Stimulation of Piezo1 by mechanical signals promotes bone anabolism

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.

Fluid shear stress induces Runx‐2 expression via upregulation of PIEZO1 in MC3T3‐E1 cells

“…PIEZO1 can also regulate the cell fate determination of mesenchymal stem cells in response to hydrostatic pressure (Sugimoto, 2017). Knockout of PIEZO1 in osteoblasts and osteocytes blunts the skeletal response to mechanical loads and resulted in the impair of bone structure and strength (Li et al, 2019; Sun et al, 2019). And PIEZO1 agonist could increase bone mass in adult mice, simulating the effects of mechanical loading (Li et al, 2019).…”

“…Knockout of PIEZO1 in osteoblasts and osteocytes blunts the skeletal response to mechanical loads and resulted in the impair of bone structure and strength (Li et al, 2019; Sun et al, 2019). And PIEZO1 agonist could increase bone mass in adult mice, simulating the effects of mechanical loading (Li et al, 2019). Also, Miyazaki et al (2019) found that PIEZO1 functions as a mechanotransducter that connects hydrostatic pressure signal to the intracellular signals during odontoblast differentiation through coordination of WNT signaling and ciliogenesis.…”

Of mice and men: converging on a common molecular understanding of osteoarthritis

“…Osteoarthritis is a mechanically driven disease. This notion is compellingly described in the epidemiological literature 6 and confirmed in basic science studies, which have shown the highly mechanosensitive nature of joint tissues, 7 , 8 , 9 , 10 , 11 , 12 the activation of inflammatory signalling by mechanical injury, 12 , 13 the dependence on mechanics in preclinical osteoarthritis, 14 , 15 and the involvement of mechanosensing mechanisms in in-vivo pathogenesis. 16 , 17 Several other important causal factors—such as obesity, age, and genetics—affect the ability of joint tissues to withstand mechanical stress over a lifetime and affect the ability to repair damaged tissues.…”

Functional Biomaterials for Bone Regeneration: A Lesson in Complex Biology

“…This is consistent with further studies demonstrating that conditional deletion of Piezo1 in osteoblasts and osteocytes reduces bone mass and bone strength in mice and that these mice displayed blunted anabolic responses to mechanical loading. [250,251] However, since the anabolic response to loading was diminished but not abolished in these conditional Piezo1 knockout mice, this suggests that additional mechanosensitive channels also play a role in the anabolic response in bone cells (Figure 4). Importantly, administration of Yoda1 to adult mice was also demonstrated to increase bone mass.…”