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Ryan Fellowship, The Ryan Foundation"},{"DOI":"10.13039\/100009857","name":"Regeneron Pharmaceuticals","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009857","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100003769","name":"Foundation for Women's Wellness","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100003769","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009857","name":"Regeneron Pharmaceuticals","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009857","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100003769","name":"Foundation for Women's Wellness","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100003769","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["asbmr.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2020,12,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Osteogenesis imperfecta (OI) is a genetic connective tissue disorder characterized by compromised skeletal integrity, altered microarchitecture, and bone fragility. Current OI treatment strategies focus on bone antiresorptives and surgical intervention with limited effectiveness, and thus identifying alternative therapeutic options remains critical. Muscle is an important stimulus for bone formation. Myostatin, a TGF-\u03b2 superfamily myokine, acts through ActRIIB to negatively regulate muscle growth. Recent studies demonstrated the potential benefit of myostatin inhibition with the soluble ActRIIB fusion protein on skeletal properties, although various OI mouse models exhibited variable skeletal responses. The genetic and clinical heterogeneity associated with OI, the lack of specificity of the ActRIIB decoy molecule for myostatin alone, and adverse events in human clinical trials further the need to clarify myostatin's therapeutic potential and role in skeletal integrity. In this study, we determined musculoskeletal outcomes of genetic myostatin deficiency and postnatal pharmacological myostatin inhibition by a monoclonal anti-myostatin antibody (Regn647) in the G610C mouse, a model of mild\u2013moderate type I\/IV human OI. In the postnatal study, 5-week-old wild-type and +\/G610C male and female littermates were treated with Regn647 or a control antibody for 11\u2009weeks or for 7\u2009weeks followed by a 4-week treatment holiday. Inhibition of myostatin, whether genetically or pharmacologically, increased muscle mass regardless of OI genotype, although to varying degrees. Genetic myostatin deficiency increased hindlimb muscle weights by 6.9% to 34.4%, whereas pharmacological inhibition increased them by 13.5% to 29.6%. Female +\/mstn +\/G610C (Dbl.Het) mice tended to have similar trabecular and cortical bone parameters as Wt showing reversal of +\/G610C characteristics but with minimal effect of +\/mstn occurring in male mice. Pharmacologic myostatin inhibition failed to improve skeletal bone properties of male or female +\/G610C mice, although skeletal microarchitectural and biomechanical improvements were observed in male wild-type mice. Four-week treatment holiday did not alter skeletal outcomes. \u00a9 2020 American Society for Bone and Mineral Research (ASBMR).<\/jats:p>","DOI":"10.1002\/jbmr.4223","type":"journal-article","created":{"date-parts":[[2020,11,29]],"date-time":"2020-11-29T11:55:15Z","timestamp":1606650915000},"page":"739-756","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Impact of Genetic and Pharmacologic Inhibition of Myostatin in a Murine Model of Osteogenesis Imperfecta"],"prefix":"10.1093","volume":"36","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0750-2129","authenticated-orcid":false,"given":"Catherine L","family":"Omosule","sequence":"first","affiliation":[{"name":"Department of Biochemistry University of Missouri Columbia MO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6494-8613","authenticated-orcid":false,"given":"Victoria L","family":"Gremminger","sequence":"additional","affiliation":[{"name":"Department of Biochemistry University of Missouri Columbia MO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashley M","family":"Aguillard","sequence":"additional","affiliation":[{"name":"Department of Biochemistry University of Missouri Columbia MO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youngjae","family":"Jeong","sequence":"additional","affiliation":[{"name":"Department of Biochemistry University of Missouri Columbia MO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily N","family":"Harrelson","sequence":"additional","affiliation":[{"name":"Department of Biochemistry University of Missouri Columbia MO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lawrence","family":"Miloscio","sequence":"additional","affiliation":[{"name":"Regeneron Pharmaceuticals Tarrytown NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason","family":"Mastaitis","sequence":"additional","affiliation":[{"name":"Regeneron Pharmaceuticals Tarrytown NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashique","family":"Rafique","sequence":"additional","affiliation":[{"name":"Regeneron Pharmaceuticals Tarrytown NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Kleiner","sequence":"additional","affiliation":[{"name":"Regeneron Pharmaceuticals Tarrytown NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ferris M","family":"Pfeiffer","sequence":"additional","affiliation":[{"name":"Department of Biomedical, Biological, and Chemical Engineering University of Missouri Columbia MO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anqing","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Biostatistics and Research Design University of Missouri Columbia MO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura C","family":"Schulz","sequence":"additional","affiliation":[{"name":"Department of Obstetrics, Gynecology, and Women's Health University of Missouri Columbia MO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7761-3783","authenticated-orcid":false,"given":"Charlotte L","family":"Phillips","sequence":"additional","affiliation":[{"name":"Department of Child Health University of Missouri Columbia MO USA"},{"name":"Department of Biochemistry University of Missouri Columbia MO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,11,29]]},"reference":[{"issue":"10028","key":"2024012713501103900_jbmr4223-bib-0001","doi-asserted-by":"crossref","first-page":"1657","DOI":"10.1016\/S0140-6736(15)00728-X","article-title":"Osteogenesis 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