Stimulation of Piezo1 by mechanical signals promotes bone anabolism.

Xuehua Li,Jinhu Xiong,Matthew J Silva,Erin Mannen,Li Han,Maria Almeida,Intawat Nookaew

doi:10.7554/elife.49631

Xuehua Li, Jinhu Xiong + Show 5 more

Open Access

https://doi.org/10.7554/elife.49631

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Abstract

Mechanical loading, such as caused by exercise, stimulates bone formation by osteoblasts and increases bone strength, but the mechanisms are poorly understood. Osteocytes reside in bone matrix, sense changes in mechanical load, and produce signals that alter bone formation by osteoblasts. We report that the ion channel Piezo1 is required for changes in gene expression induced by fluid shear stress in cultured osteocytes and stimulation of Piezo1 by a small molecule agonist is sufficient to replicate the effects of fluid flow on osteocytes. Conditional deletion of Piezo1 in osteoblasts and osteocytes notably reduced bone mass and strength in mice. Conversely, administration of a Piezo1 agonist to adult mice increased bone mass, mimicking the effects of mechanical loading. These results demonstrate that Piezo1 is a mechanosensitive ion channel by which osteoblast lineage cells sense and respond to changes in mechanical load and identify a novel target for anabolic bone therapy.

Highlights

Mechanical signals play critical roles in bone growth and homeostasis (Turner et al, 2009; Ozcivici et al, 2010)
Our results suggest that osteoblasts, osteocytes, or both, sense and respond to changes in mechanical signals in part via activation of the Piezo1 calcium channel and identify activation of Piezo1 signaling as a potential therapeutic approach for osteoporosis
To identify calcium channels that respond to mechanical signals in osteocytes, we compared gene expression profiles of the osteocytic cell line MLO-Y4 under static and fluid flow conditions by RNAseq

Summary

Introduction

Mechanical signals play critical roles in bone growth and homeostasis (Turner et al, 2009; Ozcivici et al, 2010). Mechanical stimuli increase bone mass by stimulating the activity and production of bone forming osteoblasts (Meakin et al, 2014; Klein-Nulend et al, 2012). Loss of mechanical signals decreases bone mass by reducing bone formation and stimulating production of bone resorbing osteoclasts (Kondo et al, 2005; Nakamura et al, 2013; Xiong et al, 2011). Osteocytes, which are cells buried in the bone matrix and derived from osteoblasts, are able to sense changes in mechanical load and orchestrate bone resorption and formation (Bonewald, 2011; Klein-Nulend et al, 2013).

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