Inflammation Barrier Role of Piezo1 in Chondrocytes under Aberrant Loading

The temporomandibular joint (TMJ) has a close biomechanical relationship with dental occlusion. PIEZO1 is a major mechanosensor in chondrocytes. The role Piezo1 plays in TMJ chondrocytes under aberrant occlusion loading remains obscure. In vivo, cell lineage tracing methods and tissue-specific genetic mutation techniques were adopted. An in vitro chondrocyte stretch loading model and the in vivo unilateral anterior crossbite (UAC) model were used. PIEZO1 was highly expressed in SOX9-, type II collagen (Col-II)-, and type-X collagen (Col-X)-expressing TMJ chondrocytes, and the expression was promoted by UAC stimulation. PIEZO1 was also expressed in ADTC5 cells, and the expression was promoted by stretch loading. Piezo1 knockout by gRNA, a kind of CRISPR-Cas9, led ADTC5 cells to pyroptosis, the process of which was enhanced by stretch loading. Mutation of Piezo1 in <i>Sox9-</i>, <i>Col2-</i>, or <i>Col10-</i>tissue-specific patterns led to pyroptosis of the SOX9-, Col-II-, or Col-X-expressing cells, respectively. The pyroptosis signs were more severe after UAC treatment. The pyroptosis signs were also significant in SOX9- or Col-II-positive cells in the <i>Col10^CreER; Piezo1^-/-</i> mice at 3 wk but not at 1 wk. After being treated by UAC, the pyroptosis signs at 1 wk turned to be significant in SOX9- and Col-II-positive cells in the <i>Col10^CreER; Piezo1^-/-</i> mice. Stretch loading plus gRNA2 promoted interleukin-18 (IL-18) secretion by ATDC5 cells. By adding anti-IL-18 blocked protein into the culture medium obtained from the ATDC5 cells treated with stretch loading and gRNA2, the impact of the secreted IL-18 on chondrocyte pyroptosis was confirmed. <b>Conclusions.</b> Piezo1 mutation leads to pyroptosis of not only the mutated cells but also the neighboring cells, especially under aberrant loading, owing to the inflammatory effect of the mutated chondrocytes. Piezo1 takes the role of the inflammation barrier in chondrocytes under aberrant loading. Our findings provide a better understanding of the relationship between mechanical stimulation and inflammation in osteoarthritic cartilage.