Journal
JOURNAL OF CELL BIOLOGY
Volume 193, Issue 3, Pages 551-564Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.201011051
Keywords
-
Categories
Funding
- Arthritis Research UK [17971, 19344, 17859]
- Medical Research Council
- Medical Research Council [G108/620] Funding Source: researchfish
- MRC [G108/620] Funding Source: UKRI
Ask authors/readers for more resources
Activation and disruption of Wnt/beta-catenin signaling both result in cartilage breakdown via unknown mechanisms. Here we show that both WNT-3A and the Wnt inhibitor DKK1 induced de-differentiation of human articular chondrocytes through simultaneous activation of beta-catenin-dependent and independent responses. WNT-3A activates both the beta-catenin-dependent canonical pathway and the Ca2+/CaMKII noncanonical pathways, with distinct transcriptional targets. WNT-3A promotes cell proliferation and loss of expression of the chondrocyte markers COL2A1, Aggrecan, and SOX9; however, proliferation and AXIN2 up-regulation are downstream of the canonical pathway and are rescued by DKK1, whereas the loss of differentiation markers is CaMKII dependent. Finally, we showed that in chondrocytes, the Ca2+/CaMKII-dependent and beta-catenin-dependent pathways are reciprocally inhibitory, thereby explaining why DKK1 can induce loss of differentiation through de-repression of the CaMKII pathway. We propose a novel model in which a single WNT can simultaneously activate different pathways with distinct and independent outcomes and with reciprocal regulation. This offers an opportunity for selective pharmacological targeting.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available