Lee Jin Young, Park So Jeong, Kim Da Ae, Lee Seung Hun, Koh Jung-Min, Kim Beom-Jun
Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
Division of Endocrinology and Metabolism, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
Front Cell Dev Biol. 2020 Nov 6;8:565826. doi: 10.3389/fcell.2020.565826. eCollection 2020.
Skeletal muscle and bone are highly interrelated, and previous proteomic analyses suggest that lumican is one of muscle-derived factors. To further understand the role of lumican as a myokine affecting adjacent bone metabolism, we investigated the effects of lumican on osteoblast biology. Lumican expression was significantly higher in the cell lysates and conditioned media (CM) of myotubes than those of undifferentiated myoblasts, and the known anabolic effects of myotube CM on osteoblasts were reduced by excluding lumican from the CM. Lumican stimulated preosteoblast viability and differentiation, resulting in increased calvaria bone formation. The expression of osteoblast differentiation markers was consistently increased by lumican. Lumican increased the phosphorylation of ERK, whereas ERK inhibitors completely reversed lumican-mediated stimulation of and ALP activities in osteoblasts. Results of a binding ELISA experiment in osteoblasts show that transmembrane integrin α2β1 directly interacted with lumican, and an integrin α2β1 inhibitor attenuated the stimulation of ERK and ALP activities by lumican. Taken together, the results indicate that muscle-derived lumican stimulates bone formation via integrin α2β1 and the downstream ERK signal, indicating that this is a potential therapeutic target for metabolic bone diseases.
骨骼肌与骨骼高度相关，先前的蛋白质组学分析表明，亮氨酸聚糖是肌肉衍生因子之一。为了进一步了解亮氨酸聚糖作为一种影响相邻骨代谢的肌动蛋白的作用，我们研究了亮氨酸聚糖对成骨细胞生物学的影响。与未分化的成肌细胞相比，肌管细胞裂解物和条件培养基（CM）中亮氨酸聚糖的表达显著更高，并且通过从CM中排除亮氨酸聚糖，肌管CM对成骨细胞的已知合成代谢作用降低。亮氨酸聚糖刺激前成骨细胞的活力和分化，导致颅盖骨形成增加。亮氨酸聚糖使成骨细胞分化标志物的表达持续增加。亮氨酸聚糖增加了ERK的磷酸化，而ERK抑制剂完全逆转了亮氨酸聚糖介导的成骨细胞中 和碱性磷酸酶（ALP）活性的刺激。成骨细胞中结合酶联免疫吸附测定（ELISA）实验结果表明，跨膜整合素α2β1直接与亮氨酸聚糖相互作用，并且整合素α2β1抑制剂减弱了亮氨酸聚糖对ERK和ALP活性的刺激。综上所述，结果表明肌肉衍生的亮氨酸聚糖通过整合素α2β1和下游ERK信号刺激骨形成，表明这是代谢性骨病的潜在治疗靶点。
