The Heparin-binding Domain of IGFBP-2 Has Insulin-like Growth Factor Binding-independent Biologic Activity in the Growing Skeleton
| Autor: | Wesley G. Beamer, Clifford J. Rosen, Ernesto Canalis, Xinchun Shen, Victoria E. DeMambro, David R. Clemmons, Mary L. Bouxsein, Masanobu Kawai, Anne Breggia |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
Male
medicine.medical_specialty Stromal cell Bone Marrow Cells Mice Transgenic Biology Models Biological Biochemistry Bone resorption Mice Internal medicine medicine Animals Insulin-like growth factor binding Phosphorylation Molecular Biology Protein kinase B beta Catenin Heparin PTEN Phosphohydrolase Osteoblast 3T3 Cells Cell Biology Mice Inbred C57BL Wnt Proteins Insulin-Like Growth Factor Binding Protein 2 Endocrinology medicine.anatomical_structure Adipogenesis Female Bone marrow Proto-Oncogene Proteins c-akt Protein Binding |
| Zdroj: | Journal of Biological Chemistry. 286:14670-14680 |
| ISSN: | 0021-9258 |
| Popis: | Insulin-like growth factor-binding protein 2 (IGFBP-2) is a member of a family of six highly conserved IGFBPs that are carriers for the insulin-like growth factors (IGFs). IGFBP-2 levels rise during rapid neonatal growth and at the time of peak bone acquisition. In contrast, Igfbp2(-/-) mice have low bone mass accompanied by reduced osteoblast numbers, low bone formation rates, and increased PTEN expression. In the current study, we postulated that IGFBP-2 increased bone mass partly through the activity of its heparin-binding domain (HBD). We synthesized a HBD peptide specific for IGFBP-2 and demonstrated in vitro that it rescued the mineralization phenotype of Igfbp2(-/-) bone marrow stromal cells and calvarial osteoblasts. Consistent with its cellular actions, the HBD peptide ex vivo stimulated metacarpal periosteal expansion. Furthermore, administration of HBD peptide to Igfbp2(-/-) mice increased osteoblast number, suppressed marrow adipogenesis, restored trabecular bone mass, and reduced bone resorption. Skeletal rescue in the Igfbp2(-/-) mice was characterized by reduced PTEN expression followed by enhanced Akt phosphorylation in response to IGF-I and increased β-catenin signaling through two mechanisms: 1) stimulation of its cytosolic accumulation and 2) increased phosphorylation of serine 552. We conclude that the HBD peptide of IGFBP-2 has anabolic activity by activating IGF-I/Akt and β-catenin signaling pathways. These data support a growing body of evidence that IGFBP-2 is not just a transport protein but rather that it functions coordinately with IGF-I to stimulate growth and skeletal acquisition. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|