The role of Piezo1 in bone homeostasis and mechanotransduction

Piezo1 在骨稳态和力传导中的作用

基本信息

  • 批准号:
    10238777
  • 负责人:
  • 金额:
    $ 32.44万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-08-17 至 2025-06-30
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY/ABSTRACT Mechanical stimuli promote bone growth and are critical for skeletal homeostasis during adulthood. Loss of mechanical signals decreases bone mass and increases fracture risk. Osteocytes, which are cells buried in the bone matrix and derived from osteoblasts, are able to sense changes in mechanical load and orchestrate bone remodeling. Several lines of evidence suggest that calcium channels are involved in the sensing of mechanical load by osteocytes. For example, calcium influx is one of the earliest responses of osteocytes to mechanical stimuli in vitro and in vivo. Consistent with a functional role for calcium signaling in the response to mechanical forces, the response of osteocytes to mechanical stimuli can be inhibited by blocking calcium channels using chemical blockers. Moreover, load-induced bone formation in the rat ulna is significantly blunted by calcium channel inhibitors. However, the identity of the calcium channels activated by mechanical forces and their functional role as mechanosensors in bone remain unclear. We have found that Piezo1 calcium channel is highly expressed in osteocytes, and that its expression and activity are increased by mechanical stimulation in osteocytes. In addition, deletion of Piezo1 in osteoblasts and osteocytes decreases both bone mass and bone strength in mice, consistent with loss of skeletal responsiveness to mechanical stimulation. Moreover, the skeletal response to anabolic loading is blunted in mice lacking Piezo1 in osteoblasts and osteocytes. Wnt1, a ligand for Wnt signaling that is known to be upregulated by mechanical signals and stimulate bone formation, is downregulated in Piezo1 conditional knockout mice. Importantly, activation of Piezo1 by its chemical agonist, Yoda1, mimics the effects of fluid flow on osteocytes and increases bone mass in mice. Based on this evidence, we hypothesize that osteocytes sense changes in mechanical signals through Piezo1 and thereby promote bone formation in part by activating signaling pathways that increase the expression of Wnt1. To test this hypothesis, we will determine whether Piezo1 expression by osteocytes is required for mechanical sensing in the murine skeleton. We will generate mice in which Piezo1 is deleted from osteocytes, but not osteoblasts, and compare their skeletal phenotype to that observed in mice lacking Piezo1 in osteoblasts and osteocytes. We also will delete Piezo1 postnatally in adult mice and investigate their response to mechanical loads by tibia compression (Aim 1). In addition, to understand how Piezo1 promotes bone formation, we will determine the role of Wnt1 in Piezo1-mediated bone formation in vivo using a mouse genetic approach (Aim 2). In Aim 3, we will determine whether Piezo1 is responsible for the skeletal response to unloading using a tail-suspension model. Lastly, we will determine whether pharmacological activation of Piezo1 prevents bone loss associated with unloading or increases bone mass in old mice. Successful completion of this work should establish a new model for understanding the skeletal response to anabolic mechanical loading and may suggest new strategies to develop anabolic therapies for bone loss related to disuse or aging.
项目总结/文摘

项目成果

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Jinhu Xiong其他文献

Jinhu Xiong的其他文献

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{{ truncateString('Jinhu Xiong', 18)}}的其他基金

The role of Piezo1 in bone homeostasis and mechanotransduction
Piezo1 在骨稳态和力传导中的作用
  • 批准号:
    10642770
  • 财政年份:
    2020
  • 资助金额:
    $ 32.44万
  • 项目类别:
The role of Piezo1 in bone homeostasis and mechanotransduction
Piezo1 在骨稳态和力传导中的作用
  • 批准号:
    10418767
  • 财政年份:
    2020
  • 资助金额:
    $ 32.44万
  • 项目类别:
Histology, Biomechanics, and Human Tissue Core
组织学、生物力学和人体组织核心
  • 批准号:
    10495744
  • 财政年份:
    2018
  • 资助金额:
    $ 32.44万
  • 项目类别:

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