Life sciences (1973), 2009-11, Vol.85 (19-20), p.685
2009
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- Autor(en) / Beteiligte
- Titel
- Inhibition of glycogen synthase kinase-3beta attenuates glucocorticoid-induced bone loss
- Ist Teil von
- Life sciences (1973), 2009-11, Vol.85 (19-20), p.685
- Ort / Verlag
- Netherlands
- Erscheinungsjahr
- 2009
- Quelle
- Access via ScienceDirect (Elsevier)
- Beschreibungen/Notizen
- Long-term glucocorticoid administration is known to induce bone deterioration. Glycogen synthase kinase-3beta (GSK-3beta) signaling reportedly participates in bone remodeling. This study investigated whether GSK-3beta inhibitor could regulate glucocorticoid-induced inhibition of osteoblast differentiation in vitro or bone mass in vivo. MC3T3-E1 osteoblasts were treated with kinase-inactive GSK-3beta mutant and 6-bromoindirubin-3'-oxim (BIO) and then exposed to 1microM dexamethasone. Survival and osteoblast differentiation of cell cultures were assessed by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end-labeling, quantitative RT-PCR, and von Kossa staining. Mineral density, biomechanical properties and microenvironments of BIO- and glucocorticoid-treated rat bone tissues were analyzed using dual-energy X-ray absorptiometry, material testing, and histomorphometry, respectively. Glucocorticoid decreased levels of phosphorylated Ser9-GSK-3beta and beta-catenin in osteoblast cultures. Kinase-inactive GSK-3beta mutant and BIO treatments attenuated dexamethasone-induced inhibition of beta-catenin, Runx2 abundance, and osteoblast differentiation but suppressed glucocorticoid-induced apoptosis of cell cultures. Exogenous BIO treatment alleviated methylprednisolone-induced impairment of mineral density, biomechanical strength, trabecular bone volume, osteoblast surface, and bone formation rate of rat bone tissue. BIO treatment also attenuated glucocorticoid-induced promotion of osteoclast surface and marrow adipocyte volume in bone tissue. Bone cells adjacent to glucocorticoid-stressed bone tissue displayed strong phosphorylated Ser9-GSK-3beta and beta-catenin immunostaining following BIO treatment. Inhibition of GSK-3beta abrogated glucocorticoid-induced bone loss by increasing beta-catenin- and Runx2-mediated osteoblast differentiation. Controlling GSK-3beta signaling in bone cells may be a strategy for preventing glucocorticoid-induced osteopenia.
- Sprache
- Englisch
- Identifikatoren
- eISSN: 1879-0631DOI: 10.1016/j.lfs.2009.09.009Titel-ID: cdi_pubmed_primary_19782693
- Format
- –
- Schlagworte
- 3T3 Cells, Alkaline Phosphatase - metabolism, Animals, Apoptosis - genetics, Apoptosis - physiology, beta Catenin - metabolism, Biomechanical Phenomena, Blotting, Western, Bone and Bones - anatomy & histology, Bone and Bones - drug effects, Bone Density - drug effects, Bone Matrix - drug effects, Bone Remodeling - drug effects, Calcification, Physiologic - drug effects, Cell Differentiation - drug effects, Enzyme Inhibitors - pharmacology, Glucocorticoids - antagonists & inhibitors, Glucocorticoids - toxicity, Glycogen Synthase Kinase 3 - antagonists & inhibitors, Glycogen Synthase Kinase 3 - genetics, Immunohistochemistry, Indoles - pharmacology, Methylprednisolone - antagonists & inhibitors, Methylprednisolone - toxicity, Mice, Osteoblasts - drug effects, Oximes - pharmacology, Rats, Reverse Transcriptase Polymerase Chain Reaction, Transfection