Mechanotransductive Mechanisms of Biomimetic Hydrogel Cues Modulating Meckel's Cartilage Degeneration

Abstract Meckel's cartilage, a cartilage rod present in the mandible during developmental stages, shows a unique developmental fate: while the anterior and posterior portions undergo ossification, the middle part degenerates. Previously, it was shown that a stiff environment promoted cartilage degeneration in the middle region, while a soft environment enhanced the mineralization in the anterior region of Meckel's cartilage. This study aims to elucidate the spatio‐temporal changes in the mechanosensing properties of Meckel's cartilage during its early developmental stages and clarify the mechanotransduction‐related mechanisms involved in its degeneration. The results show that the expression of Hippo pathway effector yes‐associated protein (YAP) is only detectable in the Meckel's cartilage onward embryonic day (E)14.5, indicating that mechanosensing is dependent on the tissue developmental stage. Consistently, microenvironmental stiffness‐induced cartilage degeneration can only be induced in cartilages onward E14.5, but not in those at earlier developmental stages. Expressions of integrin‐β1 and cartilage matrix‐degrading enzymes, matrix metalloproteinase 1 (MMP‐1) and MMP‐13, are significantly enhanced in the degeneration area. Moreover, verteporfin (YAP inhibitor) and integrin‐β1 antibody block the substrate stiffness‐induced degeneration by suppressing the expressions of MMP‐1 and MMP‐13. These data provide new insights into the interplay between biochemical and mechanical cues determining the fate of Meckel's cartilage.