Researchers have identified the molecular mechanism by which naringenin, a naturally occurring dietary flavonoid, protects against age-related bone loss, suggesting its potential as a natural candidate for treating senile osteoporosis.

Led by Prof. CHEN Chang at the Institute of Biophysics of the Chinese Academy of Sciences, the researchers demonstrated that naringenin counteracts bone loss by stimulating bone formation and restraining bone resorption. They also identified Runx2, a key transcription factor in osteogenic differentiation, as a direct molecular target of naringenin.

The study was published in the British Journal of Pharmacology on August 16.

NAR is a flavonoid derived from plants and commonly found in the diet. It is known for its anti-inflammatory, antioxidant, and metabolic regulatory activities. Previous studies have suggested that naringenin may benefit bone health, but its direct molecular targets and effects in age-related osteoporosis remained unclear.

Using a physiologically relevant natural aging mouse model, the researchers found that NAR treatment significantly increased bone mineral density, preserved trabecular microarchitecture, and strengthened the skeleton. Histomorphometric analyses further showed that NAR accelerated the mineral apposition rate and bone formation while reducing osteoclast activity and bone resorption.

Similarly, NAR stimulated osteogenic differentiation and mineral deposition in cultured cells. These findings demonstrate that NAR exerts a dual action on bone remodeling by simultaneously enhancing bone formation and limiting bone resorption.

To elucidate the underlying mechanism, the researchers combined RNA interference, NAR-biotin affinity pull-down and mass spectrometry with molecular docking and molecular dynamics simulations, surface plasmon resonance, drug affinity responsive target stability, and cellular thermal shift assays. The results showed that NAR interacts directly with Runx2 and promotes its osteogenic function.

These results reveal an unrecognized mechanism underlying NAR's skeletal effects and highlight this dietary flavonoid as a promising natural product for preventing and treating senile osteoporosis.

Schematic illustration of how naringenin alleviates senile osteoporosis by targeting Runx2 (Image by CHEN Chang's group)