title: Dexamethasone differentially regulates Bcl-2 family proteins in human proliferative chondrocytes: role of pro-apoptotic Bid.
abstract: Glucocorticoids (GCs) are widely used to treat inflammatory diseases and cancers. A multitude of undesired side effects have been reported in GC-treated patients including decreased linear bone growth. We have previously reported that GCs activate the caspase cascade and trigger Bax-mediated mitochondrial apoptosis in growth plate chondrocytes causing growth retardation in young mice. To further explore the role of mitochondrial apoptosis in GC-induced bone growth retardation, a number of pro- and anti-apoptotic proteins were studied in ex vivo cultures of human growth plate cartilage and human HCS-2/8 proliferative chondrocytes exposed to dexamethasone. Dexamethasone was found to increase the pro-apoptotic proteins Bcl-xS, Bad, and Bak as well as the proteolysis of Bid. Anti-Bid small interfering RNA partially rescued the chondrocytes from dexamethasone-induced apoptosis. Taken together, our data suggest that GC treatment differentially regulates Bcl-2 family member proteins to facilitate mitochondrial apoptosis in proliferative chondrocytes thereby contributing to GC-induced bone growth impairment. Prevention of this imbalance between pro- and anti-apoptotic Bcl-2 family proteins may provide a new strategy to protect from adverse effects of GCs on bone growth.
authors.affiliation: Department of Women's and Children's Health, Pediatric Endocrinology Unit, Astrid Lindgren Children's Hospital, Karolinska Institutet, Stockholm 171 76, Sweden. Electronic address: Farasat.Zaman@ki.se.
authors.forename: Farasat
authors.initials: F
authors.lastname: Zaman
authors.forename: Dionisios
authors.initials: D
authors.lastname: Chrysis
authors.forename: Kirsten
authors.initials: K
authors.lastname: Huntjens
authors.forename: Andrei
authors.initials: A
authors.lastname: Chagin
authors.forename: Masaharu
authors.initials: M
authors.lastname: Takigawa
authors.forename: Bengt
authors.initials: B
authors.lastname: Fadeel
authors.forename: Lars
authors.initials: L
authors.lastname: Sävendahl
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D051023:BH3 Interacting Domain Death Agonist Protein / Q000502:physiology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D019902:Chondrocytes / Q000737:chemistry / Q000166:cytology / Q000187:drug effects*; D003907:Dexamethasone / Q000494:pharmacology*; D006801:Humans; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis*; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000032:analysis; D051025:bcl-Associated Death Protein / Q000032:analysis; D051020:bcl-X Protein / Q000032:analysis
chemical_list: C494819:BAD protein, human; C494772:BAK1 protein, human; C494811:BCL2L1 protein, human; D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051025:bcl-Associated Death Protein; D051020:bcl-X Protein; D003907:Dexamethasone
keywords: Apoptosis; Bcl-2 family proteins; Bid; Chondrocytes; Cont; Dexa; Dexamethasone; GCs; Human growth plate; control; dexamethasone; glucocorticoids