Combined growth hormone and insulin-like growth factor 1 rescues growth retardation in glucocorticoid-treated mdx mice but does not prevent osteopenia

AUTHORS

Claire L Wood, Rob Van't Hof, Scott Dillon, Volker Straub, Sze C Wong, S Faisal Ahmed, Colin Farquharson

ABSTRACT

Short stature and osteoporosis are common in Duchenne muscular dystrophy (DMD) and its pathophysiology may include an abnormality of the growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis, which is further exacerbated by long-term glucocorticoid (GC) treatment. Hence an agent that has anabolic properties and may improve linear growth would be beneficial in this setting and therefore requires further exploration. 5-week old x-linked muscular dystrophy (mdx) mice were used as a model of DMD. They were treated with prednisolone ± GH + IGF-1 for 4-weeks and then compared to comtrol mdx mice to allow the study of both growth and skeletal structure. GC reduced cortical bone area, bone fraction, tissue area and volume and cortical bone volume, as assessed by Micro computed tomography (CT) In addition, GC caused somatic and skeletal growth retardation, but improved grip strength. The addition of GH + IGF-1 therapy rescued the somatic growth retardation and induced additional improvements in grip strength (16.9% increase, p<0.05 compared to control). There was no improvement in bone microarchitecture (assessed by Micro-CT and static histomorphometry) or biomechanical properties (assessed by three-point bending). Serum bone turnover markers (P1NP, αCTX) also remained unaffected. Further work is needed to maximise these gains before proceeding to clinical trials in boys with DMD.

A functional motif of long noncoding RNA Nron against osteoporosis

AUTHORS

Fujun Jin, Junhui Li, Yong-Biao Zhang, Xiangning Liu, Mingxiang Cai, Meijing Liu, Mengyao Li, Cui Ma, Rui Yue, Yexuan Zhu, Renfa Lai, Zuolin Wang, Xunming Ji, Huawei Wei, Jun Dong, Zhiduo Liu, Yifei Wang, Yao Sun & Xiaogang Wang

ABSTRACT

Long noncoding RNAs are widely implicated in diverse disease processes. Nonetheless, their regulatory roles in bone resorption are undefined. Here, we identify lncRNA Nron as a critical suppressor of bone resorption. We demonstrate that osteoclastic Nron knockout mice exhibit an osteopenia phenotype with elevated bone resorption activity. Conversely, osteoclastic Nron transgenic mice exhibit lower bone resorption and higher bone mass. Furthermore, the pharmacological overexpression of Nron inhibits bone resorption, while caused apparent side effects in mice. To minimize the side effects, we further identify a functional motif of Nron. The delivery of Nron functional motif to osteoclasts effectively reverses bone loss without obvious side effects. Mechanistically, the functional motif of Nron interacts with E3 ubiquitin ligase CUL4B to regulate ERα stability. These results indicate that Nron is a key bone resorption suppressor, and the lncRNA functional motif could potentially be utilized to treat diseases with less risk of side effects.