Transforming growth factor-beta prevents osteoblast apoptosis induced by skeletal unloading via PI3K/Akt, Bcl-2, and phospho-Bad signaling
| Autor: | Xavier Holy, Pierre J. Marie, Cécilie Dufour |
|---|---|
| Rok vydání: | 2008 |
| Předmět: |
Male
medicine.medical_specialty Programmed cell death Physiology Endocrinology Diabetes and Metabolism Skeletal Unloading Apoptosis Biology Bone and Bones Phosphatidylinositol 3-Kinases Transforming Growth Factor beta2 Physiology (medical) Internal medicine medicine Animals Rats Wistar Muscle Skeletal Protein kinase B PI3K/AKT/mTOR pathway Osteoblasts Osteoblast Rats Up-Regulation medicine.anatomical_structure Endocrinology Hindlimb Suspension Proto-Oncogene Proteins c-bcl-2 bcl-Associated Death Protein Signal transduction Proto-Oncogene Proteins c-akt Transforming growth factor Signal Transduction |
| Zdroj: | American journal of physiology. Endocrinology and metabolism. 294(4) |
| ISSN: | 0193-1849 |
| Popis: | Loss of mechanical loading induces rapid bone loss resulting from reduced osteoblastogenesis and decreased bone formation. The signaling mechanisms involved in this deleterious effect on skeletal metabolism remain poorly understood. We have previously shown that hindlimb suspension in rats increases osteoblast apoptosis associated with decreased phosphatidylinositol 3-kinase (PI3K) signaling. In this study, we investigated whether transforming growth factor (TGF)-β2 may prevent the altered signaling and osteoblast apoptosis induced by skeletal unloading in vivo. Hindlimb suspension-induced decreased bone volume was associated with reduced α5β1-integrin protein levels and PI3K/Akt signaling in unloaded bone. Continuous administration of TGF-β2 using osmotic minipumps prevented the decreased α5β1-integrin expression and the reduced PI3K/Akt signaling in unloaded bone, resulting in the prevention of osteoblast apoptosis. We also show that TGF-β2 prevented the decreased Bcl-2 levels induced by unloading, which suggests that TGF-β2 targets Bcl-2 via PI3K/Akt to prevent osteoblast apoptosis in unloaded bone. Furthermore, we show that TGF-β2 prevented the decrease in phosphorylated Bad, the inactive form of the proapoptotic protein Bad, induced by unloading. These results identify a protective role for TGF-β2 in osteoblast apoptosis induced by mechanical unloading via the α5β1/PI3K/Akt signaling cascade and downstream Bcl-2 and phospho-Bad survival proteins. We thus propose a novel role for TGF-β2 in protection from unloading-induced apoptosis in vivo. |
| Databáze: | OpenAIRE |
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