The Src family kinase (SFK) Fyn phosphorylates β-catenin, causing nuclear localization, an activation signal in chondrocytes that results in degradation of cartilage and osteoarthritis (OA), according to a study published in Annals of the Rheumatic Diseases.

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High levels of both β-catenin and WNT signalling are already associated with degradation of cartilage and OA, but therapies that target specific arms of these pathways to enable disease modification are not available.

In the new study, the researchers analysed cartilage from 12-month-old mice, as an ageing model of OA, with 2-month-old mice as controls. From a proteomics screen they identified Fyn as a major differentially expressed protein, being almost 12.5 times more abundant in cartilage of the older mice, with most Fyn accumulating inside chondrocytes. They also noted an increase in β-catenin activation signals.

Expression and nuclear localization patterns of Fyn match higher OA Research Society International (OARSI) scores and an increase in cartilage degeneration in these mice. By contrast, 12-month-old Fyn KO mice had less cartilage degradation than wild-type mice. The researchers also surgically induced destabilization of the medial meniscus (DMM) of wild-type and Fyn KO mice, with similar results to those in the ageing model.

This study confirms that, like other cell types, Fyn also activates β-catenin in chondrocytes and thereby identifies Fyn as a potential therapeutic target for OA. The researchers demonstrate this potential by treating (DMM) mice with AZD0530 (a SFK inhibitor) and PP1 (a Fyn and ATP-binding inhibitor).

Whether Fyn is a suitable target for human intervention in not yet clear

Whether Fyn is a suitable target for human intervention is not yet clear, particularly given the lack of Fyn specificity of the inhibitors. However, the study includes preliminary human data, including an analysis of cartilage from a small cohort of seven patients with OA compared with cartilage from four patients who underwent surgery for knee trauma. Similar to the mouse model data, accumulation of Fyn in cartilage was positively associated with OA.