Abstract
Wolff’s law and the Utah Paradigm of skeletal physiology state that bone architecture adapts to mechanical loads. These models predict the existence of a mechanostat that links strain induced by mechanical forces to skeletal remodeling. However, how the mechanostat influences bone remodeling remains elusive. Here, we find that Piezo1 deficiency in osteoblastic cells leads to loss of bone mass and spontaneous fractures with increased bone resorption. Furthermore, Piezo1-deficient mice are resistant to further bone loss and bone resorption induced by hind limb unloading, demonstrating that PIEZO1 can affect osteoblast-osteoclast crosstalk in response to mechanical forces. At the mechanistic level, in response to mechanical loads, PIEZO1 in osteoblastic cells controls the YAP-dependent expression of type II and IX collagens. In turn, these collagen isoforms regulate osteoclast differentiation. Taken together, our data identify PIEZO1 as the major skeletal mechanosensor that tunes bone homeostasis.
Highlights
Wolff’s law and the Utah Paradigm of skeletal physiology state that bone architecture adapts to mechanical loads
It has been reported that osteoblast lineage cells, including bone mesenchymal stem cells (BMSCs), osteoblast progenitor cells, osteoblasts, and osteocytes can respond to mechanical loading in bone[7]
QPCR confirmed that Piezo[1] was highly expressed in bone and skeletal cells (Supplementary Fig. 1a–c), while Piezo[2] was highly expressed in the dorsal root ganglia neurons instead of the whole bone and primary osteoblasts as reported[13,20] (Supplementary Fig. 1a–c). These results suggest that PIEZO1 could have a crucial role in osteoblasts
Summary
Wolff’s law and the Utah Paradigm of skeletal physiology state that bone architecture adapts to mechanical loads. We find that Piezo[1] deficiency in osteoblastic cells leads to loss of bone mass and spontaneous fractures with increased bone resorption. In response to mechanical loads, PIEZO1 in osteoblastic cells controls the YAP-dependent expression of type II and IX collagens. PIEZO1 has been reported to mediate the function of hydrostatic pressure on cell fate determination of mesenchymal stem cells[19] It is unknown whether PIEZO1 can regulate bone remodeling responding to mechanical load. Our study advances understanding and stimulates targeted therapeutic approaches for disuse osteoporosis
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