Reduced expression of Sfrp1 during chondrogenesis and in articular chondrocytes correlates with osteoarthritis in STR/ort mice

Pasold, Juliane; Osterberg, Anja; Peters, Kirsten; Taipaleenmäki, Hanna; Säämänen, Anna‐Marja; Vollmar, Brigitte; Müller‐Hilke, Brigitte

doi:10.1016/j.yexcr.2012.12.012

Cited by 26 publications

(26 citation statements)

References 31 publications

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“…Instead, the authors identified a QTL for the OA phenotype that is mapped to chromosome 4 . Chromosome 8 was, however, revisited, and fine‐mapping of the OA QTL in a more recent study revealed Wnt‐related genes associated with altered chondrogenesis, including dickkopf 4 ( Dkk4 ), secreted Frizzled‐related protein 1 ( Sfrp1 ), and fibroblast growth factor 1 ( Fgfr1 ) . While a number of genes, including Wnt‐related genes, have been implicated in OA by association studies in human populations, there is a distinct lack of functional data to support a causative link between these associated genes and OA.…”

Section: Discussionmentioning

confidence: 99%

Endochondral Growth Defect and Deployment of Transient Chondrocyte Behaviors Underlie Osteoarthritis Onset in a Natural Murine Model

Staines

Madi

Mirczuk

et al. 2016

Arthritis & Rheumatology

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ObjectiveTo explore whether aberrant transient chondrocyte behaviors occur in the joints of STR/Ort mice (which spontaneously develop osteoarthritis [OA]) and whether they are attributable to an endochondral growth defect.MethodsKnee joints from STR/Ort mice with advanced OA and age‐matched CBA (control) mice were examined by Affymetrix microarray profiling, multiplex polymerase chain reaction (PCR) analysis, and immunohistochemical labeling of endochondral markers, including sclerostin and MEPE. The endochondral phenotype of STR/Ort mice was analyzed by histologic examination, micro–computed tomography, and ex vivo organ culture. A novel protocol for quantifying bony bridges across the murine epiphysis (growth plate fusion) using synchrotron x‐ray computed microtomography was developed and applied.ResultsMeta‐analysis of transcription profiles showed significant elevation in functions linked with endochondral ossification in STR/Ort mice (compared to CBA mice; P < 0.05). Consistent with this, immunolabeling revealed increased matrix metalloproteinase 13 (MMP‐13) and type X collagen expression in STR/Ort mouse joints, and multiplex quantitative reverse transcriptase–PCR showed differential expression of known mineralization regulators, suggesting an inherent chondrocyte defect. Support for the notion of an endochondral defect included accelerated growth, increased zone of growth plate proliferative chondrocytes (P < 0.05), and widespread type X collagen/MMP‐13 labeling beyond the expected hypertrophic zone distribution. OA development involved concomitant focal suppression of sclerostin/MEPE in STR/Ort mice. Our novel synchrotron radiation microtomography method showed increased numbers (P < 0.001) and mean areal growth plate bridge densities (P < 0.01) in young and aged STR/Ort mice compared to age‐matched CBA mice.ConclusionTaken together, our data support the notion of an inherent endochondral defect that is linked to growth dynamics and subject to regulation by the MEPE/sclerostin axis and may represent an underlying mechanism of pathologic ossification in OA.

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Section: Discussionmentioning

confidence: 99%

Endochondral Growth Defect and Deployment of Transient Chondrocyte Behaviors Underlie Osteoarthritis Onset in a Natural Murine Model

Staines

Madi

Mirczuk

et al. 2016

Arthritis & Rheumatology

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“…Effective regulation of the Wnt pathway is proving critical in OA joint pathology 59 and levels of sFRP1, the Wnt inhibitor, are reduced in AC chondrocytes of young STR/ort mice 32 . We have reported a role for another Wnt inhibitor, sclerostin.…”

Section: Articular Cartilage Phenotype Of Str/ort Micementioning

confidence: 92%

“…Revisiting chromosome 8 and fine mapping of the OA-QTL revealed Wnt-related genes associated with altered chondrogenesis, including dickkopf 4 ( Dkk4 ), secreted frizzled related protein 1 ( Sfrp1 ) and fibroblast growth factor 1 ( Fgfr1 ), with 23 polymorphic changes in the Sfrp1 gene identified in STR/ort in comparison to C57BL/6 mice 32 , suggesting that reduced Sfrp1 expression not only increases Wnt/β-catenin signalling early in life but also renders the AC prone to premature OA 32 . This is similar to various genome-wide expression profiling studies in human OA which have also identified members of the Wnt/β-catenin signalling pathway as candidate genes associated with OA 33, 34…”

Section: Genetic Studies In the Str/ort Mousementioning

confidence: 99%

The STR/ort mouse model of spontaneous osteoarthritis – an update

Staines

Poulet

Wentworth

et al. 2017

Osteoarthritis and Cartilage

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SummaryOsteoarthritis is a degenerative joint disease and a world-wide healthcare burden. Characterized by cartilage degradation, subchondral bone thickening and osteophyte formation, osteoarthritis inflicts much pain and suffering, for which there are currently no disease-modifying treatments available. Mouse models of osteoarthritis are proving critical in advancing our understanding of the underpinning molecular mechanisms. The STR/ort mouse is a well-recognized model which develops a natural form of osteoarthritis very similar to the human disease. In this Review we discuss the use of the STR/ort mouse in understanding this multifactorial disease with an emphasis on recent advances in its genetics and its bone, endochondral and immune phenotypes.

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“…Lipoprotein receptor‐related protein 1 (LRP1) could inhibit tumour necrosis factor (TNF)‐α‐induced apoptosis and inflammation in chondrocytes . The reduced expression of secreted frizzled related protein 1 (SFRP1) increased the activation of the Wnt/β‐catenin signalling and rendered the articular cartilage prone to premature . We selected five SNPs (DVL1 rs61735963, WNT16 rs2908004, ITIH5 rs10795550, LRP1 rs1799986 and SFRP1 rs1127379) and investigated their association with OA risk in a Chinese population.…”

Section: Discussionmentioning

confidence: 99%

Variations of Wnt/β‐catenin pathway‐related genes in susceptibility to knee osteoarthritis: A three‐centre case‐control study

Huang

Jiang

Yang

et al. 2019

J Cellular Molecular Medi

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Excessive activation of the Wnt signalling pathway in the articular cartilage is demonstrated to be related to the onset and severity of osteoarthritis (OA). However, few studies have investigated the association between variants in Wnt‐pathway‐related genes and the risk of OA by searching Pubmed and EMBASE. Totally, 471 knee OA patients and 532 controls were recruited from three hospitals to evaluate the associations of five genetic variants (rs61735963, rs2908004, rs10795550, rs1799986 and rs1127379) with the risk of knee OA. These polymorphisms were genotyped through polymerase chain reaction and Sanger sequencing. Genetic risk scores (GRSs) were calculated to evaluate the combined effect of these genetic variants. No significant association was found between OA risk and polymorphisms (rs61735963, rs10795550 or rs1127379). However, WNT16 rs2908004 polymorphism was correlated with a decreased risk of OA, especially among females, smokers, non‐drinkers and individuals with age < 60 years or BMI ≥ 25. This SNP was also associated with Kellgren‐Lawrence grade and CRP. Similarly, LRP1 rs1799986 polymorphism decreased the risk of OA among males, smokers, drinkers and individuals with age < 60 years or BMI ≥ 25. TT genotype was more frequent in the group of VAS ≥ 6 versus VAS < 6. A low GRS was positively correlated with a decreased risk of OA. In addition, rs2908004 or rs1799986 polymorphism reduces the expression of WNT16 or LRP1. In conclusion, two SNPs (rs2908004 and rs1799986) are associated with the decreased risk of OA by regulating the Wnt pathway.

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Reduced expression of Sfrp1 during chondrogenesis and in articular chondrocytes correlates with osteoarthritis in STR/ort mice

Cited by 26 publications

References 31 publications

Endochondral Growth Defect and Deployment of Transient Chondrocyte Behaviors Underlie Osteoarthritis Onset in a Natural Murine Model

Endochondral Growth Defect and Deployment of Transient Chondrocyte Behaviors Underlie Osteoarthritis Onset in a Natural Murine Model

The STR/ort mouse model of spontaneous osteoarthritis – an update

Variations of Wnt/β‐catenin pathway‐related genes in susceptibility to knee osteoarthritis: A three‐centre case‐control study

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