Leptin signaling through the JAK2‐STAT3 pathway under Zn deficiency in osteoblastic MC3T3‐E1 cells

In vitro studies have suggested a positive effect of Zn on proliferation/differentiation on osteoblasts, while leptin has been reported to be a key regulator of bone formation. We investigated whether Zn deficiency modulates leptin signaling through the JAK2‐STAT3 pathway in osteoblastic MC3T3‐E1 cells. Cells were cultured in control (normal osteogenic differentiation medium), Zn‐deficiency (1μM Zn) and Zn‐adequacy (15μM Zn) for 24h with the addition of 5μM TPEN as intracellular Zn chelator. Zn‐deficiency increased leptin gene/protein expression and extracellular leptin secretion. Leptin‐receptor (OB‐Rb) gene/protein expressions for intracellular leptin signaling were also increased in Zn‐deficiency, perhaps due to the increased leptin secretion. Protein expression of cytosolic signaling molecules (JAK2, pJAK2, STAT3 and pSTAT3) were increased and conveyed the leptin signal by increasing pSTAT3 protein levels in the nucleus in Zn‐deficiency. The study results suggest that Zn‐deficiency increases leptin expression and secretion outside the osteoblasts, and that this increased leptin secretion may increase OB‐Rb gene/protein expression, which may activate the leptin‐JAK2/STAT3 pathway in osteoblasts. Further study is required to elucidate whether the increased leptin signal in Zn‐deficiency would cause cell apoptosis in osteoblasts. (Supported by KRF, R05‐2004‐000‐11036‐0 & KOSEF, R01‐2006‐000‐10640‐0)