Leiden University Scholarly Publications

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Vinuesa, A.G. de; Sanchez Duffhues, G.; Blaney-Davidson, E.; Caam, A. van; Lodder, K.; Ramos, Y.; ... ; Dijke, P. ten (2021)

Cripto favors chondrocyte hypertrophy via TGF-beta SMAD1/5 signaling during development of osteoarthritis

Article / Letter to editor
Chondrocytes in mice developing osteoarthritis (OA) exhibit an aberrant response to the secreted cytokine transforming growth factor (TGF)-beta, consisting in a potentiation of intracellular signaling downstream of the transmembrane type I receptor kinase activin receptor-like kinase (ALK)1 against canonical TGF-beta receptor ALK5-mediated signaling. Unfortunately, the underlying mechanisms remain elusive. In order to identify novel druggable targets for OA, we aimed to investigate novel molecules regulating the ALK1/ALK5 balance in OA chondrocytes. We performed gene expression analysis of TGF-beta signaling modulators in joints from three different mouse models of OA and found an upregulated expression of the TGF-beta co-receptor Cripto (Tdgf1), which was validated in murine and human cartilage OA samples at the protein level. In vitro and ex vivo, elevated expression of Cripto favors the hypertrophic differentiation of chondrocytes, eventually contributing to tissue calcification....Show moreChondrocytes in mice developing osteoarthritis (OA) exhibit an aberrant response to the secreted cytokine transforming growth factor (TGF)-beta, consisting in a potentiation of intracellular signaling downstream of the transmembrane type I receptor kinase activin receptor-like kinase (ALK)1 against canonical TGF-beta receptor ALK5-mediated signaling. Unfortunately, the underlying mechanisms remain elusive. In order to identify novel druggable targets for OA, we aimed to investigate novel molecules regulating the ALK1/ALK5 balance in OA chondrocytes. We performed gene expression analysis of TGF-beta signaling modulators in joints from three different mouse models of OA and found an upregulated expression of the TGF-beta co-receptor Cripto (Tdgf1), which was validated in murine and human cartilage OA samples at the protein level. In vitro and ex vivo, elevated expression of Cripto favors the hypertrophic differentiation of chondrocytes, eventually contributing to tissue calcification. Furthermore, we found that Cripto participates in a TGF-beta-ALK1-Cripto receptor complex in the plasma membrane, thereby inducing catabolic SMAD1/5 signaling in chondrocytes. In conclusion, we demonstrate that Cripto is expressed in OA and plays a functional role promoting chondrocyte hypertrophy, thereby becoming a novel potential therapeutic target in OA, for which there is no efficient cure or validated biomarker. (C) 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.Show less
TGF-beta
BMP
ALK
Tdgf1
cartilage
bone
calcification
joint
ageing
All authors
Vinuesa, A.G. de; Sanchez Duffhues, G.; Blaney-Davidson, E.; Caam, A. van; Lodder, K.; Ramos, Y.; Kloppenburg, M.; Meulenbelt, I.; Kraan, P. van der; Goumans, M.J.; Dijke, P. ten
Date
2021-09-06
Journal
The Journal of Pathology
Volume
255
Issue
3
Pages
330 - 342
DOI
doi:10.1002/path.5774
Link
https://pathsocjournals.onlinelibrary.wiley.com/doi/10.1002/path.5774