Article Text
Abstract
Background and Objectives 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.
Materials and Methods Surgical destabilisation 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 characterised by slowly progressive joint damage. Overexpression of Frzb stimulates chondrogenesis by its inhibitory role on Wnt/beta-catenin signalling.