The mechanism of anti-osteoporosis effects of 3-hydroxybutyrate and derivatives under simulated microgravity

Skeletons have significant bone loss (osteoporosis) under microgravity environment. This study showed that microbial polyhydroxyalkanoates (PHA) degradation product, and also ketone body 3-hydroxybutyrate acid (3HB) and its derivative 3-hydroxybutyrate methyl ester (3HBME) inhibit the development of osteoporosis in mice maintained under simulated microgravity, helping preserve bone microstructure and mechanical property. Mice orally administrated with 3HB or 3HBME recovered much more quickly from osteoporosis resulted from simulated microgravity compared with the controls without 3HB or 3HBME treatments due to less calcium loss to the sera. It was known that abnormal activation of osteoclasts induced by microgravity led to bone tissue absorption and thus osteoporosis. In this study, it was found that 3HB or 3HBME down-regulated the nuclear factor of activated T-cells cytoplasmic 1 (NFATc1), which is the transcription factor of pre-osteoclast differentiation. When NFATc1 activation and downstream functions were inhibited, 3HB or 3HBME was able to strongly reduce pre-osteoclast differentiation. As a result, bone absorption was prevented. It was demonstrated that 100 mg/kg 3HB resulted in the most obvious effect on osteoporosis prevention. Based on these results, 3HB and 3HBME should be further developed as novel drug candidates against osteoporosis induced by microgravity.