Abstract
Purpose: Polymorphisms in Frizzled-related protein (FRZB), a WNT antagonist, have been associated with osteoarthritis (OA). However, a recent meta-analysis failed to find a consistent effect of FRZB genetic variants on OA susceptibility. Our transcriptomics analysis in Frzb-/- mice provided evidence for a tight regulation of WNT signalling and highlighted the complex role for FRZB in joint homeostasis. We previously demonstrated that Frzb-/- mice have increased damage when dramatically challenged by papain, collagenase or severe inflammation. As these models are acute and short-term, we aimed to further investigate the effect of Frzb loss in a true translational model of OA and to study molecular interactions in the ATDC5 micromass in vitro model using RT-PCR and Western blot analysis. Methods: Surgical destabilization of the medial meniscus (DMM) was performed on the right knee of eight-week-old male Frzb-/- and wild-type mice. Eight weeks after surgery, mice were sacrificed and histological scores were determined for the femoral and tibial articular surfaces following the OARSI histopathology initiative guidelines. Results: Overexpression of Frzb in ATDC5 micro-masses boosted chondrogenesis with up-regulation of Col2a1 and Aggrecan transcription, whereas downregulation of Frzb lead to a decreased expression of Col2a1 and Aggrecan. These results corresponded with a reduction or increase in the activation of canonical WNT signalling pathway, respectively. Fluctuating levels of Frzb did not influence the Wnt/CamKII signalling pathway. The semi-quantitative OARSI score showed a significant increase in cartilage erosion in DMM-operated Frzb-/- mice compared to wild-type. Conclusions: Our data show that, in addition to the higher susceptibility to OA in acute induced models, Frzb-/- mice are more prone to OA in a full translational model of the disease characterized by slowly progressive joint damage. Overexpression of Frzb stimulates chondrogenesis by its inhibitory role on WNT/β-catenin signalling.
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