A new gene linked to osteoporosis identified

Osteoporosis, an age-related weakening of bones, affects millions of people worldwide, and the number increases each year as the world's population ages. It is associated with the aging, or “senescence,” of bone cells, but the cell types and underlying mechanisms have been unclear.

However, a research team from Osaka University has identified a key gene linked to osteoporosis, Men1, and developed a new animal model of the disease.

Bones contain cells called osteoblasts and osteoclasts. Osteoclasts break down old bone tissue in a process called resorption, allowing it to be replaced with new, healthy bone made by osteoblasts. Osteoporosis can occur when the breakdown of old bone occurs at a faster rate than new bone is formed. Cellular senescence of osteoblasts, which reduces their effectiveness, may be one underlying reason for this imbalance.

A gene called Men1 is linked to a genetic disease called MEN1, which causes benign tumors and is associated with both cellular senescence and the development of osteoporosis early in life. The team investigated the role of Men1 in age-related osteoporosis and found that aged mice had both reduced levels of Men1 and increased activity of senescence-related genes in osteoblasts.

They then generated a mouse model in which Men1 could be specifically inactivated in osteoblasts. The bones of these mice resembled the fragile bones seen in older humans.

“Osteoblasts showed reduced bone formation activity and accelerated cellular senescence through a pathway called mTORC1,” explains lead author Yuichiro Ukon, “while the number of osteoclasts increased, increasing bone resorption.” Inactivation of Men1 thus disrupted the balance between bone degradation and formation, leading to the development of osteoporosis.

This new mouse model is particularly important because most osteoporosis studies use aged mice to mimic human symptoms. However, natural aging involves multiple factors that influence the onset of osteoporosis, including reduced activity with age and hormonal changes related to menopause.

“This model is the first time that the cellular senescence underlying osteoporosis has been modeled without the confounding factors present in aged mice,” says corresponding author Takashi Kaito, “and therefore represents a key step in our understanding of the biological mechanisms underlying this disease.”

The team also showed that the use of a drug called metformin, known to suppress the mTORC1 cellular senescence pathway, was able to suppress this senescence in osteoblastic cells in vitro and partially restore bone structure in deficient mice. in Men1, indicating the potential effectiveness of osteoporosis treatments targeting cellular senescence.

This study is therefore very important to advance our understanding of osteoporosis and potential treatments, as well as to identify biomarkers of the disease to evaluate the effectiveness of prospective therapies.

The mice developed here also provide a new model of osteoporosis, essential for ongoing research. Since cellular senescence has been linked to other age-related diseases and cancers, this work could provide insights into many other diseases.

The article “Cellular senescence by loss of Men1 in osteoblasts is critical for age-related osteoporosis” was published in Cellular aging.