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Ablation of the pro-apoptotic protein Bax protects mice from glucocorticoid-induced bone growth impairment
Farasat Zaman1, Dionisios Chrysis, Kirsten Huntjens
1Pediatric Endocrinology Unit, Department of Women's and Children's Health, Astrid Lindgren Children's Hospital, Karolinska Institutet, Stockholm, Sweden. Farasat.Zaman@ki.se
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.
Insights
Dexamethasone treatment causes bone growth impairment by inducing chondrocyte apoptosis. Targeting Bax, a key protein in this process, may prevent these harmful effects.
Area of Science:
- Biochemistry
- Cell Biology
- Pediatric Endocrinology
Background:
- Glucocorticoids like dexamethasone (Dexa) are vital for treating inflammatory conditions.
- However, Dexa treatment can lead to adverse effects, including osteoporosis, obesity, and impaired longitudinal bone growth in children.
- Glucocorticoids are known to induce apoptosis (programmed cell death) in growth plate chondrocytes.
Purpose of the Study:
- To investigate the role of Bax, a pro-apoptotic protein, in dexamethasone-induced chondrocyte apoptosis and bone growth impairment.
- To determine if targeting Bax can prevent these adverse effects.
Main Methods:
- Experiments were conducted using the human HCS-2/8 chondrocytic cell line.
- Small-interfering (si) RNA was used to silence Bax expression.
- Studies involved female mice with Bax ablation.
- Human growth plate cartilage specimens were cultured ex vivo.
Main Results:
- Silencing Bax expression using siRNA effectively blocked dexamethasone-induced apoptosis in chondrocytic cells.
- Ablation of Bax in female mice conferred protection against dexamethasone-induced bone growth impairment.
- Dexamethasone was confirmed to activate Bax in human growth plate cartilage ex vivo.
Conclusions:
- Bax plays a critical role in dexamethasone-induced chondrocyte apoptosis and subsequent bone growth impairment.
- Targeting Bax presents a potential therapeutic strategy to prevent glucocorticoid-induced bone growth deficits.
