Department of Women's and Children's Health, Karolinska Institutet and Pediatric Endocrinology Unit, Karolinska University Hospital, Solna, Sweden.
Leonard Davis School of Gerontology, University of Southern California, Los Angeles, California, USA.
FASEB J. 2019 Apr;33(4):4962-4974. doi: 10.1096/fj.201801741R. Epub 2019 Jan 18.
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.
糖皮质激素（GCs）常用于治疗儿童的慢性疾病，包括炎症和癌症。长期使用 GCs 已知会损害骨骼生长，这种效应与生长板软骨细胞凋亡增加和增殖受抑制有关。我们假设内源性抗凋亡蛋白人源神经保护因子（HN）可能预防这些作用。有趣的是，在 HN 过表达小鼠、HN 处理的野生型小鼠和 HN 处理的培养大鼠跖骨中，GC 诱导的骨生长障碍和软骨细胞凋亡得到了预防。HN 还预防了 GC 诱导的软骨细胞增殖抑制。此外，GC 处理降低了野生型小鼠生长板中的印度刺猬表达，但在 HN 过表达小鼠或 HN 处理的野生型动物中则没有。刺猬（Hh）拮抗剂维莫德吉（vismodegib）被发现可抑制培养的大鼠跖骨生长，而 HN 可预防这种作用。重要的是，HN 不干扰 GCs 的抗炎作用。我们得出结论，HN 是 Hh 信号的新型调节剂，可预防 GC 诱导的骨生长障碍，而不干扰 GCs 的预期作用。我们的数据可能为探索通过与 HN 共同治疗来预防 GC 诱导的骨生长障碍的新的可能策略提供临床研究的依据。-扎曼，F.，赵，Y.，塞尔文，B.，梅塔，H. H.，万，J.，克里西斯，D.，奥尔森，C.，法德尔，B.，科恩，P.，萨文达尔，L. 人源神经保护因子是刺猬信号的新型调节剂，可预防糖皮质激素诱导的骨生长障碍。
