Abstract
IntroductionOsteoarthritis 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.MethodsGREM1, 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.ResultsGREM1, 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.ConclusionsTogether, 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.
Highlights
Osteoarthritis is, at least in a subset of patients, associated with hypertrophic differentiation of articular chondrocytes
In this study we have addressed this hypothesis by analyzing mRNA expression of Gremlin 1 (GREM1), Frizzled-related protein (FRZB) and Dickkopf 1 homolog (DKK1) in human cartilage biopsies and in primary human chondrocytes stimulated with factors that are able to influence, or correlate with, the development of osteoarthritis
GREM1, FRZB and DKK1 mRNA levels are decreased in osteoarthritic cartilage Osteoarthritic cartilage is characterized by evidence of increased hypertrophic differentiation in at least a subset of patients [32]
Summary
Osteoarthritis is, at least in a subset of patients, associated with hypertrophic differentiation of articular chondrocytes. 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. A growing body of evidence suggests that hypertrophic differentiation of articular chondrocytes underlies the pathogenesis of osteoarthritis, at least in a subset of patients [1]. Evidence suggests that articular cartilage is able to inhibit hypertrophic differentiation. We recently identified the BMP and WNT antagonists Gremlin 1 (GREM1), frizzled-related protein (FRZB) and dickkopf 1 homolog (Xenopus laevis) (DKK1) as prime candidates for these articular cartilage secreted factors that inhibit chondrocyte hypertrophy [23]. We have demonstrated that a SNP mutation in the GREM1 gene associates with hip osteoarthritis [23]
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