title: Ablation of the pro-apoptotic protein Bax protects mice from glucocorticoid-induced bone growth impairment.
abstract: Dexamethasone (Dexa) is a widely used glucocorticoid to treat inflammatory diseases; however, a multitude of undesired effects have been reported to arise from this treatment including osteoporosis, obesity, and in children decreased longitudinal bone growth. We and others have previously shown that glucocorticoids induce apoptosis in growth plate chondrocytes. Here, we hypothesized that Bax, a pro-apoptotic member of the Bcl-2 family, plays a key role in Dexa-induced chondrocyte apoptosis and bone growth impairment. Indeed, experiments in the human HCS-2/8 chondrocytic cell line demonstrated that silencing of Bax expression using small-interfering (si) RNA efficiently blocked Dexa-induced apoptosis. Furthermore, ablation of Bax in female mice protected against Dexa-induced bone growth impairment. Finally, Bax activation by Dexa was confirmed in human growth plate cartilage specimens cultured ex vivo. Our findings could therefore open the door for new therapeutic approaches to prevent glucocorticoid-induced bone growth impairment through specific targeting of Bax.
authors.affiliation: Pediatric Endocrinology Unit, Department of Women's and Children's Health, Astrid Lindgren Children's Hospital, Karolinska Institutet, Stockholm, Sweden. 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: Bengt
authors.initials: B
authors.lastname: Fadeel
authors.forename: Lars
authors.initials: L
authors.lastname: Sävendahl
mesh_terms: D000293:Adolescent; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D019902:Chondrocytes / Q000378:metabolism* / Q000473:pathology; D003907:Dexamethasone / Q000009:adverse effects / Q000494:pharmacology; D005260:Female; D005938:Glucocorticoids / Q000009:adverse effects / Q000494:pharmacology; D006132:Growth Plate / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009765:Obesity / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D010024:Osteoporosis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: C494826:BAX protein, human; C494827:Bax protein, mouse; D005938:Glucocorticoids; D051028:bcl-2-Associated X Protein; D003907:Dexamethasone