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Insulin-Like Growth Factor-I Regulates Proliferation and Osteoblastic Differentiation of Calcifying Vascular Cells via Extracellular Signal-Regulated Protein Kinase And Phosphatidylinositol 3-Kinase Pathways

2005; Lippincott Williams & Wilkins; Volume: 96; Issue: 4 Linguagem: Inglês

10.1161/01.res.0000157671.47477.71

1524-4571

Kris E. Radcliff, Tri-Bang Tang, Jina Lim, Zina Zhang, Moeen Abedin, Linda L. Demer, Yin Tintut,

Bone health and treatments

Vascular calcification develops within atherosclerotic lesions and results from a process similar to osteogenesis. One of the paracrine regulators of bone-derived osteoblasts, insulin-like growth factor-I (IGF-I), is also present in atherosclerotic lesions. To evaluate its possible role in vascular calcification, we assessed its in vitro effects on proliferation and differentiation in calcifying vascular cells (CVCs), a subpopulation of bovine aortic medial cells. Results showed that IGF-I inhibited spontaneous CVC differentiation and mineralization as evidenced by decreased alkaline phosphatase (AP) activity and decreased matrix calcium incorporation, respectively. Furthermore, IGF-I inhibited the AP activity induced by bacterial lipopolysaccharide, TNF-α, or H 2 O 2 . It also induced CVC proliferation based on 3 H-thymidine incorporation. Results from Northern analysis and tests using IGF-I analogs suggest that IGF-I effects are mediated through the IGF-I receptor. IGF-I also activated both the extracellular signal-regulated protein kinase (ERK) and phosphatidylinositol 3-kinase (PI3K) pathways. Inhibition of either the ERK or PI3K pathway reversed IGF-I effects on CVC proliferation and AP activity, suggesting a common downstream target. Overexpression of ERK activator also mimicked IGF-I inhibition of lipopolysaccharide-induced AP activity. These results suggest that IGF-I promotes proliferation and inhibits osteoblastic differentiation and mineralization of vascular cells via both ERK and PI3K pathways.