Gao Xueqin, Cui Yan, Zhang Greg, Ruzbarsky Joseph J, Wang Bing, Layne Jonathan E, Xiao Xiang, Huard Johnny
Linda and Mitch Hart Center for Regenerative and Personalized Medicine, Steadman Philippon Research Institute, Vail, CO 81657, USA.
Department of Orthopaedic Surgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
Cells. 2025 Jan 14;14(2):116. doi: 10.3390/cells14020116.
Duchenne muscular dystrophy (DMD) is a severe genetic muscle disease occurring due to mutations of the dystrophin gene. There is no cure for DMD. Using a dystrophinutrophin (DKO-Hom) mouse model, we investigated the PGE2/EP2 pathway in the pathogenesis of dystrophic muscle and its potential as a therapeutic target. We found that Ep2, Ep4, Cox-2, 15-Pgdh mRNA, and PGE2 were significantly increased in DKO-Hom mice compared to wild-type (WT) mice. The EP2 and EP4 receptors were mainly expressed in CD68 macrophages and were significantly increased in the muscle tissues of both dystrophin (mdx) and DKO-Hom mice compared to WT mice. Osteogenic and osteoclastogenic gene expression in skeletal muscle also increased in DKO-Hom mice, which correlates with severe muscle heterotopic ossification (HO). Treatment of DKO-Hom mice with the EP2 antagonist PF04418948 for 2 weeks increased body weight and reduced HO and muscle pathology by decreasing both total macrophages (CD68) and senescent macrophages (CD68P21), while increasing endothelial cells (CD31). PF04418948 also increased bone volume/total volume (BV/TV), the trabecular thickness (Tb.Th) of the tibia trabecular bone, and the cortical bone thickness of both the femur and tibia without affecting spine trabecular bone microarchitecture. In summary, our results indicate that targeting EP2 improves muscle pathology and improves bone mass in DKO mice.
杜氏肌营养不良症（DMD）是一种由于肌营养不良蛋白基因突变而引发的严重遗传性肌肉疾病。目前尚无治愈DMD的方法。我们利用一种肌营养不良蛋白-神经营养蛋白（DKO-Hom）小鼠模型，研究了前列腺素E2（PGE2）/EP2信号通路在营养不良性肌肉发病机制中的作用及其作为治疗靶点的潜力。我们发现，与野生型（WT）小鼠相比，DKO-Hom小鼠的Ep2、Ep4、Cox-2、15-Pgdh mRNA和PGE2显著增加。EP2和EP4受体主要在CD68巨噬细胞中表达，与WT小鼠相比，在肌营养不良蛋白缺陷（mdx）小鼠和DKO-Hom小鼠的肌肉组织中均显著增加。DKO-Hom小鼠骨骼肌中成骨和成破骨基因表达也增加，这与严重的肌肉异位骨化（HO）相关。用EP2拮抗剂PF04418948治疗DKO-Hom小鼠2周，可增加体重，减少HO和肌肉病变，这是通过减少总巨噬细胞（CD68）和衰老巨噬细胞（CD68P21），同时增加内皮细胞（CD31）实现的。PF04418948还增加了骨体积/总体积（BV/TV）、胫骨小梁骨的小梁厚度（Tb.Th）以及股骨和胫骨的皮质骨厚度，而不影响脊柱小梁骨的微结构。总之，我们的结果表明，靶向EP2可改善DKO小鼠的肌肉病变并增加骨量。
