ESPE Yearbook of Paediatric Endocrinology

Abstract: FASEB J. 2019;33:4962–4974.

In brief: Glucocorticoid-induced growth impairment is reverted by the mitochondrial peptide humanin in dexamethasone-treated mice without attenuation of anti-inflammatory effects.

Comment: Humanin (HN) is a 24 aminoacid peptide that was originally discovered as a neuroprotective factor and later shown to have multiple modes of action including anti-inflammatory and anti-apoptotic effects (1). Glucocorticoid (GC)-induced bone disease is one of the most prevalent causes for growth cessation and secondary osteoporosis in children worldwide (2). Treatment options are limited as systemic GH treatment lacks efficacy (3) and there is no therapeutic option that specifically targets GC-induced growth impairment. The authors previously identified the proapoptotic protein Bax as an important mediator of GC-induced growth plate alterations and the neuroprotective factor humanin as a specific Bax-inhibitor (4).

Using both humanin-overexpressing mice and humanin analogue treatments, the authors show complete rescue of Dexamethasone-induced linear growth impairment in vivo, in vitro and ex vivo. On a molecular level, the reduced expression of Indian hedgehog (Ihh) was identified as a critical regulator of growth plate chondrocyte proliferation. The authors showed restoration of Ihh expression by cotreatment with humanin and further confirmed a rescue of GC-induced apoptosis rates in human growth plate chondrocytes. Importantly, anti-inflammatory effects of GC seemed to be unaffected in the murine model – an essential criterion for the humanin-pathway as a target for therapeutic applicability.

Humanin has been demonstrated to exert cyto-protective effects in several murine disease models. If the effect on GC-induced growth retardation without loss of anti-inflammatory potential can be reproduced in human studies, a completely new treatment strategy to avoid GC-induced growth impairment may become available.

References: 1. Kim, S. J., Guerrero, N., Wassef, G., Xiao, J., Mehta, H. H., Cohen, P., Yen, K. (2016) The mitochondrial-derived peptide humanin activates the ERK1/2, AKT, and STAT3 signaling pathways and has age-dependent signaling differences in the hippocampus. Oncotarget 7, 46899–46912.

2. Hansen, K. E., Kleker, B., Safdar, N. & Bartels, C. M. A systematic review and meta-analysis of glucocorticoid-induced osteoporosis in children. Semin. Arthritis Rheum. 44, 47–54 (2014).

3. Simon, D. et al. Effects of recombinant human growth hormone for 1 year on body composition and muscle strength in children on long-term steroid therapy: randomized controlled, delayed-start study. J. Clin. Endocrinol. Metab. 98, 2746–2754 (2013).

4. Zaman, F., Chrysis, D., Huntjens, K., Fadeel, B. & Sävendahl, L. Ablation of the Pro-Apoptotic Protein Bax Protects Mice from Glucocorticoid-Induced Bone Growth Impairment. PLOS ONE 7, e33168 (2012).