Normal (left) and Piezo1-deficient (right) mouse limb. Credit: Li et al. (CC BY 4.0)
Bone size and strength depend on physical activity. Increased forces on the skeleton, such as those that occur during exercise, trigger more bone formation and make bones stronger. Conversely, reduced forces, caused for example by the lack physical activity, cause bone loss and increase the risk of fractures.
Bones contain cells called osteocytes. These cells sense the forces exerted on bone and orchestrate bone formation in response. Calcium channels are one type of molecule that has been proposed to help osteocytes to sense forces. Calcium channels reside in the cell membrane and can change their structure to allow calcium ions to flow into the cell. Some of them allow calcium ions into the cell in direct response to physical forces, communicating to the cell that a force has been applied. These are called mechanosensitive ion channels. Until now, however, no specific calcium channels involved in force sensing had been identified in osteocytes.
Li et al. searched for calcium channels in osteocytes, and found high levels of a mechanosensitive ion channel called Piezo1. Then, Li et al. made genetically modified mice that did not have any Piezo1 in these cells. The skeleton of these mice was small and weak. Moreover, the bones of these modified mice did not respond to forces like the bones of normal mice. To demonstrate this, Li et al. applied a short bout of increased force to the leg bones of unmodified mice and to those of the Piezo1 deficient mice. After two weeks, the bones of the unmodified mice had increased in thickness, whereas the bones lacking Piezo1 had not. A separate study by Sun, Chi et al. showed similar results when Piezo1 was removed from bone cells grown in the laboratory.
Finally, Li et al. tested the impact of a chemical called Yoda1 on bones. Yoda1 makes the Piezo1 channel open, thus mimicking a physical force. These experiments showed that mice treated with Yoda1 had thicker bones than untreated mice.
The ability of human bone to become stronger in response to exercise decreases with age, which contributes to the development of osteoporosis. Conditions that require severely restricted exercise, such as disability or extended bedrest, also lead to bone loss. These experiments show that Piezo1 allows bone to respond to physical force, and suggest Piezo1 as a promising therapeutic target to help curtail bone loss in these conditions.
