During spaceflight, lack of mechanical stimulation lowers Piezo1 levels leading to bone density loss (left). When mechanical stimulation is applied, like in exercise, levels of Piezo1 increase leading to higher bone density (right). Image credit: Yingxian Li, Weijia Sun and Shukuan Ling (CC BY 4.0)
The bones in our skeletons are constantly exposed to mechanical forces, including those exerted by our muscles and also Earth’s gravity. These forces normally help osteoblasts, the cells which build new bone tissue, ensure that bones grow correctly and remain strong. Removing mechanical loads from bones, however, disrupts this process, leading to rapid loss of bone tissue. This is why both astronauts in space (where gravity is much weaker) and bed-ridden patients often go on to develop brittle bones.
To detect and respond to mechanical forces, cells use specialized sensor proteins. One such ‘mechanosensor’ is a protein called Piezo1, which is found on the surface of many different types of cells in our bodies. It helps cells respond to touch, pressure, or stretching of the surrounding tissue. For example, Piezo1 in nerve cells underpins our sense of touch, while in the cells lining our blood vessels it senses the force exerted by blood flow.
Although osteoblasts clearly respond to mechanical stimuli, exactly how they do so has remained unknown. Sun et al. therefore wanted to find out if Piezo1 also acted as a mechanosensor in osteoblasts, and if so, what role it might play in the loss or formation of bone tissue after changes in the amount of force the bone is exposed to.
Experiments using mouse cells grown in the laboratory revealed that Piezo1 was present in osteoblasts and did indeed help the cells respond to mechanical impact of being poked by a microscopic probe. Mice that had been genetically engineered to remove Piezo1 from their osteoblasts did not grow properly, appearing stunted in adulthood. In these mice, the bones supporting most of the body’s weight were also shorter and weaker.
Crucially, putting normal bone cells in a low-gravity simulator – therefore mimicking space flight – or exposing mice to conditions mimicking bed-rest was enough to reduce the level of Piezo1 in osteoblasts. In human patients with osteoporosis, where bones become brittle with age, a decrease in levels of Piezo1 is correlated with increasing bone loss. These results show that Piezo1 is required to make healthy bone tissue, and that its loss is probably involved in the increasing fragility that occurs when mechanical forces applied to bones are reduced.
This work is an important step towards understanding how our bones are built and maintained. In the future, increasing Piezo1 activity within osteoblasts may lead to treatments for bone loss, whether in hospital patients or astronauts.
