Loss of MEN1 Expression in Osteoblasts Plays a Role in Osteoporosis

Bone tissue is constantly remodeled, created by osteoblasts and broken down by osteoclasts. Osteoporosis, a progressive age-related loss of bone density that leads to fracture and incapacity, occurs due to an imbalance between these cell populations that favors osteoclasts over osteoblasts. Researchers here note that Men1 expression declines with age in osteoblasts, and may be an important proximate cause of osteoporosis via mechanisms that include increased cellular senescence in bone tissue. Finding ways to increase Men1 expression in bone-related cell populations may prove to be a useful point of intervention.

Recent evidence suggests an association between age-related osteoporosis and cellular senescence in the bone; however, the specific bone cells that play a critical role in age-related osteoporosis and the mechanism remain unknown. Results revealed that age-related osteoporosis is characterized by the loss of osteoblast Men1. Osteoblast-specific inducible knockout of Men1 caused structural changes in the mice bones, matching the phenotypes in patients with age-related osteoporosis.

Histomorphometrically, Men1-knockout mice femurs decreased osteoblastic activity and increased osteoclastic activity, hallmarks of age-related osteoporosis. Loss of Men1 induces cellular senescence via mTORC1 activation and AMPK suppression, rescued by metformin treatment. In bone morphogenetic protein-indued bone model, loss of Men1 leads to accumulation of senescent cells and osteoporotic bone formation, which are ameliorated by metformin. Our results indicate that cellular senescence in osteoblasts plays a critical role in age-related osteoporosis and that osteoblast-specific inducible Men1-knockout mice offer a promising model for developing therapeutics for age-related osteoporosis.

Link: https://doi.org/10.1111/acel.14254