Zinc (Zn) has been reported to mediate leptin secretion, and thus leptin can be an important candidate molecule linking Zn with bone formation. The present study investigated whether zinc deficiency induces leptin secretion by activating a JAK2/STAT3 signaling pathway and leads to osteoblastic apoptosis. MC3T3-E1 cells were incubated for 24 h in normal osteogenic differentiation medium (OSM) or OSM treated with either 1 μM (Low Zn) or 15 μM (High Zn) of ZnCl2 containing 5 μM TPEN (Zn chelator). Our results demonstrated that low Zn stimulated extracellular leptin secretion and increased mRNA and protein expression of leptin in osteoblastic MC3T3-E1 cells. The OB-Rb (long isoform of leptin receptor) expressions were also elevated in osteoblasts under depletion of Zn. Leptin-signaling proteins, JAK2 and p-JAK2 in the cytosol of low Zn osteoblast conveyed leptin signaling, which ultimately induced higher p-STAT3 expression in the nucleus. Apoptotic effects of JAK2/STAT3 pathway were shown by increased caspase-3 in low Zn osteoblasts as well as apoptotic morphological features observed by TEM. Together, these data suggest that low Zn modulates leptin secretion by activating JAK2/STAT3 signaling pathway and induces apoptosis of osteoblastic MC3T3-E1 cells.

Osteoporosis, which is caused by the structural weakness of bone tissue, is a systemic skeletal disease that decreases bone mass and increases the risk of fractures. For the aging population, osteoporosis is a major cause of morbidity and health expenditure. The objective of the present study was to investigate the potential anti-osteoporotic properties of cow milk-derived extracellular vesicles (EVs) on the differentiation and mineralization in osteoblastic MC3T3-E1 cells. MC3T3-E1 cells were cultured in 0, 1, 5, and 10 μg/mL cow milk-derived EVs for 3 and 7 days. It was observed that the average diameter of EVs from cow milk isolated by ultracentrifugation was 156±2.5 nm, and the presence of EV-associated marker protein CD63 and whey protein-specific marker lactoferrin was confirmed by immunoblot analysis. Our results determined that cow milk-derived EVs were increased osteoblastic cell proliferation and extracellular alkaline phosphatase (ALP) activity. Markedly, cow milk-derived EVs were significantly elevated the mineralized nodules in a does dependent manner for 3 and 7 days. Taken together, our results clearly demonstrated that cow milk-derived EVs may be useful in preventing osteoporosis by stimulating osteoblastic differentiation and mineralization.

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