Piezo1-Mediated Mechanotransduction as Key Regulator of Bone Health in Adult Mice
Abstract
This project addresses the FY20 PRMRP Topic Area “Musculoskeletal Health”. Regulation of bone health by biochemical cues has been studied extensively. However, despite the fact that mechanical strain is a known key regulator of bone formation and remodeling, our understanding of how bone health is impacted by physical cues such as mechanical forces lags behind, largely due to unclear mechanisms for mechanosensation. Recent advancement in mechanotransduction research has identified Piezo1 and Piezo2 as the best characterized biological force-sensing systems, and we have shown that Piezo1 is required in mesenchymal progenitor cells and early osteoblast cells to promote osteoblast differentiation and maturation during long bone development in vivo. We also found that Piezo1 is required for osteoblast differentiation from bone marrow stromal cells (BMSCs) by promoting both Wnt signaling and Yap activities. We showed that Piezo1 is required for BMSCs to sense fluid sheer stress and matrix rigidity. While these findings identified Piezo1 as a key biological force sensor in controlling bone formation and remodeling, we are still at the tip of an iceberg to understand the downstream signaling events. In this study, we will investigate the functional mechanisms of Piezo1 in osteocytes in adult mice. Osteocytes comprise the overwhelming majority (over 90%-95%) of all bone cells in the adult animals. They are surrounded by fluid filled spaces known as lacunae and embedded in mineralized matrix that they also directly reorganize. Long dendritic processes of osteocytes form a lacuno-canalicular network (LCN) connecting the neighboring osteocytes and the cells on the bone surface such as osteoblasts, osteoclasts, and BMSCs. Mechanical signals exerted by fluid sheer stress in the lacunae are sensed mainly by dendrites of the osteocytes. Osteocytes, in turn, respond by changing gene expression and protein secretion, by which osteocytes impact bone formation and remodeling. In this proposal, with sophisticated mouse genetic techniques, we will remove Piezo1 specifically from the osteocytes in adult mice after bone development has completed. We have found that bone mass was reduced in such mice, and we will further determine the cellular and molecular defects in these mice that are responsible for the observed bone loss. We will identify and test the functions of mechanotransduction components downstream of Piezo1 and use chemical inhibitors or activators targeting these components to test whether these chemicals can reverse bone defects caused by Piezo1 loss. These studies will provide insights into therapeutic development to improve bone formation that is reduced in many diseases or during aging or due to loading abnormalities. We will also determine how mechanical forces act through Piezo1 to change gene expression in osteocytes to gain more insight into how forces regulate cellular behaviors and tissue properties. Using novel and powerful mouse models, our systematical and rigorous investigation of the cellular and molecular changes caused by Piezo1 activation and inactivation will advance our current knowledge of mechanotransduction and the results will be essential to provide new insights into treatment of bone diseases. The knowledge gained will benefit military personnel and Veterans, among whom musculoskeletal disorder are more prevalent.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110449
Entities
People
- Yingzi Yang
Organizations
- Harvard University
- United States Army