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Abstract
Insulin-like growth factor-I (IGF-I) is an important regulator of endochondral ossification. However, little is known about the signaling pathways activated by IGF-I in growth plate chondrocytes. We have previously shown that NF-kappaB-p65 facilitates growth plate chondrogenesis. In this study, we first cultured rat metatarsal bones with IGF-I and/or pyrrolidine dithiocarbamate (PDTC), a known NF-kappaB inhibitor. The IGF-I-mediated stimulation of metatarsal growth and growth plate chondrogenesis was neutralized by PDTC. In rat growth plate chondrocytes, IGF-I induced NF-kappaB-p65 nuclear translocation. The inhibition of NF-kappaB-p65 expression and activity (by p65 short interfering RNA and PDTC, respectively) in chondrocytes reversed the IGF-I-mediated induction of cell proliferation and differentiation and the IGF-I-mediated prevention of cell apoptosis. Moreover, the inhibition of the phosphatidylinositol 3-kinase and Akt abolished the effects of IGF-I on NF-kappaB activation. In conclusion, our findings indicate that IGF-I stimulates growth plate chondrogenesis by activating NF-kappaB-p65 in chondrocytes.
Highlights
The fact that Insulin-like growth factor-I (IGF-I) null mice have a reduced growth plate height clearly suggests a facilitatory role for IGF-I on growth plate chondrogenesis and, in turn, on longitudinal bone growth
Because the rate of longitudinal bone growth depends primarily on the rate of growth plate chondrogenesis, we evaluated the effects of IGF-I on chondrocyte proliferation and chondrocyte hypertrophy/differentiation
To confirm the findings observed in the whole metatarsal bones, we evaluated the effects of IGF-I on transfected growth plate chondrocyte proliferation, differentiation, and apoptosis
Summary
The fact that IGF-I null mice have a reduced growth plate height clearly suggests a facilitatory role for IGF-I on growth plate chondrogenesis and, in turn, on longitudinal bone growth. Upon activation by a wide variety of stimuli (proinflammatory cytokines, growth factors, and viral proteins), NF-B translocates to the nucleus, where it modulates the expression of target genes involved in cell growth, survival, adhesion, and death (6, 7). These target genes include anti-apoptotic (8) as well as pro-apoptotic ones (9), suggesting that the effects of NF-B on cell growth and survival may depend on the cell type and on the nature of the extracellular stimuli. We evaluated the effects of the selective inhibition of the IGF-I receptor-activated intracellular signaling pathways on the IGF-I-mediated induction of NF-B activity
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