease and the propensity for foot involve- ment in juvenile SpA both attest to factors linked to resident cells and tissue as being the key determinants of the disease process of SpA. In 1984, Bywaters suggested that morbid pathology had little left to offer in the study of SpA, which to him appeared as a mechanically driven disease given the propensity for disease localisation to the enthesis and to the aortic root. 8 Noting that clinically occult enthesitis was common in inflamed synovial joints in SpA—and noting that perientheseal oste- itis was common in SpA and that its distri- bution often equated with apparent bone stressing patterns—we proposed that human SpA may be primarily a biomech- anically driven disease with secondary adaptive immune response modifying the clinical phenotype. 9 The entheseal organ is the visible face of complex joint mechanical stressing, but there are other important locations that exhibit similar features. These include wrap around tendons and fibrocartilagen- ous synovial joints, both of which also show a proclivity for disease localisation in man and in experimental models of arthritis. 10 In the present study, Jacques et al used a well-established tumour necrosis factor (TNF) transgenic model that develops a Crohn’s-like colitis and arthritis (both sacroiliitis and peripheral arthritis) to show that disease localises pri- marily to the enthesis. They also provided MRI evidence of sacroiliac joint osteitis, although this finding was not histologi- cally confirmed. The actual joint unloading was per- formed using a tail suspension procedure with the animals being placed at 30°, which apparently permitted some limited contact with the ground. Careful histological evaluation in early disease con- firmed an enthesitis-based peripheral arth- ritis at three different locations, including interphalangeal joints, Achilles tendons and the hip joints. As previously shown by this group, arthritis development was inde- pendent of the adaptive immune response as it also developed in RAG1 knockout mice, which lack T lymphocytes. 11 Histological evaluation of animals in the later stages of disease showed extensive secondary synovitis and bone erosion. Remarkably the joint unloading procedure almost completely blocked the arthritis development, and furthermore no increase of arthritis was reported in the anterior limbs, which were not unloaded. The TNF transgenic mouse model is not charac- terised by significant new bone forma- tion, 12 and consequently the authors explored the effect of tail suspension in the SpA model of male DBA1 mice. Again, tail suspension alleviated the course of arthritis that was associated with marked reduction of new bone formation at the enthesis. Therefore, mechanical stress appears to play a significant role in both inflammation and new bone formation in different model systems. In order to explore the molecular basis for these findings, the authors investigated those intracellular signalling pathways that have previously been shown to be respon- sive to mechanical stress in stromal and other cell types. 13–16 Specifically, ERK1 and ERK2, two mitogen-activated protein kinases, appear to be important signalling components linking biomechanical stress to the development of enthesitis. However, given the multiplicity of func- tions of ERKs, including mediating the cytokine signalling, it remains unclear whether ERK inhibition directly antago- nises the mechanical stress response or indirectly through modulation of the inflammatory response. The findings of Jacques and colleagues revitalise the concept of biomechanical factors translating to biochemical tissue responses and envision a pivotal role of mechanical stress in the pathogenesis of human SpA. Several questions arise from these findings: 1. How do genetic factors, particularly the HLA-B27 and the IL-23 pathway, influence this process? 2 17 18 It can be speculated that genetic factors in SpA patients lower the threshold of patho- logical mechanical stress, which renders entheseal organs more vulnerable to phys- ical forces. Alternatively, genetic factors may solely alter the inflammatory response to stress but not tissue 1 Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK; 2 Leeds Musculoskeletal and Biomedical Research Unit, Leeds Teaching Hospitals NHS Trust, Chapel Allerton Hospital, Leeds, UK; 3 Department of Medicine III, University Hospital of Erlangen, Erlangen, Germany Correspondence to Professor D G McGonagle, Leeds Musculoskeletal and Biomedical Research Unit, Leeds Teaching Hospitals NHS Trust, Chapel Allerton Hospital, Leeds LS7 4SA, UK; d.g.mcgonagle@leeds.ac.uk McGonagle D, et al. 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