[54]

Ubiquitin ligase Cbl-b downregulates bone formation through suppression of IGF-1 signaling in osteoblasts during denervation.    C. Yamada,1 Y. Onishi,1 N. Suzue,2 K. Hirasaka,1 K. Kishi,1 T. Nikawa.1 1Department of Nutrition, The University of Tokushima School of Medicine, Tokushima, Japan; 2Department of Orthopedics, The University of Tokushima School of Medicine, Tokushima, Japan.

    Unloading occasionally prevents the bone formation by osteoblasts. Since Cbl-b functions as a ubiquitin ligase that negatively regulates tyrosine kinase signaling, we examined the role of Cbl-b in unloading-mediated osteopenia. We subjected Cbl-b-deficient (Cbl-b-/-) or wild-type mice to denervation (sciatic neurectomy) and examined the effects on bone formation in femur. We also examined the response of Cbl-b-overexpressing or -deficient osteoblastic cells to IGF-1. Denervation increased the amount of Cbl-b protein in osteoprogenitor cells of hindlimb bones. Denervation decreased bone formation in wild-type mice, whereas deficiency of Cbl-b gene cancelled the decline in bone formation. On a cellular level, primary osteoblastic cells from Cbl-b-/- mice were more sensitive to IGF-I treatment than those from wild-type mice. In Cbl-b-overexpressing osteoblastic UMR106 cells, IGF-1 treatment induced binding of Cbl-b to the IGF-1 signaling molecules, leading to loss of IRS-1 protein, as well as significantly inhibited proliferation. These results suggest that Cbl-b induces resistance of osteoblasts to IGF-I, at least in part, by suppressing IRS-1/PI3K/Akt pathway, resulting in decreased bone formation of osteoblastic cells in bone atrophic diseases.