Novel peptides from sea cucumber intestinal hydrolysates promote longitudinal bone growth in adolescent mice through accelerating cell cycle progress by regulating glutamine metabolism

Sea cucumber intestines are recognized as a major by-product in the sea cucumber processing industry and have been shown to exhibit bioactive properties. However, whether the sea cucumber intestine is beneficial for osteogenesis remains unknown. In this study, low molecular weight peptides rich in glutamate/glutamine were obtained from sea cucumber intestines (SCIP) by enzymatic hydrolysis, and orally administered to adolescent mice to investigate the effects on longitudinal bone growth. The results showed that the SCIP supplement significantly increased the femur length and new bone formation rate by 9.6% and 56.3%, and elevated the levels of serum osteogenic markers alkaline phosphatase (ALP), Collagen I and osteocalcin (OCN). Notably, H&E staining showed that SCIP significantly increased the height of the growth plate, in which the height of the proliferation zone was elevated by 95.6%. Glutamine is a major determinant of bone growth. SCIP supplement significantly increased glutamine levels in the growth plate by 44.2% and upregulated the expression of glutamine metabolism-related enzymes glutaminase 1 (Gls1) and glutamate dehydrogenase 1 (GLUD1) in the growth plate. Furthermore, SCIP supplement upregulated growth plate acetyl coenzyme A levels to promote histone acetylation and accelerated cell cycle progression by upregulating Sox9 expression, thereby contributing to rapid chondrocyte proliferation. To the best of our knowledge, this is the first report where SCIP could enhance longitudinal bone growth via promoting growth plate chondrocyte proliferation. The present study will provide new ideas and a theoretical basis for the high-value utilization of sea cucumber intestines.