Department of Bioengineering, Imperial College London, London, UK.
Department of Mechanical, Manufacturing, and Biomedical Engineering, School of Engineering, Trinity College Dublin, Dublin, Ireland.
Sci Adv. 2023 Jan 25;9(4):eade2155. doi: 10.1126/sciadv.ade2155.
Biophysical cues are essential for guiding skeletal development, but the mechanisms underlying the mechanical regulation of cartilage and bone formation are unknown. TRPV4 is a mechanically sensitive ion channel involved in cartilage and bone cell mechanosensing, mutations of which lead to skeletal developmental pathologies. We tested the hypothesis that loading-driven prenatal skeletal development is dependent on TRPV4 activity. We first establish that mechanically stimulating mouse embryo hindlimbs cultured ex vivo stimulates knee cartilage growth, morphogenesis, and expression of TRPV4, which localizes to areas of high biophysical stimuli. We then demonstrate that loading-driven joint cartilage growth and shape are dependent on TRPV4 activity, mediated via control of cell proliferation and matrix biosynthesis, indicating a mechanism by which mechanical loading could direct growth and morphogenesis during joint formation. We conclude that mechanoregulatory pathways initiated by TRPV4 guide skeletal development; therefore, TRPV4 is a valuable target for the development of skeletal regenerative and repair strategies.
生物物理线索对于指导骨骼发育至关重要，但机械调节软骨和骨形成的机制尚不清楚。 TRPV4 是一种机械敏感的离子通道，参与软骨和骨细胞的机械感受，其突变会导致骨骼发育病理学。我们测试了这样一个假设，即加载驱动的产前骨骼发育依赖于 TRPV4 活性。我们首先证实，体外培养的小鼠胚胎后肢的机械刺激可刺激膝关节软骨生长、形态发生和 TRPV4 的表达，而 TRPV4 定位于高生物物理刺激区域。然后，我们证明了负载驱动的关节软骨生长和形状依赖于 TRPV4 活性，这是通过控制细胞增殖和基质生物合成来介导的，表明机械加载可以在关节形成过程中指导生长和形态发生的一种机制。我们的结论是，由 TRPV4 启动的机械调节途径指导骨骼发育；因此，TRPV4 是骨骼再生和修复策略发展的有价值的靶点。
