Chewing-Activated TRPV4/PIEZO1– <i>HIF-1α</i> –Zn Axes in a Rat Periodontal Complex

The upstream mechanobiological pathways that regulate the downstream mineralization rates in periodontal tissues are limitedly understood. Herein, we spatially colocalized and correlated compression and tension strain profiles with the expressions of mechanosensory ion channels (MS-ion) TRPV4 and PIEZO1, biometal zinc, mitochondrial function marker (<i>MFN2</i>), cell senescence indicator (<i>p16</i>), and oxygen status marker hypoxia-inducible factor-1α (<i>HIF-1α</i>) in rats fed hard and soft foods. The observed zinc and related cellular homeostasis in vivo were ascertained by TRPV4 and PIEZO1 agonists and antagonists on human periodontal ligament fibroblasts ex vivo. Four-week-old male Sprague-Dawley rats were fed hard (<i>n</i> = 3) or soft (<i>n</i> = 3) foods for 4 wk (in vivo). Significant changes in alveolar socket and root shapes with decreased periodontal ligament space and increased cementum volume fraction were observed in maxillae on reduced loads (soft food). Reduced loads impaired distally localized compression-stimulated PIEZO1 and mesially localized tension-stimulated TRPV4, decreased mitochondrial function (<i>MFN2</i>), and increased cell senescence in mesial and distal periodontal regions. The switch in <i>HIF-1α</i> from hard food-distal to soft food-mesial indicated a plausible effect of shear-regulated blood and oxygen flows in the periodontal complex. Blunting or activating TRPV4 or PIEZO1 MS-ion channels by channel-specific antagonists or agonists in human periodontal ligament fibroblast cultures (in vitro) indicated a positive correlation between zinc levels and zinc transporters but not with MS-ion channel expressions. The effects of reduced chewing loads in vivo were analogous to TRPV4 and PIEZO1 antagonists in vitro. Study results collectively illustrated that tension-induced TRPV4 and compression-induced PIEZO1 activations are necessary for cell metabolism. An increased hypoxic state with reduced functional loads can be a conducive environment for cementum growth. From a practical standpoint, dose rate-controlled loads can modulate tension and compression-specific MS-ion channel activation, cellular zinc, and <i>HIF-1α</i> transcription. These mechanobiochemical events indicate the plausible catalytic role of biometal zinc in mineralization, periodontal maintenance, and dentoalveolar joint function.