The alteration of advanced glycation end products and its potential role on bone loss under microgravity

Abstract

Bone loss occurs in astronauts during long-term space flight, and hardly recover to the normal level after back to the earth. This is because the mechanism of microgravity-induced osteoporosis is still unclear. Advanced glycation end products (AGEs) are formed between reducing sugars and long-lived proteins and are verified to be the pathogenic mechanism for diabetic and aging osteoporosis. These non-enzymatic glycation products are considered to have adverse effects on bone metabolism and bone quality which consist of bone microstructure and bone organic matrix. However, whether AGEs accumulation happened under microgravity is not clear yet. AGEs accumulation can be induced by hyperglycemia in diabetic patients and senior people. Hyperglycemia was also found to occur in astronauts during spaceflight or under simulated microgravity, however, whether it also can cause bone matrix AGEs accumulation remains unrevealed, and whether AGEs involve in the disuse osteoporosis is as well not clear yet. Therefore, in this study, we explored the AGEs changes and genesis, together with its potential relationship with disuse osteoporosis under simulated microgravity by using a rat tail-suspended model. Sixteen 8-week-old female Sprague-Dawley rats were randomly distributed into control (CON) and tail-suspension (TS) groups. After 21-days of an experiment, fluorescent total AGEs and pentosidine in bone matrix were separately detected by fluorescence microscope and High Performance Liquid Chromatography (HPLC); soluble AGEs and glucose-related biomarkers in serum were detected by ELISA; bone microstructure was evaluated by Micro-CT, and mRNA expression of bone metabolism biomarkers (OCN, ALP, RANKL/OPG) in bone was determined by QPCR. Results showed that after tail-suspension AGEs fluorescent intensity and PEN content increased in trabecular bone while no significant changes in cortical bone; serum glucose increased and was positively correlated with bone matrix AGEs; trabecular bone microstructure was deteriorated, ALP and OCN mRNA expression decreased while RANKL/OPG mRNA expression increased, and all of them showed correlations with bone matrix AGEs. The results suggested under simulated microgravity, bone matrix AGEs accumulation may be attributed to the elevated serum glucose, and preferred to occur in trabecular bone first. AGEs accumulation in bone matrix accompanied negative effects on trabecular bone microstructure and bone metabolism activities under simulated microgravity, suggesting AGEs accumulation may be a culprit in disused bone loss.