Researchers identify key gene linked to osteoporosis and develop new mouse model of disease

Osteoporosis – the weakening of the bones with age – affects millions of people worldwide and this figure is increasing every year as the global population ages. It is linked to senescence, or ‘senescence’, of bone cells, but the underlying cell types and mechanisms were unclear. Now, however, a research team from Osaka University has identified a key gene linked to osteoporosis, Men 1and developed a new animal model of this 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 result when the breakdown of old bone occurs at a faster rate than the formation of new bone. Cellular senescence of osteoblasts, reducing their efficiency, may be a reason for this imbalance.

A gene called Men 1 it is linked to a genetic condition known as MEN1, which causes benign tumors and is associated with cellular aging and the development of osteoporosis early in life. The team investigated the role of Men 1 in age-related osteoporosis and found that aged mice exhibited both reduced levels of Men 1 and increased activity of senescence-related genes in osteoblasts.

They then created a mouse model where Men 1 can be specifically inactivated in osteoblasts. The bones of these mice resembled the brittle bones seen in older humans. “Osteblasts showed reduced bone-forming activity and accelerated cellular aging through a pathway called mTORC1,” explains lead author Yuichiro Ukon, “while the number of osteoclasts increased, increasing bone resorption.” Inactivation of Men 1 thereby disrupting the balance between bone breakdown and formation, leading to the development of osteoporosis.

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

This model is the first time that cellular senescence underlying osteoporosis has been modeled without the confounding factors present in aged mice and is therefore a key step forward in our understanding of the biological mechanisms underlying this disease.”

Takashi Kaito, corresponding author

The team also showed that using a drug called metformin, known to suppress the cellular aging pathway mTORC1, was able to suppress this aging in osteoblast cells. in vitroand to partially restore the bone structure in Men 1-deficient mice, demonstrating the potential effectiveness of osteoporosis treatments targeting cellular senescence.

Therefore, this study is very significant in advancing our understanding of osteoporosis and potential treatments, as well as identifying disease biomarkers for evaluating the efficacy of future therapies. The mice developed here also provide a new model of osteoporosis that is key to ongoing research. Because cellular senescence has been linked to other age-related diseases and cancers, this work could provide insights into many other diseases.