Cripto favors chondrocyte hypertrophy via TGF‐β SMAD1/5 signaling during development of osteoarthritis

Abstract

Chondrocytes in mice developing osteoarthritis (OA) exhibit an aberrant response to the secreted cytokine transforming growth factor (TGF)-β, consisting in a potentiation of intracellular signaling downstream of the transmembrane type I receptor kinase activin receptor-like kinase (ALK)1 against canonical TGF-β 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-β signaling modulators in joints from three different mouse models of OA and found an upregulated expression of the TGF-β 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-β-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.

Immunohistochemical Study of 78kDa Glucose-regulated Protein (Grp78) and Cripto in the Spheno-occipital Synchondrosis

“…Apart from the expression pattern of Grp78, our results showed that the chondrocytes of the proliferating zone were weakly immunopositive to Cripto, while the chondrocytes of the hypertrophic zone were strongly immunopositive to both Cripto and Grp78. A recent study has shown that immunofluoroscene labeling positivity to Cripto was found at the boundaries of the area containing hypertrophic chondrocytes in a metatarsal organ culture derived from E15.5 to E17.5 mouse hind limb [19]. This result indicates that the protein expression pattern of Cripto in the hypertrophic chondrocytes of the SOS would be similar to that of chondrocytes in the endochondral ossification of long bones.…”

Identification of Transcription Factors Responsible for a Transforming Growth Factor-β-Driven Hypertrophy-like Phenotype in Human Osteoarthritic Chondrocytes

“…Additionally, Qu et al demonstrated that high doses of TGF-β contribute to degeneration of nucleus pulposus cells in the intervertebral disc via upregulation of ALK1 and SMAD1/5 [ 121 ]. Moreover, gene expression analysis in experimental OA models and human OA samples showed upregulation of the TGF-β co-receptor Cripto, which participates in a TGF-β-ALK1-Cripto receptor complex, thereby inducing SMAD1/5 signaling in chondrocytes and induction of hypertrophy [ 126 ]. Thus, the impact of increased TGF-β activation in articular cartilage may move from homeostatic SMAD2/3 signaling towards pathological SMAD1/5 signaling, depending on its levels, context and receptor usage.…”

Strontium Regulates the Proliferation and Differentiation of Isolated Primary Bovine Chondrocytes via the TGFβ/SMAD Pathway

“…Similarly, these results were also in agreement with data in human primary chondrocytes demonstrating that Sr chondroitin sulfate markedly upregulated the expression of COL2A1 and ACAN ( Ma et al, 2017 ). The TGFβ co-receptor Cripto promoted COL10A1 by inducing SMAD1/5/9 signaling in ATDC5 cells and immortalized C28/12 human chondrocytes ( Garcia de Vinuesa et al, 2021 ). A role for ALPL in the maturation and mineralization as well as the inhibitory effect of Sr on SPP1, COL10A1, and ALPL was reported in murine chondrocytes ( Ehirchiou et al, 2020 ).…”