Background/Purpose: Osteoarthritis (OA) is a common degenerative disease leading to pain and disability in >6million british people. The TGFb signalling pathway has been shown to play a major role in joint homeostasis and in OA development. Fibrillin-1 is an extracellular matrix protein that may play a structural role in the matrix of articular cartilage, but also regulates the bioavailability of TGFb to the cell. Thus Fibrillin-1 mutations, such as those seen in the Tight Skin mouse (or TSK), have been shown to increase TGFb signalling. The aim of this study is therefore to determine changes in fibrillin-1 expression during osteoarthritis in mice and to characterise the effect of Fibrillin-1 mutations in ageing-induced OA development in TSK mice.

Methods: Immunohistochemistry for Fibrillin-1 expression was performed in Str/ort mice, a known model of spontaneous OA, and in control aged-matched non-OA CBA mice, in knee joints with different degrees of OA severity. The knees of TSK and littermate control male mice of 60-80wks of age were fixed and microCT scanned. Abnormal ectopic calcified regions were analysed. After scanning, joints were decalcified and processed for paraffin embedding; serial coronal sections were cut at 6um and sections at regular intervals stained with Toluidine Blue.

Results: Fibrillin-1 was localised in the pericellular matrix of articular chondrocytes in normal joints. During the development of OA in Str/ort mice, however, Fibrillin-1 immunolabelling was decreased, in particular around articular cartilage lesions. TSK mice microCT images showed important ectopic calcification in various ligaments, as well as osteophyte formation on the margins of the joints. Preliminary data suggest that articulate cartilage degradation was increased in TSK mice compared to aged-matched control mice.

Conclusion: Our preliminary study shows that Fibrillin-1 protein expression is decreased during OA development in a well known model of spontaneous OA, suggesting TGFb bioavailability may be modified during this period. In addition, mutations in Fibrillin-1 in the TSK mouse lead to abnormal ossification in the knee joint as well as severe OA development. These data suggest that Fibrillin-1 plays an important role in joint homeostasis and that abnormal expression or mutations in its gene can lead to OA development.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/fibrillin-1-expression-and-function-is-needed-for-normal-joint-function-and-mutations-leads-to-osteoarthritis/