{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:37:09Z","timestamp":1787027829018,"version":"build-2736575974"},"reference-count":76,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2025,1,14]],"date-time":"2025-01-14T00:00:00Z","timestamp":1736812800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["R01AR065445"],"award-info":[{"award-number":["R01AR065445"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>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\u2212\/\u2212utrophin\u2212\/\u2212 (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\u2212\/\u2212 (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 (CD68+P21+), 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.<\/jats:p>","DOI":"10.3390\/cells14020116","type":"journal-article","created":{"date-parts":[[2025,1,14]],"date-time":"2025-01-14T11:28:31Z","timestamp":1736854111000},"page":"116","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Targeting EP2 Receptor Improves Muscle and Bone Health in Dystrophin\u2212\/\u2212\/Utrophin\u2212\/\u2212 Double-Knockout Mice"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5833-1548","authenticated-orcid":false,"given":"Xueqin","family":"Gao","sequence":"first","affiliation":[{"name":"Linda and Mitch Hart Center for Regenerative and Personalized Medicine, Steadman Philippon Research Institute, Vail, CO 81657, USA"},{"name":"Department of Orthopaedic Surgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Cui","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Greg","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph J.","family":"Ruzbarsky","sequence":"additional","affiliation":[{"name":"Linda and Mitch Hart Center for Regenerative and Personalized Medicine, Steadman Philippon Research Institute, Vail, CO 81657, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5185-3500","authenticated-orcid":false,"given":"Bing","family":"Wang","sequence":"additional","affiliation":[{"name":"Vascular Medicine Institute, Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15260, USA"},{"name":"Pittsburgh VA Healthcare System, Pittsburgh, PA 15240, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9245-0989","authenticated-orcid":false,"given":"Jonathan E.","family":"Layne","sequence":"additional","affiliation":[{"name":"Linda and Mitch Hart Center for Regenerative and Personalized Medicine, Steadman Philippon Research Institute, Vail, CO 81657, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiang","family":"Xiao","sequence":"additional","affiliation":[{"name":"Glassell School of Art, The Museum of Fine Arts, Houston, TX 77006, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johnny","family":"Huard","sequence":"additional","affiliation":[{"name":"Linda and Mitch Hart Center for Regenerative and Personalized Medicine, Steadman Philippon Research Institute, Vail, CO 81657, USA"},{"name":"Department of Orthopaedic Surgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,1,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1016\/0092-8674(87)90504-6","article-title":"Complete cloning of the Duchenne muscular dystrophy (DMD) cDNA and preliminary genomic organization of the DMD gene in normal and affected individuals","volume":"50","author":"Koenig","year":"1987","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1016\/0092-8674(87)90579-4","article-title":"Dystrophin: The protein product of the Duchenne muscular dystrophy locus","volume":"51","author":"Hoffman","year":"1987","journal-title":"Cell"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1016\/S0092-8674(00)80533-4","article-title":"Skeletal and cardiac myopathies in mice lacking utrophin and dystrophin: A model for Duchenne muscular dystrophy","volume":"90","author":"Grady","year":"1997","journal-title":"Cell"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"4786","DOI":"10.1093\/hmg\/ddu194","article-title":"Rapid depletion of muscle progenitor cells in dystrophic mdx\/utrophin\u2212\/\u2212 mice","volume":"23","author":"Lu","year":"2014","journal-title":"Hum. 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