Leijten J.C.H. - GREM1, FRZB and DKK1 are key regulators of human articular cartilage homeostasis

Leijten JC, van Blitterwijk CA, Karperien M, Emons J, van Gool S, Wit JM, Sticht C, Decker E, Rappold G, Uitterlinden A, Rivadeneira F, van Meurs J, Hofman A, Scherjon S

Arthritis and Rheumatism 2012



The development of osteoarthritis 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. In this study, we set out to elucidate the molecular mechanism responsible for the difference in propensity to undergo hypertrophic differentiation between human articular and growth plate cartilage.


Whole genome gene expression micro-array analysis of healthy human growth-plate and articular cartilage derived from the same adolescent donors was performed. Candidate genes, enriched in articular cartilage, were validated at the mRNA and protein level and examined for their potential to inhibit hypertrophic differentiation in two models. In addition, we studied a possible genetic association with osteoarthritis.


Pathway analysis demonstrated decreased Wnt-signaling in articular cartilage compared to growth-plate cartilage. This was at least partially due to increased expression of BMP- and Wnt-antagonists GREM1, FRZB and DKK1 at mRNA and protein level 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 show that SNP-rs12593365, located in a genomic control region of GREM1, significantly associates with a 20% reduced risk for radiographic hip-osteoarthritis in two population-based cohorts.


Taken together, our data identifies GREM1, FRZB and DKK1 as natural brakes of hypertrophic differentiation in articular cartilage. As hypertrophic differentiation of articular cartilage may contribute to the development of osteoarthritis, our findings may open new avenues for therapeutic intervention. © 2012 American College of Rheumatology.