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Open Access Research article

GREM1, FRZB and DKK1 mRNA levels correlate with osteoarthritis and are regulated by osteoarthritis-associated factors

Jeroen CH Leijten1, Steffan D Bos2, Ellie BM Landman1, Nicole Georgi1, Holger Jahr3, Ingrid Meulenbelt2, Janine N Post1, Clemens A van Blitterswijk4 and Marcel Karperien1*

Author Affiliations

1 Department of Developmental BioEngineering, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, P.O. Box 217, 7500AE Enschede, the Netherlands

2 Department of Molecular Epidemiology, Leiden University Medical Centre, Section of Molecular Epidemiology, Wassenaarseweg 72, 2333 AL Leiden, Netherlands

3 Department of Orthopaedic Surgery, University Hospital RWTH Aachen, Pauwelsstraße 30, 52074 Aachen, Germany

4 Department of Tissue Regeneration, University of Twente, Drienerlolaan 5, 7522NB Overijsse, Netherlands

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Arthritis Research & Therapy 2013, 15:R126  doi:10.1186/ar4306

Published: 19 September 2013

Abstract

Introduction

Osteoarthritis is, at least in a subset of patients, associated with hypertrophic differentiation of articular chondrocytes. Recently, we identified the bone morphogenetic protein (BMP) and wingless-type MMTV integration site (WNT) signaling antagonists Gremlin 1 (GREM1), frizzled-related protein (FRZB) and dickkopf 1 homolog (Xenopus laevis) (DKK1) as articular cartilage’s natural brakes of hypertrophic differentiation. In this study, we investigated whether factors implicated in osteoarthritis or regulation of chondrocyte hypertrophy influence GREM1, FRZB and DKK1 expression levels.

Methods

GREM1, FRZB and DKK1 mRNA levels were studied in articular cartilage from healthy preadolescents and healthy adults as well as in preserved and degrading osteoarthritic cartilage from the same osteoarthritic joint by quantitative PCR. Subsequently, we exposed human articular chondrocytes to WNT, BMP, IL-1β, Indian hedgehog, parathyroid hormone-related peptide, mechanical loading, different medium tonicities or distinct oxygen levels and investigated GREM1, FRZB and DKK1 expression levels using a time-course analysis.

Results

GREM1, FRZB and DKK1 mRNA expression were strongly decreased in osteoarthritis. Moreover, this downregulation is stronger in degrading cartilage compared with macroscopically preserved cartilage from the same osteoarthritic joint. WNT, BMP, IL-1β signaling and mechanical loading regulated GREM1, FRZB and DKK1 mRNA levels. Indian hedgehog, parathyroid hormone-related peptide and tonicity influenced the mRNA levels of at least one antagonist, while oxygen levels did not demonstrate any statistically significant effect. Interestingly, BMP and WNT signaling upregulated the expression of each other’s antagonists.

Conclusions

Together, the current study demonstrates an inverse correlation between osteoarthritis and GREM1, FRZB and DKK1 gene expression in cartilage and provides insight into the underlying transcriptional regulation. Furthermore, we show that BMP and WNT signaling are linked in a negative feedback loop, which might prove essential in articular cartilage homeostasis by balancing BMP and WNT activity.