Targeting EP2 Receptor Improves Muscle and Bone Health in Dystrophin<sup>−/−</sup>/Utrophin<sup>−/−</sup> Double-Knockout Mice
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 dystrophin<sup>−/−</sup>utrophin<sup>−/−</sup> (DKO-Hom) mouse model, we investigated the PGE2/EP2 pathway in the pathogen...
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2025-01-01
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| author | Xueqin Gao Yan Cui Greg Zhang Joseph J. Ruzbarsky Bing Wang Jonathan E. Layne Xiang Xiao Johnny Huard |
| author_facet | Xueqin Gao Yan Cui Greg Zhang Joseph J. Ruzbarsky Bing Wang Jonathan E. Layne Xiang Xiao Johnny Huard |
| author_sort | Xueqin Gao |
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| description | 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 dystrophin<sup>−/−</sup>utrophin<sup>−/−</sup> (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<sup>+</sup> macrophages and were significantly increased in the muscle tissues of both dystrophin<sup>−/−</sup> (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<sup>+</sup>) and senescent macrophages (CD68<sup>+</sup>P21<sup>+</sup>), while increasing endothelial cells (CD31<sup>+</sup>). 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. |
| format | Article |
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| institution | Kabale University |
| issn | 2073-4409 |
| language | English |
| publishDate | 2025-01-01 |
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| spelling | doaj-art-bc2116cc94d84d92a53fed6d18b9d47f2025-01-24T13:26:44ZengMDPI AGCells2073-44092025-01-0114211610.3390/cells14020116Targeting EP2 Receptor Improves Muscle and Bone Health in Dystrophin<sup>−/−</sup>/Utrophin<sup>−/−</sup> Double-Knockout MiceXueqin Gao0Yan Cui1Greg Zhang2Joseph J. Ruzbarsky3Bing Wang4Jonathan E. Layne5Xiang Xiao6Johnny Huard7Linda and Mitch Hart Center for Regenerative and Personalized Medicine, Steadman Philippon Research Institute, Vail, CO 81657, USADepartment of Orthopaedic Surgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USADepartment of Orthopaedic Surgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USALinda and Mitch Hart Center for Regenerative and Personalized Medicine, Steadman Philippon Research Institute, Vail, CO 81657, USAVascular Medicine Institute, Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15260, USALinda and Mitch Hart Center for Regenerative and Personalized Medicine, Steadman Philippon Research Institute, Vail, CO 81657, USAGlassell School of Art, The Museum of Fine Arts, Houston, TX 77006, USALinda and Mitch Hart Center for Regenerative and Personalized Medicine, Steadman Philippon Research Institute, Vail, CO 81657, USADuchenne 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 dystrophin<sup>−/−</sup>utrophin<sup>−/−</sup> (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<sup>+</sup> macrophages and were significantly increased in the muscle tissues of both dystrophin<sup>−/−</sup> (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<sup>+</sup>) and senescent macrophages (CD68<sup>+</sup>P21<sup>+</sup>), while increasing endothelial cells (CD31<sup>+</sup>). 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.https://www.mdpi.com/2073-4409/14/2/116muscular dystrophyEP2EP4PGE2bone microarchitectureheterotopic ossification |
| spellingShingle | Xueqin Gao Yan Cui Greg Zhang Joseph J. Ruzbarsky Bing Wang Jonathan E. Layne Xiang Xiao Johnny Huard Targeting EP2 Receptor Improves Muscle and Bone Health in Dystrophin<sup>−/−</sup>/Utrophin<sup>−/−</sup> Double-Knockout Mice Cells muscular dystrophy EP2 EP4 PGE2 bone microarchitecture heterotopic ossification |
| title | Targeting EP2 Receptor Improves Muscle and Bone Health in Dystrophin<sup>−/−</sup>/Utrophin<sup>−/−</sup> Double-Knockout Mice |
| title_full | Targeting EP2 Receptor Improves Muscle and Bone Health in Dystrophin<sup>−/−</sup>/Utrophin<sup>−/−</sup> Double-Knockout Mice |
| title_fullStr | Targeting EP2 Receptor Improves Muscle and Bone Health in Dystrophin<sup>−/−</sup>/Utrophin<sup>−/−</sup> Double-Knockout Mice |
| title_full_unstemmed | Targeting EP2 Receptor Improves Muscle and Bone Health in Dystrophin<sup>−/−</sup>/Utrophin<sup>−/−</sup> Double-Knockout Mice |
| title_short | Targeting EP2 Receptor Improves Muscle and Bone Health in Dystrophin<sup>−/−</sup>/Utrophin<sup>−/−</sup> Double-Knockout Mice |
| title_sort | targeting ep2 receptor improves muscle and bone health in dystrophin sup sup utrophin sup sup double knockout mice |
| topic | muscular dystrophy EP2 EP4 PGE2 bone microarchitecture heterotopic ossification |
| url | https://www.mdpi.com/2073-4409/14/2/116 |
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