Abstract：
Clinical evidence indicates a close association between muscle dysfunction and bone loss; however, the underlying mechanisms remain unclear. Here, we report that muscle dysfunction-related bone loss in humans with limb-girdle muscular dystrophy is associated with decreased expression of folliculin-interacting protein 1 (FNIP1) in muscle tissue. Supporting this finding, murine gain- and loss-of-function genetic models demonstrated that muscle-specific ablation of FNIP1 caused decreased bone mass, increased osteoclastic activity, and mechanical impairment that could be rescued by myofiber-specific expression of FNIP1. Myofiber-specific FNIP1 deficiency stimulated expression of nuclear translocation of transcription factor EB, thereby activating transcription of insulin-like growth factor 2 (Igf2) at a conserved promoter-binding site and subsequent IGF2 secretion. Muscle-derived IGF2 stimulated osteoclastogenesis through IGF2 receptor signaling. AAV9-mediated overexpression of IGF2 was sufficient to decrease bone volume and impair bone mechanical properties in mice. Further, we found that serum IGF2 concentration was negatively correlated with bone health in humans in the context of osteoporosis. Our findings elucidate a muscle-bone cross-talk mechanism bridging the gap between muscle dysfunction and bone loss. This cross-talk represents a potential target to treat musculoskeletal diseases and osteoporosis.
摘要：
临床证据表明肌肉功能障碍与骨丢失密切相关；然而，潜在机制尚不清楚.这里,我们报道,在患有肢体带型肌营养不良的人中,肌肉功能障碍相关的骨丢失与肌肉组织中Folliculin相互作用蛋白1(FNIP1)的表达降低有关.支持这一发现，小鼠的功能增益和功能丧失遗传模型表明，FNIP1的肌肉特异性消融导致骨量减少，破骨细胞活动增加，以及可以通过肌纤维特异性表达FNIP1来挽救的机械损伤。肌纤维特异性FNIP1缺陷刺激转录因子EB核易位的表达，从而在保守的启动子结合位点激活胰岛素样生长因子2（Igf2）的转录，并随后分泌IGF2。肌肉来源的IGF2通过IGF2受体信号传导刺激破骨细胞生成。AAV9介导的IGF2过表达足以降低小鼠的骨体积并损害骨机械性能。Further,我们发现,在骨质疏松的情况下,血清IGF2浓度与人类骨骼健康呈负相关.我们的发现阐明了一种肌肉-骨骼串扰机制，该机制弥合了肌肉功能障碍和骨质流失之间的差距。这种串扰代表了治疗肌肉骨骼疾病和骨质疏松症的潜在目标。
