Humanin prevents undesired apoptosis of chondrocytes without interfering with the anti-inflammatory effect of dexamethasone in collagen-induced arthritis.

ABSTRACT

OBJECTIVES: Prolonged use of glucocorticoids (GCs) for treatment of inflammatory and autoimmune conditions may have several negative side effects, such as impaired bone growth which has been linked to increased apoptosis in growth plate chondrocytes. It has recently been shown that humanin, a small mitochondrial derived peptide, rescues growth plate chondrocytes from GC-induced apoptosis. Our aim was to study if a synthetic analogue of humanin, [Gly14]-HNG (HNG), can be safely used to prevent GC-induced toxicity in growth plate chondrocytes without interfering with the desired anti-inflammatory effect in an in vivo model of arthritis. METHODS: Arthritis was induced in DBA/1 mice by collagen type II in complete Freund's adjuvant and the animals were treated with Dexamethasone (Dexa) (0.25 mg/kg/day) with or without HNG (100 µg/kg/day) for 14 days. The animals were observed daily for the presence of arthritis including signs of erythema and swelling of the joints. The paws were scored based on the severity of the swelling. After termination, histological scoring was performed of all paws. Chondrocyte apoptosis and proliferation were analysed by TUNEL assay and PCNA staining, respectively. RESULTS: We found that HNG treatment in combination with Dexa protected from Dexa-induced chondrocyte apoptosis in both articular and growth plate cartilage. Furthermore, based on clinical and histology scoring analyses, HNG did not interfere with the desired anti-inflammatory effect of Dexa. CONCLUSIONS: Our results suggest that the combination of HNG and GCs may provide a new treatment strategy in conditions of chronic inflammation, which could potentially prevent bone growth impairment.