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Glucocorticoids (GCs) are frequently used to treat chronic disorders in children, including inflammation and cancer. Prolonged treatment with GCs is well known to impair bone growth, an effect linked to increased apoptosis and suppressed proliferation in growth plate chondrocytes. We hypothesized that the endogenous antiapoptotic protein humanin (HN) may prevent these effects. Interestingly, GC-induced bone growth impairment and chondrocyte apoptosis was prevented in HN overexpressing mice, HN-treated wild-type mice, and in HN-treated cultured rat metatarsal bones. GC-induced suppression of chondrocyte proliferation was also prevented by HN. Furthermore, GC treatment reduced Indian Hedgehog expression in growth plates of wild-type mice but not in HN overexpressing mice or HN-treated wild-type animals. A Hedgehog (Hh) antagonist, vismodegib, was found to suppress the growth of cultured rat metatarsal bones, and this effect was also prevented by HN. Importantly, HN did not interfere with the desired anti-inflammatory effects of GCs. We conclude that HN is a novel regulator of Hh signaling preventing GC-induced bone growth impairment without interfering with desired effects of GCs. Our data may open for clinical studies exploring a new possible strategy to prevent GC-induced bone growth impairment by cotreating with HN.-Zaman, F., Zhao, Y., Celvin, B., Mehta, H. H., Wan, J., Chrysis, D., Ohlsson, C., Fadeel, B., Cohen, P., Savendahl, L. Humanin is a novel regulator of Hedgehog signaling and prevents glucocorticoid-induced bone growth impairment.

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.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.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.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.