title: Reduced expression of Sfrp1 during chondrogenesis and in articular chondrocytes correlates with osteoarthritis in STR/ort mice.
abstract: To circumvent the problems of genetic and environmental diversity hampering the analysis in humans, we turned to a murine model for human knee osteoarthritis (OA) and fine mapped a previously defined OA-quantitative trait locus (QTL). We here focused on one of the candidate genes within the OA-QTL encoding the Wnt antagonist secreted frizzled related protein 1 (Sfrp1). Sequence analysis of the Sfrp1 gene in the OA strain STR/ort revealed 23 polymorphic changes with a potential to alter the gene expression. Indeed, a reduced expression in STR/ort mice was demonstrated for articular chondrocytes and hypertrophic chondrocytes of the femoral growth plate as shown by immunohistochemistry. RT-PCR of in vitro generated mesenchymal stem cells (MSC) and chondrogenically differentiated MSC (cMSC) confirmed the reduced Sfrp1 expression in STR/ort mice. This reduced Sfrp1 expression in MSC correlated with an increased amount of cytoplasmic β-catenin, a downregulation of the Wnt target gene PPARγ and an upregulation of Runx2 as well as a preferential differentiation of the MSC along the osteoblasts lineage. Given the role of Wnt signalling during chondrogenesis and in maintaining the integrity of the long lived articular chondrocytes, we conclude from our results that the reduced Sfrp1 expression in STR/ort mice not only leads to an increased activation of the Wnt/β-catenin signalling early in life but also renders the articular cartilage prone to premature ageing and to the development of OA.
authors.affiliation: Institute of Immunology, University of Rostock, Rostock, Germany.
authors.forename: Juliane
authors.initials: J
authors.lastname: Pasold
authors.forename: Anja
authors.initials: A
authors.lastname: Osterberg
authors.forename: Kirsten
authors.initials: K
authors.lastname: Peters
authors.forename: Hanna
authors.initials: H
authors.lastname: Taipaleenmäki
authors.forename: Anna-Marja
authors.initials: AM
authors.lastname: Säämänen
authors.forename: Brigitte
authors.initials: B
authors.lastname: Vollmar
authors.forename: Brigitte
authors.initials: B
authors.lastname: Müller-Hilke
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D002358:Cartilage, Articular / Q000166:cytology / Q000378:metabolism*; D002454:Cell Differentiation; D002478:Cells, Cultured; D019902:Chondrocytes / Q000166:cytology / Q000378:metabolism*; D020219:Chondrogenesis / Q000502:physiology*; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D006801:Humans; D007124:Immunoenzyme Techniques; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D010003:Osteoarthritis / Q000378:metabolism* / Q000473:pathology; D040641:Quantitative Trait Loci; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D000094742:Secreted Frizzled-Related Proteins
chemical_list: D015415:Biomarkers; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D012333:RNA, Messenger; C485539:Sfrp1 protein, mouse; D000094742:Secreted Frizzled-Related Proteins