The Regulation of Pericellular Matrix Synthesis During Articular Cartilage Tissue Engineering

Articular cartilage, vital to the health and functioning of joints, remains challenging to regenerate. The pericellular matrix (PCM) is critical for transducing biophysical stimuli to the articular chondrocytes (ACs) that it envelops. Given the mechanobiological sensitivity of ACs, it is pivotal in maintaining the chondrogenic phenotype and the production of extracellular matrix (ECM) during articular cartilage tissue engineering. While the maintenance of the native PCM significantly improves the quality of neocartilage, current isolation methods are limited. A solution to this challenge is facilitating ACs to regenerate their PCM. However, the regulation of PCM synthesis remains poorly understood, hindering the development of effective tissue engineering strategies. This narrative review aims to provide a comprehensive analysis of the complex interplay between extracellular cues and intracellular pathways regulating PCM synthesis during articular cartilage tissue engineering. Our analysis reveals that mechanical cues, such as material stiffness and mechanical stimulation, are the primary regulators of PCM synthesis. Additionally, the use of scaffold-free techniques potentially affects the structuring of newly created PCM. Tuning these stimuli can significantly impact the quality of the formed PCM, ultimately influencing neocartilage quality. Furthermore, we highlight intracellular mechanisms involved in the transduction of these extracellular cues, including actin polymerization, yes-associated protein and transcriptional coactivator with PDZ-binding motif localization, and transforming growth factor beta-induced Smad signaling. Although the current literature suggests the involvement of these signaling pathways in regulating the synthesis of PCM components, we found that studies investigating these processes in ACs are lacking. Elucidating the relationships between extracellular stimuli, intracellular signaling, and the expression of PCM components could provide a framework for designing new cartilage tissue engineering approaches that facilitate proper PCM synthesis. Ultimately, this can improve ECM quality and advance articular cartilage regeneration.