Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.

Osteoblasts undergo apoptosis both in vitro and in vivo in response to high dose glucocorticoid (GC) treatment. However, the molecular mechanisms remain elusive, hindering the prevention and treatment of this side-effect. Apoptosis was induced by dexamethasone (Dex) in murine MBA-15.4 osteoblasts within 24-48 h of treatment. We found dose- and time-dependent upregulation of Bim protein, a pro-apoptotic Bcl-2 family member, with highest levels at 24-48 h for 1 microM Dex. This was also observed in primary human bone marrow stromal cells. Bim is subjected to stringent transcriptional and post-translational regulation in osteoblasts. Bim mRNA was upregulated in response to 1 microM Dex; both cycloheximide and the GC receptor antagonist, RU486, prevented Dex-induction of Bim protein, indicating transcriptional regulation involving the GC receptor. The proteasome inhibitor, MG132, potently increased Bim protein levels. Bim was also upregulated in osteoblasts undergoing apoptosis in response to serum deprivation and matrix detachment. Gene silencing experiments show that short interference RNA (siRNA) specific for Bim or the downstream effector Bax both reduced apoptosis induced by Dex in osteoblastic cells. These findings suggest that Bim is a novel regulator of osteoblast apoptosis and may be a therapeutic target.

Type

Journal article

Journal

Journal of cellular physiology

Publication Date

05/2008

Volume

215

Pages

488 - 496

Addresses

The Botnar Research Centre, Oxford Institute of Musculoskeletal Sciences, Nuffield Department of Orthopaedic Surgery, Oxford, UK. mbespina@humv.es

Keywords

Bone Marrow Cells, Cells, Cultured, Extracellular Matrix, Osteoblasts, Stromal Cells, Humans, Cycloheximide, Mifepristone, Dexamethasone, Leupeptins, Membrane Proteins, Proto-Oncogene Proteins, Receptors, Glucocorticoid, RNA, Small Interfering, RNA, Messenger, Cysteine Proteinase Inhibitors, Glucocorticoids, Culture Media, Serum-Free, Apoptosis, Up-Regulation, Dose-Response Relationship, Drug, Time Factors, Apoptosis Regulatory Proteins, bcl-2-Associated X Protein