Abstract: Bone's ability to adapt to mechanical stress is a fundamental principle in orthopedics, stated by Wolff's Law, which posits that bone formation and strength are directly related to the degree of mechanical loading they experience. We have discovered that the mechanosensitive ion channel Piezo1 plays a crucial role in the osteogenic differentiation of bone marrow-derived LepR+Osteolectin+ cells (Osteolectin+ cells), a process integral to bone formation. Specifically, we have shown that exercise-induced mechanical stimulation activates Piezo1, thereby promoting bone formation and reinforcing the relevance of Wolff's Law in the context of peri-arteriolar stromal cells. Despite Piezo1's broad expression across LepR+ cells, including peri-sinusoidal LepR+Oln– cells, the precise reason for the dependency of peri-arteriolar Osteolectin+ cells on Piezo1 for their function is not fully understood. To address this, we developed Piezo1-GCaMP mice, which feature a genetically encoded fluorescent probe allowing for non-invasive optical monitoring of Piezo1 activity. Our studies revealed a significant increase in Piezo1 activation in peri-arteriolar LepR+Osteolectin+ cells, compared to peri-sinusoidal cells, highlighting the selective role of mechanosensing in these cells. Importantly, we observed that weight-bearing bones, which are more responsive to mechanical loading, have a higher frequency of Osteolectin+ cells and are more affected by the conditional deletion of Piezo1 in LepR+ cells, leading to a loss of bone mineral density and cortical bone thickness. Our ongoing work is focused on uncovering the molecular mechanisms downstream of Piezo1 that contribute to these observations, with a hypothesis that peri-arteriolar Osteolectin+ cells exhibit increased mechanosensitivity due to enhanced matrix protein deposition and local stiffness near arterioles. This research underscores the critical importance of Piezo1-mediated mechanosensing in peri-arteriolar Osteolectin+ cells for bone formation, particularly in weight-bearing bones, which have a higher mechanosensitivity and a greater abundance of Osteolectin+ cells.
