The role of Alk-1 and Alk-5 in the mechanosensing of chondrocytes

Abstract

Abbreviations used: Alk-1 -activin receptor-like kinase 1; Alk-5 -activin receptor-like kinase 5; FGFR3 -fibroblast growth factor receptor 3; FA -focal adhesions; MSCsmesenchymal stem cells; OA -osteoarthritis; TGFβ -transforming growth factor β; Col2 -type II collagen; Col1 -type I collagen; Col10 -type X collagen Abstract: We aim to demonstrate the role of Alk receptors in the response of hydrogel expansion. Chondrocytes from rat knees were cultured onto plastic and hydrogel surfaces. Alk-1 and Alk-5 were overexpressed or silenced and the effects on cells during expansion were tested and confirmed using peptide inhibitors for TGFβ. Overexpression of Alk-5 and silencing of Alk-1 led to a loss of the chondrocyte phenotype, proving that they are key regulators of chondrocyte mechanosensing. An analysis of the gene expression profile during the expansion of these modified cartilage cells in plastic showed a better maintenance of the chondrocyte phenotype, at least during the first passages. These passages were also assayed in a mouse model of intramuscular chondrogenesis. Our findings indicate that these two receptors are important mediators in the response of chondrocytes to changes in the mechanical environment, making them suitable targets for modulating chondrogenesis. Inhibition of TGFβ could also be effective in improving chondrocyte activity in aged or expanded cells that overexpress Alk-1.

Differential bioactivity of four BMP-family members as function of biomaterial stiffness

“…In fact, ALK5 is historically known as a TGF-β receptor 47 and for its involvement in EMT in breast epithelial 48 and endothelial cells 49 . It was already shown to be involved in the response to shear stress in the endothelium 50 , in chondrocyte mechanosensing 51 and in the activation of focal adhesion kinase (FAK) in lung epithelial cells 52 . Our data revealed an important mechano-sensitive role of ACTR-IIA in cell adhesion, notably in response to both bBMP-4 and bBMP-7 (Fig.…”

Reversely immortalized mouse salivary gland cells presented a promising metabolic and fibrotic response upon BMP9/Gdf2 stimulation

“…It has recently attracted significant attention concerning the use of gene delivery to rescued salivary function [ 13 , 48 ]. BMP9 plays a role in various organ fibroses, including liver fibrosis, cardiac functions through classical BMPs/Smads signaling pathways and nonclassical pathways, and a variety of signals and cytokines [ 49 ]. BMP9 also plays important roles in inhibiting hepatic glucose production, inducing the expression of key enzymes of lipid metabolism.…”