Lee Jennifer K, Gegg Courtney A, Hu Jerry C, Kass Philip H, Athanasiou Kyriacos A
Department of Biomedical Engineering, University of California, One Shields Avenue, Davis, CA 95616, USA.
Department of Population Health and Reproduction, School of Veterinary Medicine, University of California, 1089 Veterinary Medicine Drive, Davis, CA 95616, USA.
J Biomech. 2014 Nov 28;47(15):3712-8. doi: 10.1016/j.jbiomech.2014.09.018. Epub 2014 Oct 2.
Osteoarthritis, a degenerative disease of the load-bearing joints, greatly reduces quality of life for millions of Americans and places a tremendous cost on the American healthcare system. Due to limitations of current treatments, tissue engineering of articular cartilage may provide a promising therapeutic option to treat cartilage defects. However, cartilage tissue engineering has yet to recapitulate the functional properties of native tissue. During normal joint loading, cartilage tissue experiences variations in osmolarity and subsequent changes in ionic concentrations. Motivated by these known variations in the cellular microenvironment, this study sought to improve the mechanical properties of neocartilage constructs via the application of hyperosmolarity and transient receptor potential vanilloid 4 (TRPV4) channel activator 4α-phorbol 12,13-didecanoate (4αPDD). It was shown that 4αPDD elicited significant increases in compressive properties. Importantly, when combined, 4αPDD positively interacted with hyperosmolarity to modulate its effects on tensile stiffness and collagen content. Thus, this study supports 4αPDD-activated channel TRPV4 as a purported mechanosensor and osmosensor that can facilitate the cell and tissue level responses to improve the mechanical properties of engineered cartilage. To our knowledge, this study is the first to systematically evaluate the roles of hyperosmolarity and 4αPDD on the functional (i.e., mechanical and biochemical) properties of self-assembled neotissue. Future work may combine 4αPDD-induced channel activation with other chemical and mechanical stimuli to create robust neocartilages suitable for treatment of articular cartilage defects.
骨关节炎是一种承重关节的退行性疾病，极大地降低了数百万美国人的生活质量，并给美国医疗保健系统带来了巨大成本。由于当前治疗方法的局限性，关节软骨组织工程可能为治疗软骨缺损提供一种有前景的治疗选择。然而，软骨组织工程尚未重现天然组织的功能特性。在正常关节负荷期间，软骨组织会经历渗透压的变化以及随后离子浓度的改变。受细胞微环境中这些已知变化的启发，本研究试图通过应用高渗和瞬时受体电位香草酸受体4（TRPV4）通道激活剂4α-佛波醇12,13-十四烷酸酯（4αPDD）来改善新软骨构建体的力学性能。结果表明，4αPDD可显著提高压缩性能。重要的是，当联合使用时，4αPDD与高渗呈正相互作用，以调节其对拉伸刚度和胶原蛋白含量的影响。因此，本研究支持4αPDD激活的通道TRPV4作为一种所谓的机械传感器和渗透压感受器，可促进细胞和组织水平的反应，以改善工程软骨的力学性能。据我们所知，本研究首次系统评估了高渗和4αPDD对自组装新组织功能（即力学和生化）特性的作用。未来的工作可能将4αPDD诱导的通道激活与其他化学和机械刺激相结合，以创建适用于治疗关节软骨缺损的强健新软骨。
