{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T01:34:25Z","timestamp":1791855265597,"version":"4.3.4"},"reference-count":42,"publisher":"Oxford University Press (OUP)","issue":"20","license":[{"start":{"date-parts":[[2019,8,14]],"date-time":"2019-08-14T00:00:00Z","timestamp":1565740800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases for a Wellstone Cooperative Muscular Dystrophy Center","award":["U54AR052646"],"award-info":[{"award-number":["U54AR052646"]}]},{"name":"P30 Muscular Dystrophy Core Center","award":["NIAMS-P30AR057230-01"],"award-info":[{"award-number":["NIAMS-P30AR057230-01"]}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["RO1 AR046911"],"award-info":[{"award-number":["RO1 AR046911"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 HL140938"],"award-info":[{"award-number":["R01 HL140938"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005693","name":"Parent Project Muscular Dystrophy","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100005693","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005202","name":"Muscular Dystrophy Association","doi-asserted-by":"publisher","award":["479350"],"award-info":[{"award-number":["479350"]}],"id":[{"id":"10.13039\/100005202","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,10,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Duchenne muscular dystrophy (DMD) is caused by mutations in the gene encoding dystrophin. Prior work has shown that DMD progression can vary, depending on the genetic makeup of the patient. Several modifier alleles have been identified including LTBP4 and SPP1. We previously showed that Spp1 exacerbates the DMD phenotype in the mdx mouse model by promoting fibrosis and by skewing macrophage polarization. Here, we studied the mechanisms involved in Spp1's promotion of fibrosis by using both isolated fibroblasts and genetically modified mice. We found that Spp1 upregulates collagen expression in mdx fibroblasts by enhancing TGF\u03b2 signaling. Spp1's effects on TGF\u03b2 signaling are through induction of MMP9 expression. MMP9 is a protease that can release active TGF\u03b2 ligand from its latent complex. In support for activation of this pathway in our model, we showed that treatment of mdx fibroblasts with MMP9 inhibitor led to accumulation of the TGF\u03b2 latent complex, decreased levels of active TGF\u03b2 and reduced collagen expression. Correspondingly, we found reduced active TGF\u03b2 in Spp1\u2212\/\u2212mdxB10 and Mmp9\u2212\/\u2212mdxB10 muscles in vivo. Taken together with previous observations of reduced fibrosis in both models, these data suggest that Spp1 acts upstream of TGF\u03b2 to promote fibrosis in mdx muscles. We found that in the context of constitutively upregulated TGF\u03b2 signaling (such as in the mdxD2 model), ablation of Spp1 has very little effect on fibrosis. Finally, we performed proof-of-concept studies showing that postnatal pharmacological inhibition of Spp1 reduces fibrosis and improves muscle function in mdx mice.<\/jats:p>","DOI":"10.1093\/hmg\/ddz181","type":"journal-article","created":{"date-parts":[[2019,8,11]],"date-time":"2019-08-11T00:45:23Z","timestamp":1565484323000},"page":"3431-3442","source":"Crossref","is-referenced-by-count":97,"title":["Spp1 (osteopontin) promotes TGF\u03b2 processing in fibroblasts of dystrophin-deficient muscles through matrix metalloproteinases"],"prefix":"10.1093","volume":"28","author":[{"given":"Irina","family":"Kramerova","sequence":"first","affiliation":[{"name":"Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chino","family":"Kumagai-Cresse","sequence":"first","affiliation":[{"name":"Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles"},{"name":"Center for Genetic Medicine, Northwestern University Feinberg School of Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia","family":"Ermolova","sequence":"first","affiliation":[{"name":"Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ekaterina","family":"Mokhonova","sequence":"first","affiliation":[{"name":"Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masha","family":"Marinov","sequence":"first","affiliation":[{"name":"Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joana","family":"Capote","sequence":"first","affiliation":[{"name":"Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles"},{"name":"Molecular, Cellular and Integrative Physiology, University of California, Los Angeles"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana","family":"Becerra","sequence":"first","affiliation":[{"name":"Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mattia","family":"Quattrocelli","sequence":"first","affiliation":[{"name":"Center for Genetic Medicine, Northwestern University Feinberg School of Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachelle H","family":"Crosbie","sequence":"first","affiliation":[{"name":"Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles"},{"name":"Department of Integrative Biology and Physiology, University of California, Los Angeles"},{"name":"Paul Wellstone Muscular Dystrophy Center"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ellen","family":"Welch","sequence":"first","affiliation":[{"name":"PTC Therapeutics"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth M","family":"McNally","sequence":"first","affiliation":[{"name":"Center for Genetic Medicine, Northwestern University Feinberg School of Medicine"},{"name":"Paul Wellstone Muscular Dystrophy Center"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa J","family":"Spencer","sequence":"first","affiliation":[{"name":"Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles"},{"name":"Paul Wellstone Muscular Dystrophy Center"},{"name":"Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2019,8,14]]},"reference":[{"key":"2020070810442106600_ref1","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/S1474-4422(09)70271-6","article-title":"Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and pharmacological and psychosocial management","volume":"9","author":"Bushby","year":"2010","journal-title":"Lancet Neurol."},{"key":"2020070810442106600_ref2","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/S1474-4422(09)70272-8","article-title":"Diagnosis and management of Duchenne muscular dystrophy, part 2: implementation of multidisciplinary care","volume":"9","author":"Bushby","year":"2010","journal-title":"Lancet Neurol."},{"key":"2020070810442106600_ref3","doi-asserted-by":"crossref","first-page":"3703","DOI":"10.1172\/JCI39845","article-title":"Latent TGF-beta-binding protein 4 modifies muscular dystrophy in mice","volume":"119","author":"Heydemann","year":"2009","journal-title":"J. Clin. Invest."},{"key":"2020070810442106600_ref4","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.matbio.2015.05.005","article-title":"Latent TGF-\u03b2-binding proteins","volume":"47","author":"Robertson","year":"2015","journal-title":"Matrix Biol."},{"key":"2020070810442106600_ref5","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1002\/ana.23819","article-title":"LTBP4 genotype predicts age of ambulatory loss in Duchenne muscular dystrophy","volume":"73","author":"Flanigan","year":"2013","journal-title":"Ann. Neurol."},{"key":"2020070810442106600_ref6","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1212\/WNL.0b013e31825f04ea","article-title":"Importance of SPP1 genotype as a covariate in clinical trials in Duchenne muscular dystrophy","volume":"79","author":"Bello","year":"2012","journal-title":"Neurology"},{"key":"2020070810442106600_ref7","doi-asserted-by":"crossref","first-page":"684","DOI":"10.1002\/ana.24370","article-title":"Genetic modifiers of ambulation in the cooperative international neuromuscular research group Duchenne natural history study","volume":"77","author":"Bello","year":"2015","journal-title":"Ann. Neurol."},{"key":"2020070810442106600_ref8","doi-asserted-by":"crossref","first-page":"e1006019","DOI":"10.1371\/journal.pgen.1006019","article-title":"Overexpression of latent TGF\u03b2 binding protein 4 in muscle ameliorates muscular dystrophy through myostatin and TGF\u03b2","volume":"12","author":"Lamar","year":"2016","journal-title":"PLoS Genet."},{"key":"2020070810442106600_ref9","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1083\/jcb.201510086","article-title":"Osteopontin ablation ameliorates muscular dystrophy by shifting macrophages to a pro-regenerative phenotype","volume":"213","author":"Capote","year":"2016","journal-title":"J. Cell Biol."},{"key":"2020070810442106600_ref10","doi-asserted-by":"crossref","first-page":"1583","DOI":"10.1172\/JCI37662","article-title":"Osteopontin promotes fibrosis in dystrophic mouse muscle by modulating immune cell subsets and intramuscular TGF-beta","volume":"119","author":"Vetrone","year":"2009","journal-title":"J. Clin. 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