The discovery could allow bones to benefit from exercise without movement

The team discovered that a specific protein acts as an internal “exercise sensor” that allows bones to respond to physical movement. This insight opens up the possibility of developing drugs that replicate the benefits of exercise, offering new hope to older adults, bedridden patients, and individuals with chronic illnesses who face a higher risk of fracture. The findings were published in a journal Signal transduction and targeted therapy.

“Osteoporosis and age-related bone loss affect millions of people around the world, often making elderly and bedridden patients prone to fractures and loss of independence,” said Professor Xu Aimin, director of the State Key Laboratory of Pharmaceutical Biotechnology and senior professor at the Department of Medicine, School of Clinical Medicine, HKUMed, who led the study. “Current treatments rely heavily on physical activity, which many patients simply can’t do. We need to understand how our bones get stronger when we move or exercise before we can find a way to replicate the benefits of exercise at the molecular level. This study is a critical step toward that goal.”

Why does bone loss become more severe with age?

Bone fractures caused by osteoporosis are a widespread global health problem. According to the World Health Organization, about one in three women and one in five men over the age of 50 will experience a fracture due to weakened bones. In Hong Kong, the impact is particularly significant as the population ages, with osteoporosis affecting 45% of women and 13% of men aged 65 and over. These fractures often result in long-term pain, reduced mobility and loss of independence, while also placing a heavy burden on healthcare systems.

As people age, bones naturally lose density and become more porous. Inside the bone marrow are mesenchymal stem cells that can develop into either bone tissue or fat cells. These cells respond strongly to physical forces such as movement and pressure. But over time, aging shifts this balance, causing more of these stem cells to turn into fat cells instead of bone.

When fat builds up inside the bone marrow, it crowds out healthy bone tissue. This process further weakens the bones, creating a cycle of deterioration that is difficult to reverse with current therapies.

Piezo1 functions as a bone load sensor

Through experiments using mouse models and human stem cells, the researchers identified a protein called Piezo1 located on the surface of mesenchymal stem cells in the bone marrow. This protein acts as a mechanical sensor that detects the physical forces generated during movement and exercise.

When Piezo1 is activated by physical activity in mice, it reduces fat accumulation in the bone marrow and promotes new bone formation. When protein is missing, the opposite happens. Stem cells are more likely to become fat cells, which accelerates bone loss. Piezo1 deficiency also triggers the release of inflammatory signals (Ccl2 and lipocalin-2) that further push stem cells to produce fat and impair bone growth. Blocking these signals has been shown to help restore a healthier bone state.

Mimicking exercise for people who can’t move

“We basically decoded how the body converts movement into stronger bones,” said Professor Xu Aimin. “We have identified the molecular sensor of exercise, Piezo1, and the signaling pathways it controls. This gives us a clear target for intervention. By activating the Piezo1 pathway, we can mimic the benefits of exercise and effectively trick the body into thinking it is exercising, even when it is not moving.”

Dr Wang Baile, research assistant professor in the same department and co-leader of the study, emphasized the importance of the findings for vulnerable populations. “This discovery is particularly important for elderly individuals and patients who cannot exercise due to frailty, injury or chronic disease. Our findings open the door to the development of ‘exercise mimetics’ – drugs that chemically activate the Piezo1 pathway to help maintain bone mass and promote independence.”

Professor Eric Honoré, team leader at the Institute of Molecular and Cellular Pharmacology, French National Center for Scientific Research, and co-leader of the research, highlighted the wider potential impact. “This offers a promising strategy beyond traditional physical therapy. In the future, we could potentially provide the biological benefits of exercise through targeted treatment, thereby slowing bone loss in vulnerable groups such as bedridden patients or patients with limited mobility, and substantially reducing their risk of fracture.”

Moving towards a new treatment for osteoporosis

The research team is now focused on translating these findings into clinical applications. Their goal is to develop new therapies that preserve bone strength and improve the quality of life of aging and bedridden individuals.

The joint study was led by Professor Xu Aimin, Rosie TT Young Professor of Endocrinology and Metabolism, Chair and Director, and Dr. Wang Baile, Research Assistant, State Key Laboratory of Pharmaceutical Biotechnology, Institute of Medicine, HKUMed. The project also involved Professor Eric Honoré from the Institute of Molecular and Cellular Pharmacology, the French National Center for Scientific Research (CNRS), the Université Côte d’Azur (UniCA) and the French National Institute of Health and Medical Research (Inserm), who is also visiting professor at the Department of Pharmacology and Pharmacy, HKUMed.

This research was supported by the Areas of Excellence Scheme and the General Research Fund of the Research Grants Council; Health and Medical Research Fund under the Health Bureau, Government of the Hong Kong Special Administrative Region of the People’s Republic of China; China’s National Key Research and Development Program; National Natural Science Foundation of China; Human Frontier Science Program; French National Research Agency; Foundation de France; Foundation for Medical Research; and Macau Science and Technology Development Fund.