Bone morphogenetic protein-2 and -9 regulate the interaction of insulin-like growth factor-I with growth plate chondrocytes

Abstract

Insulin-like growth factor-I (IGF-I) is thought to play an important role in skeletal growth and development through its mitogenic and anabolic effects on epiphyseal growth plate chondrocytes. The bone morphogenetic proteins (BMPs) have been shown to promote endochondral osteogenesis, and some members of the BMP family, including BMP-2 and BMP-9, have anabolic effects on chondrocyte metabolism. We tested the hypothesis that BMP-2 and BMP-9 interact with IGF-I to modulate growth plate chondrocyte mitotic activity. IGF-I, but neither BMP-2 nor BMP-9, stimulated chondrocyte DNA synthesis. However, both BMP-2 and BMP-9 augmented the mitogenic action of IGF-I. BMP-2, but not BMP-9 increased IGF-I binding to growth plate chondrocytes in kinetic studies. In affinity labeling studies, 125I-IGF-I predominantly labeled an Mr ∼135-kDa moiety, consistent with the α subunit of the type 1 IGF receptor and an Mr ∼250-kDa moiety consistent with the type 2 IGF receptor. 125I-IGF-I labeling also appeared at Mr ∼43 kDa, consistent with 125I-IGF-I binding to insulin-like growth binding protein-3. Treatment of chondrocytes with BMP-2, but not with BMP-9, increased the intensity of the Mr ∼135-kDa band and decreased the intensity of the Mr ∼43-kDa band. Taken together, these data suggest that the BMPs may modulate the action of IGF-I via the type 1 IGF receptor and/or IGF binding proteins.