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

Arthritis Res Ther. 2013 Sep 19;15(5):R126. doi: 10.1186/ar4306.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Aged
  • Aged, 80 and over
  • Animals
  • Bone Morphogenetic Protein 2 / genetics
  • Bone Morphogenetic Protein 2 / pharmacology
  • Cattle
  • Cell Hypoxia
  • Cell Line, Tumor
  • Cells, Cultured
  • Child
  • Chondrocytes / drug effects
  • Chondrocytes / metabolism
  • Gene Expression / drug effects
  • Gene Expression / genetics*
  • Glycoproteins / genetics*
  • Humans
  • Intercellular Signaling Peptides and Proteins / genetics*
  • Interleukin-1beta / pharmacology
  • Intracellular Signaling Peptides and Proteins
  • Middle Aged
  • Osmolar Concentration
  • Osteoarthritis / genetics*
  • Osteoarthritis / metabolism
  • Osteoarthritis / pathology
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Recombinant Proteins / pharmacology
  • Reverse Transcriptase Polymerase Chain Reaction
  • Stress, Mechanical
  • Wnt3A Protein / genetics
  • Wnt3A Protein / pharmacology

Substances

  • Bone Morphogenetic Protein 2
  • DKK1 protein, human
  • GREM1 protein, human
  • Glycoproteins
  • Intercellular Signaling Peptides and Proteins
  • Interleukin-1beta
  • Intracellular Signaling Peptides and Proteins
  • RNA, Messenger
  • Recombinant Proteins
  • WD repeat containing planar cell polarity effector
  • Wnt3A Protein