Humanin is a novel regulator of Hedgehog signaling and prevents glucocorticoid‐induced bone growth impairment

Abstract

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., Sävendahl, L. Humanin is a novel regulator of Hedgehog signaling and prevents glucocorticoid‐induced bone growth impairment. FASEB J. 33, 4962–4974 (2019). http://www.fasebj.org

The mitochondrial derived peptide humanin is a regulator of lifespan and healthspan

“…Humanin-tg mice were protected from cyclophosphamide treatment to the same extent as our previous study showing that C57BL6/J mice injected with humanin were also protected from cyclophosphamide [49]. Combined with our previous publication showing that the humanin-transgenic mice were equally protected from glucocorticoid toxicity as humanin injected mice [48], these results demonstrate that our humanin-transgenic model is phenotypically equivalent to daily injections of humanin and in future studies we will examine the lifespan of the humanin transgenic mice. Based on these results combined with those in worms, we predict a lifespan increase in these mice.…”

“…Mice harboring the humanin transgene were both viable and fertile. We have previously published that there is a 16% increase in circulating humanin levels in these mice [48]. With this model, the effects of long-term exposure to humanin were assessed.…”

“…The creation of this strain has been previously described [48]. In brief we developed a transgenic mouse model using a construct that included the humanin-ORF driven by a CMV promoter that was injected into the pronucleus of fertilized B6D2F1 mice ova.…”

“…We generated HN transgenic (HN-tg) mice expressing a CMV-promoter driven humanin transgene as previously described [48]. After genotyping, 1) groups of 7 adult (5-10 month-old) HN-tg and age-matched wildtype (WT) mice were used for the characterization of male reproductive phenotype, and 2) groups of 6 adult HN-tg and age-matched WT mice were treated with a singledose of CP injection (i.p.…”

MOTS‐c: A Mitochondrial‐Encoded Regulator of the Nucleus

“…HN keeps Bax from translocating to the mitochondria, thereby acting as an antiapoptotic factor . The cytoprotective effects of HN have been demonstrated in various pathophysiological conditions, including the brain, the cardiovascular system, eyes, bone, metabolism, and cellular senescence …”