July 2, 2024

Breakthrough in Osteoporosis Research: Identification of Key Gene and Development of Novel Mouse Model

Osteoporosis, characterized by the weakening of bones with age, affects millions globally, and its prevalence is rising as the population ages. This condition is linked to the aging, or 'senescence,' of bone cells, but the specific cell types and mechanisms involved were previously unclear. Now, a research team from Osaka University has identified a critical gene, Men1, related to osteoporosis and has developed a new animal model for this disease.

Bones contain osteoblasts and osteoclasts. Osteoclasts break down old bone tissue in a process called 'resorption,' allowing it to be replaced by new healthy bone formed by osteoblasts. Osteoporosis can occur when the breakdown of old bone outpaces the formation of new bone. Cellular senescence of osteoblasts, which reduces their efficiency, might be a contributing factor to this imbalance.

The gene Men1 is associated with a genetic condition known as MEN1, which causes benign tumors and is linked to both cellular senescence and the early development of osteoporosis. The research team investigated Men1's role in age-related osteoporosis and discovered that elderly mice exhibited both reduced Men1 levels and increased activity of senescence-related genes in osteoblasts.

The researchers then created a mouse model where Men1 could be specifically inactivated in osteoblasts. The bones of these mice resembled the fragile bones seen in elderly humans. "The 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, leading to greater bone resorption." Inactivation of Men1 thus disrupted the balance between bone breakdown and formation, resulting in osteoporosis.

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

"This model is the first time that the cellular senescence underlying osteoporosis has been modeled without the confounding factors present in elderly mice, marking a key step forward in understanding the biological mechanisms behind this disease," says corresponding author Takashi Kaito.

The research team also demonstrated that metformin, a drug known to suppress the mTORC1 cellular senescence pathway, could reduce senescence in osteoblast cells in vitro and partially restore bone structure in Men1-deficient mice. This indicates the potential effectiveness of osteoporosis treatments targeting cellular senescence.

This study significantly advances our understanding of osteoporosis and its potential treatments, as well as identifying biomarkers for evaluating the efficiency of prospective therapies. The newly developed mouse model provides a novel tool for ongoing research. Given that cellular senescence is linked to other age-related diseases and cancers, this work may also offer insights into many other conditions.