Novel Peptides from Sea Cucumber Intestinal Enzyme Hydrolysates Promote Osteogenic Differentiation of Bone Mesenchymal Stem Cells via Phosphorylation of PPARγ at Serine 112.

SCOPE: Osteo-adipogenic differentiation imbalance of bone mesenchymal stem cells (BMSCs) has been linked to a variety of pathophysiological processes such as obesity and osteoporosis. Recent studies report that the phosphorylation of peroxisome proliferator-activated receptor gamma (PPARγ) Ser112 affects the fate decision of BMSCs. Novel peptides from the sea cucumber intestinal peptide (SCIP) have been proved to promote the growth of longitudinal bone. However, it is unclear the effect of SCIP on BMSCs differentiation fate. METHODS AND RESULTS: BMSCs in vitro and glucocorticoid induced mice are employed to investigate the effects of SCIP on osteo-adipogenic differentiation of BMSCs. In vitro results show that SCIP supplement significantly promotes the proliferation and osteogenic differentiation of BMSCs, upregulates the expression of osteogenic marker. In vivo results show that SCIP supplement ameliorates the osteo-adipogenic differentiation imbalance in glucocorticoid-treated mice, decreases bone marrow fat, and elevates bone mineral density. Mechanistically, SCIP supplement promotes and maintains the phosphorylation of PPARγ Ser112 through AMPK/ERK and TAZ signals, thereby inducing the osteogenic differentiation of BMSCs. CONCLUSION: Supplement with SCIP promotes BMSCs to differentiate into osteoblasts. These results suggest that SCIP has potential as a functional food to improve obesity and osteoporosis.

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.