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Tight regulation of wingless-type signaling in the articular cartilage - subchondral bone biomechanical unit: transcriptomics in Frzb-knockout mice

Abstract : Introduction: The aim of this research was to study molecular changes in the articular cartilage and subchondral bone of the tibial plateau from mice deficient in frizzled-related protein (Frzb) compared to wild-type mice by transcriptome analysis. Methods: Gene-expression analysis of the articular cartilage and subchondral bone of three wild-type and three Frzb-/-mice was performed by microarray. Data from three wild-type and two Frzb-/-samples could be used for pathway analysis of differentially expressed genes and were explored with PANTHER, DAVID and GSEA bioinformatics tools. Activation of the wingless-type (WNT) pathway was analysed using Western blot. The effects of Frzb gain and loss of function on chondrogenesis and cell proliferation was examined using ATDC5 micro-masses and mouse ribcage chondrocytes. Results: Extracellular matrix-associated integrin and cadherin pathways, as well as WNT pathway genes were up-regulated in Frzb-/-samples. Several WNT receptors, target genes and other antagonists were up-regulated, but no difference in active b-catenin was found. Analysis of ATDC5 cell micro-masses overexpressing FRZB indicated an up-regulation of aggrecan and Col2a1, and down-regulation of molecules related to damage and repair in cartilage, Col3a1 and Col5a1. Silencing of Frzb resulted in down-regulation of aggrecan and Col2a1. Pathways associated with cell cycle were down-regulated in this transcriptome analysis. Ribcage chondrocytes derived from Frzb-/-mice showed decreased proliferation compared to wild-type cells. Conclusions: Our analysis provides evidence for tight regulation of WNT signalling, shifts in extracellular matrix components and effects on cell proliferation and differentiation in the articular cartilage-subchondral bone unit in Frzb-/-mice. These data further support an important role for FRZB in joint homeostasis and highlight the complex biology of WNT signaling in the joint.
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Liesbet Lodewyckx, Frederic Cailotto, Sarah Thysen, Frank Luyten, Rik Lories. Tight regulation of wingless-type signaling in the articular cartilage - subchondral bone biomechanical unit: transcriptomics in Frzb-knockout mice. Arthritis Research and Therapy, BioMed Central, 2012, 14 (1), pp.R16. ⟨10.1186/ar3695⟩. ⟨hal-01704470⟩

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