Fibrillin-1 mutant mice (tight skin) show increased spontaneous and trauma-induced osteoarthritis development

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Purpose: Osteoarthritis development is a major chronic disorder affected >8million British people. Despite the high prevalence of OA, there are currently no therapies to slow disease progression. Fibrillin-1 is an extracellular matrix protein found in elastic fibres. One of its main roles is to control growth factor bioavailability, which play vital functions in joint homeostasis. Fibrillin-1 mutations, as those found in Tight Skin mice (TSK), can increase TGFß signalling, and leads to tight skin, myocardial hypertrophy, marfan-like skeletal phenotype and lung emphysema. The aim of this study is to assess OA development in TSK mice in spontaneous and in trauma-induced models. Methods: Immunohistochemistry for Fibrillin-1 was performed in CBA and Str/ort mice (spontaneous OA), and in trauma-induced OA. For the ageing model, knees from 35wk-old TSK and littermate control male mice were collected, microCT scanned and used for histology. The non-invasive loading model was used and the right knee of male TSK and WT mice were loaded i) a single time at 7 or 9N loads and joints analysed 1 weeks later; or ii) repetitively for 2 weeks to induce OA progression, and joints assessed 6 weeks after the last loading episode. Histology was performed on these joints after decalcification (10% formic acid), serial sections cut across the whole joint at 6μm, and AC degradation severity assessed (OARSI grading system). Results: Fibrillin-1 was found in the pericellular matrix of chondrocytes in both the growth plate (resting and hypertrophic cells) and in the uncalcified articular cartilage in healthy CBA mice. During the development of OA in Str/ort mice and in response to mechanical trauma, Fibrillin-1 immunolabelling was decreased. TSK mice showed spontaneous increased joint space mineralised tissue volume (including meniscus and ligament calcification) and increased AC degradation compared to WT at 35wks of age. In contrast, no significant differences were seen in tibial epiphyseal bone (medial and lateral; BV/TV, Trabecular Thickness, Trabecular Separation, Trabecular number). A single loading episode at both 9 and 7N produced AC lesions in the lateral femur in both WT and TSK mice, however severity of lesions created were more severe in TSK mice (preliminary data). Repetitive loading episodes lead to slight increase in mineralised joint space tissue between TSK and litter mate WT controls (preliminary data), which from our previous studies has shown to be correlated with OA severity. Conclusions: This study shows that Fibrillin-1 is decreased from the pericellular matrix during OA development in spontaneous and trauma-induced OA, suggesting increased Fibrillin-1 degradation. In addition, mutations in Fibrillin-1 in the TSK mouse lead to increased spontaneous and trauma-induced OA development. These data suggest that normal Fibrillin-1 expression and function may play an important role in joint homeostasis and that abnormal expression or mutations promote OA development initiation and progression.