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

Jeroen Christianus Hermanus Leijten, Steffan D. Bos, Ellie Landman, Nicole Georgi, Holger Jahr, Ingrid Meulenbelt, Janine Nicole Post, Clemens van Blitterswijk, Hermanus Bernardus Johannes Karperien

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38 Citations (Scopus)
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Abstract

Introduction: Osteoarthritis is, at least in a subset of patients, associated with hypertrophic differentiation of articular chondrocytes. Recently, we have 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, interleukin 1 beta (IL1B), Indian hedgehog (IHH), parathyroid hormone related peptide (PTHrP), mechanical loading, different medium tonicities or distinct oxygen levels and investigated on 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 down-regulation is stronger in degrading cartilage compared to macroscopically preserved cartilage from the same osteoarthritic joint. WNT, BMP, IL1B signaling and mechanical loading regulated GREM1, FRZB and DKK1 mRNA levels. IHH, PTHrP 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 up-regulated 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.
Original languageEnglish
Article numberR126
Pages (from-to)1-11
JournalArthritis research & therapy
Volume15
Issue number5
DOIs
Publication statusPublished - 19 Sep 2013

Keywords

  • METIS-297536
  • IR-87219

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