title: Gremlin 1, frizzled-related protein, and Dkk-1 are key regulators of human articular cartilage homeostasis.
abstract: OBJECTIVE
  The development of osteoarthritis (OA) may be caused by activation of hypertrophic differentiation of articular chondrocytes. Healthy articular cartilage is highly resistant to hypertrophic differentiation, in contrast to other hyaline cartilage subtypes, such as growth plate cartilage. The purpose of this study was to elucidate the molecular mechanism responsible for the difference in the propensity of human articular cartilage and growth plate cartilage to undergo hypertrophic differentiation.
  
  
  METHODS
  Whole-genome gene-expression microarray analysis of healthy human growth plate and articular cartilage derived from the same adolescent donors was performed. Candidate genes, which were enriched in the articular cartilage, were validated at the messenger RNA (mRNA) and protein levels and examined for their potential to inhibit hypertrophic differentiation in two models. In addition, we studied a possible genetic association with OA.
  
  
  RESULTS
  Pathway analysis demonstrated decreased Wnt signaling in articular cartilage as compared to growth plate cartilage. This was at least partly due to increased expression of the bone morphogenetic protein and Wnt antagonists Gremlin 1, Frizzled-related protein (FRP), and Dkk-1 at the mRNA and protein levels in articular cartilage. Supplementation of these proteins diminished terminal hypertrophic differentiation without affecting chondrogenesis in long-bone explant cultures and chondrogenically differentiating human mesenchymal stem cells. Additionally, we found that single-nucleotide polymorphism rs12593365, which is located in a genomic control region of GREM1, was significantly associated with a 20% reduced risk of radiographic hip OA in 2 population-based cohorts.
  
  
  CONCLUSIONS
  Taken together, our study identified Gremlin 1, FRP, and Dkk-1 as natural brakes on hypertrophic differentiation in articular cartilage. As hypertrophic differentiation of articular cartilage may contribute to the development of OA, our findings may open new avenues for therapeutic intervention.
authors.affiliation: University of Twente, Enschede, The Netherlands.
authors.forename: J C H
authors.initials: JC
authors.lastname: Leijten
authors.forename: J
authors.initials: J
authors.lastname: Emons
authors.forename: C
authors.initials: C
authors.lastname: Sticht
authors.forename: S
authors.initials: S
authors.lastname: van Gool
authors.forename: E
authors.initials: E
authors.lastname: Decker
authors.forename: A
authors.initials: A
authors.lastname: Uitterlinden
authors.forename: G
authors.initials: G
authors.lastname: Rappold
authors.forename: A
authors.initials: A
authors.lastname: Hofman
authors.forename: F
authors.initials: F
authors.lastname: Rivadeneira
authors.forename: S
authors.initials: S
authors.lastname: Scherjon
authors.forename: J M
authors.initials: JM
authors.lastname: Wit
authors.forename: J
authors.initials: J
authors.lastname: van Meurs
authors.forename: C A
authors.initials: CA
authors.lastname: van Blitterswijk
authors.forename: M
authors.initials: M
authors.lastname: Karperien
mesh_terms: D000293:Adolescent; D000818:Animals; D002358:Cartilage, Articular / Q000166:cytology / Q000378:metabolism*; D002648:Child; D019902:Chondrocytes / Q000166:cytology / Q000378:metabolism; D020869:Gene Expression Profiling; D055106:Genome-Wide Association Study; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism*; D006132:Growth Plate / Q000378:metabolism; D006706:Homeostasis / Q000235:genetics*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D000099274:Frizzled-Related Proteins
chemical_list: D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D000099274:Frizzled-Related Proteins; C501126:DKK1 protein, human; C486399:GREM1 protein, human