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Arthritis Research & Therapy
Published in: Arthritis Research & Therapy 5/2013

Open Access 01-10-2013 | Research article

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

Authors: Jeroen CH Leijten, Steffan D Bos, Ellie BM Landman, Nicole Georgi, Holger Jahr, Ingrid Meulenbelt, Janine N Post, Clemens A van Blitterswijk, Marcel Karperien

Published in: Arthritis Research & Therapy | Issue 5/2013

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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.
Appendix
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Metadata
Title
GREM1, FRZB and DKK1 mRNA levels correlate with osteoarthritis and are regulated by osteoarthritis-associated factors
Authors
Jeroen CH Leijten
Steffan D Bos
Ellie BM Landman
Nicole Georgi
Holger Jahr
Ingrid Meulenbelt
Janine N Post
Clemens A van Blitterswijk
Marcel Karperien
Publication date
01-10-2013
Publisher
BioMed Central
Published in
Arthritis Research & Therapy / Issue 5/2013
Electronic ISSN: 1478-6362
DOI
https://doi.org/10.1186/ar4306

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