The authors have no conflict of interest.
Skeletal Unloading Induces Resistance to Insulin-Like Growth Factor-I (IGF-I) by Inhibiting Activation of the IGF-I Signaling Pathways†
Article first published online: 22 DEC 2003
Copyright © 2004 ASBMR
Journal of Bone and Mineral Research
Volume 19, Issue 3, pages 436–446, March 2004
How to Cite
Sakata, T., Wang, Y., Halloran, B. P., Elalieh, H. Z., Cao, J. and Bikle, D. D. (2004), Skeletal Unloading Induces Resistance to Insulin-Like Growth Factor-I (IGF-I) by Inhibiting Activation of the IGF-I Signaling Pathways. J Bone Miner Res, 19: 436–446. doi: 10.1359/JBMR.0301241
- Issue published online: 2 DEC 2009
- Article first published online: 22 DEC 2003
- Manuscript Accepted: 9 OCT 2003
- Manuscript Revised: 18 SEP 2003
- Manuscript Received: 14 JUN 2003
- skeletal unloading;
- insulin-like growth factor-I;
- αVβ3 integrin
We showed that unloading markedly diminished the effects of IGF-I to activate its signaling pathways, and the disintegrin echistatin showed a similar block in osteoprogenitor cells. Furthermore, unloading decreased αVβ3 integrin expression. These results show that skeletal unloading induces resistance to IGF-I by inhibiting activation of the IGF-I signaling pathways at least in part through downregulation of integrin signaling.
Introduction: We have previously reported that skeletal unloading induces resistance to insulin-like growth factor-I (IGF-I) with respect to bone formation. However, the underlying mechanism remains unclear. The aim of this study was to clarify how skeletal unloading induces resistance to the effects of IGF-I administration in vivo and in vitro with respect to bone formation.
Materials and Methods: We first determined the response of bone to IGF-I administration in vivo during skeletal unloading. We then evaluated the response of osteoprogenitor cells isolated from unloaded bones to IGF-I treatment in vitro with respect to activation of the IGF-I signaling pathways. Finally we examined the potential role of integrins in mediating the responsiveness of osteoprogenitor cells to IGF-I.
Results: IGF-I administration in vivo significantly increased proliferation of osteoblasts. Unloading markedly decreased proliferation and blocked the ability of IGF-I to increase proliferation. On a cellular level, IGF-I treatment in vitro stimulated the activation of its receptor, Ras, ERK1/2 (p44/42 MAPK), and Akt in cultured osteoprogenitor cells from normally loaded bones, but these effects were markedly diminished in cells from unloaded bones. These results were not caused by altered phosphatase activity or changes in receptor binding to IGF-I. Inhibition of the Ras/MAPK pathway was more impacted by unloading than that of Akt. The disintegrin echistatin (an antagonist of the αVβ3 integrin) blocked the ability of IGF-I to stimulate its receptor phosphorylation and osteoblast proliferation, similar to that seen in cells from unloaded bone. Furthermore, unloading significantly decreased the mRNA levels both of αV and β3 integrin subunits in osteoprogenitor cells.
Conclusion: These results indicate that skeletal unloading induces resistance to IGF-I by inhibiting the activation of IGF-I signaling pathways, at least in part, through downregulation of integrin signaling, resulting in decreased proliferation of osteoblasts and their precursors.