Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement

Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.

Activation of Wnt and Bone Morphogenetic Protein Signalling Pathways in the Articular Cartilage in Frzb/ Mice.

Lodewyckx1,  Liesbet, Eyckmans3,  Jeroen, Luyten2,  Frank P., Lories1,  Rik

KU Leuven, Leuven, Belgium
KU Leuven, Leuven, Belgium
KU Leuven


Frizzled related protein (FRZB/sFRP3) is a secreted WNT antagonist isolated from articular cartilage and expressed in developing skeletal elements. Polymorphisms in the human FRZB gene are associated with susceptibility for osteoarthritis. Induction of experimental osteoarthritis in Frzb-/- mice results in enhanced cartilage degradation associated with increased Wnt signaling, Mmp3 expression, Mmp activity and cortical bone thickness. In this study we used a whole mouse genome micro-array analysis and a bioinformatics approach to investigate differences between healthy cartilage in wild-type and Frzb-/- mice.


Articular cartilage from the tibia was isolated from 6 weeks old Frzb-/- mice and wild-type littermates. RNA was isolated using the Rneasy Fibrous tissue mini kit (Qiagen). RNA quality was assessed using an Agilent 2100 Bioanalyzer and RNA nanochips (Agilent technologies Inc). The transcriptional profiles were analysed using the whole genome Affymetrix GeneChip® Mouse Genome 430 2.0 Array. Articular cartilage from one tibia from 3 wild-type mice and 2 Frzb-/- mice was used (3 vs. 2 chips comparison). Gene expression analysis was based on the RMA expression values and the MAS 5.0 detection calls. PANTHER Classification System software, DAVID bioinformatics resources and FUNNET transcriptional analysis were used for pathway analysis.


Using Benjamini-Hochberg corrected P-values (p < 0,001) in combination with a cut-off fold change |log2-ratio|>1 the analysis showed that 696 transcripts were significantly upregulated in the Frzb-/- sample group. PANTHER pathway analysis identified overrepresentation of genes linked to the Integrin, Wnt and Cadherin signalling pathways (corrected p-values 3*10-9, 5*10-5 and 6*10-4 respectively). Not surprisingly, genes linked to skeletal development and extracellular matrix were enriched in the analysis. DAVID analysis similarly identified the Wnt and Integrin pathways but also EGF signalling. FUNNET identified both Wnt and TGF/BMP signalling. With the Wnt signalling pathway both different Frizled receptor, Wnt9a ligand and distinct intracellular and extracellular antagonists were upregulated suggesting compensatory mechanisms in the absence of Frzb. In addition, upregulation of bone morphogenetic protein and other transforming growth factor beta superfamily members and receptors suggests compensatory upregulation of this pathway. The link with integrin upregulation further supports our earlier data that support of role for Frzb in mechanobiology.


In this study we demonstrated that loss of Frzb results in the upregulation of the WNT signalling pathway and a possible compensatory upregulation of BMP signalling. The upregulation of the integrin and cadherin signalling pathway suggest an important role for Frzb in the interactions of cells with surrounding cells and extracellular matrix.

To cite this abstract, please use the following information:
Lodewyckx, Liesbet, Eyckmans, Jeroen, Luyten, Frank P., Lories, Rik; Activation of Wnt and Bone Morphogenetic Protein Signalling Pathways in the Articular Cartilage in Frzb/ Mice. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :1468
DOI: 10.1002/art.29234

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