Background: Glucocorticoids (GCs) are widely used for treatment of inflammatory and autoimmune conditions. Prolonged use of GCs, however, has several negative side effects, including bone growth impairment in children. Previous studies have shown that GC-induced apoptosis in growth plate chondrocytes is mediated by inhibition of the PI3KAkt signaling pathway and activation of the pro-apoptotic protein Bax. Humanin, a small mitochondrial derived peptide, has shown promising effects in rescuing chemotherapy-induced apoptosis in growth plate chondrocytes by suppressing Bax. Here we have extended our findings in combination with GCs in a disease specific mouse model of arthritis.
Aim and objective: The aim of this study was to investigate if the synthetic analog to humanin, [Gly14]-HNG (HNG), prevents apoptosis of growth plate chondrocytes without interfering with the anti-inflammatory effect of dexamethasone (Dexa) in an in vivo model of collagen type II-induced arthritis (CIA).
Methods: CIA was induced in DBA/1 mice and the animals were treated with Dexa (0.25 mg/kg per day) with/without HNG (100 μg/kg per day) for 14 days. The animals were observed daily for the presence of arthritis including signs of erythema and swelling of the joints and the paws were scored based on the severity of the swelling. Sections of femur growth plate were also analyzed for cell death using TUNEL assay.
Results: Based on the clinical scoring we observed that humanin in combination with Dexa does not interfere with the desired anti-inflammatory effect of Dexa in the CIA model. Most importantly, we found that humanin protects chondrocytes from GC-induced cell death in femur growth plates of these mice.
Conclusion: Our results suggest that the combination of humanin and GCs may provide a new treatment strategy for preventing bone growth impairment in children.
01 Oct 2015 - 03 Oct 2015