{"doi":"10.1172/jci152571","title":"Targeting TGF-β for treatment of osteogenesis imperfecta","abstract":null,"journal":"Journal of Clinical Investigation","year":2022,"id":633727,"datarank":0.6782682865573562,"base_score":4.5217885770490405,"endowment":4.5217885770490405,"self_citation_contribution":0.6782682865573562,"citation_network_contribution":0.0,"self_endowment_contribution":0.6782682865573562,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":91,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":296131,"name":"Sandesh C.S. Nagamani","orcid":"0000-0001-6818-7367","position":1,"is_corresponding":false},{"id":676178,"name":"Dianne Nguyen","orcid":null,"position":2,"is_corresponding":false},{"id":406298,"name":"Ingo Grafe","orcid":"0000-0002-3447-3987","position":3,"is_corresponding":false},{"id":36505,"name":"V. Reid Sutton","orcid":"0000-0002-6450-8554","position":4,"is_corresponding":false},{"id":688525,"name":"Francis H. Gannon","orcid":null,"position":5,"is_corresponding":false},{"id":500136,"name":"Elda Munivez","orcid":null,"position":6,"is_corresponding":false},{"id":407893,"name":"Ming-Ming Jiang","orcid":null,"position":7,"is_corresponding":false},{"id":1643213,"name":"Alyssa Tran","orcid":null,"position":8,"is_corresponding":false},{"id":506139,"name":"Maegen Wallace","orcid":"0000-0001-6278-9412","position":9,"is_corresponding":false},{"id":1643215,"name":"Paul Esposito","orcid":null,"position":10,"is_corresponding":false},{"id":405442,"name":"Salma Musaad","orcid":"0000-0003-1733-830X","position":11,"is_corresponding":false},{"id":1643217,"name":"Elizabeth Strudthoff","orcid":null,"position":12,"is_corresponding":false},{"id":1643219,"name":"Sharon McGuire","orcid":null,"position":13,"is_corresponding":false},{"id":940805,"name":"Michele Thornton","orcid":null,"position":14,"is_corresponding":false},{"id":1643220,"name":"Vinitha Shenava","orcid":null,"position":15,"is_corresponding":false},{"id":1643222,"name":"Scott Rosenfeld","orcid":null,"position":16,"is_corresponding":false},{"id":2210,"name":"Shixia Huang","orcid":"0000-0003-2878-4129","position":17,"is_corresponding":false},{"id":925003,"name":"Roman J. Shypailo","orcid":"0000-0002-1134-2482","position":18,"is_corresponding":false},{"id":250536,"name":"Eric Orwoll","orcid":"0000-0002-8520-7355","position":19,"is_corresponding":false},{"id":249412,"name":"Brendan Lee","orcid":"0000-0001-8573-4211","position":20,"is_corresponding":false},{"id":576048,"name":"I-Wen Song","orcid":"0000-0003-1579-4328","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Targeting TGF-β for treatment of osteogenesis imperfecta","abstract":"BACKGROUNDCurrently, there is no disease-specific therapy for osteogenesis imperfecta (OI). Preclinical studies demonstrate that excessive TGF-β signaling is a pathogenic mechanism in OI. Here, we evaluated TGF-β signaling in children with OI and conducted a phase I clinical trial of TGF-β inhibition in adults with OI.METHODSHistology and RNA-Seq were performed on bones obtained from children. Gene Ontology (GO) enrichment assay, gene set enrichment analysis (GSEA), and Ingenuity Pathway Analysis (IPA) were used to identify dysregulated pathways. Reverse-phase protein array, Western blot, and IHC were performed to evaluate protein expression. A phase I study of fresolimumab, a TGF-β neutralizing antibody, was conducted in 8 adults with OI. Safety and effects on bone remodeling markers and lumbar spine areal bone mineral density (LS aBMD) were assessed.RESULTSOI bone demonstrated woven structure, increased osteocytes, high turnover, and reduced maturation. SMAD phosphorylation was the most significantly upregulated GO molecular event. GSEA identified the TGF-β pathway as the top activated signaling pathway, and IPA showed that TGF-β1 was the most significant activated upstream regulator mediating the global changes identified in OI bone. Treatment with fresolimumab was well-tolerated and associated with increases in LS aBMD in participants with OI type IV, whereas participants with OI type III and VIII had unchanged or decreased LS aBMD.CONCLUSIONIncreased TGF-β signaling is a driver pathogenic mechanism in OI. Anti-TGF-β therapy could be a potential disease-specific therapy, with dose-dependent effects on bone mass and turnover.TRIAL REGISTRATIONClinicalTrials.gov NCT03064074.FUNDINGBrittle Bone Disorders Consortium (U54AR068069), Clinical Translational Core of Baylor College of Medicine Intellectual and Developmental Disabilities Research Center (P50HD103555) from National Institute of Child Health and Human Development, USDA/ARS (cooperative agreement 58-6250-6-001), and Sanofi Genzyme.","is_dataset_classified":null,"base_score":4.48863636973214,"endowment":4.48863636973214,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"35113812","pmcid":"PMC8970679","openalex_id":"https://openalex.org/W4210246475","authors":[],"funders":[{"funder_name":"Brittle Bone Disorders Consortium","grant_id":"U54AR068069","title":null},{"funder_name":"The Clinical Translational Core of BCM IDDRC","grant_id":"P50HD103555","title":null},{"funder_name":"USDA/ARS under Cooperative Agreement","grant_id":"58-6250-6-001","title":null},{"funder_name":"NCI NIH HHS","grant_id":"P30 CA125123","title":null},{"funder_name":"National Institutes of Health","grant_id":"3U54AR068069-08S1","title":"DIVERSITY SUPPLEMENT:  BRITTLE BONE DISORDERS CONSORTIUM OF THE RARE DISEASE CLINICAL RESEARCH NETWORK"},{"funder_name":"National Institutes of Health","grant_id":"1P50HD103555-01","title":"Baylor College of Medicine Intellectual and Developmental Disabilities Research Center"},{"funder_name":"National Institutes of Health","grant_id":"3P30CA125123-09S3","title":"Baylor College of Medicine Cancer Center"}],"total_grants":7,"fwci":11.7711,"citation_percentile":0.9899997,"influential_citations":0,"citation_trend":[{"year":2020,"count":1},{"year":2022,"count":5},{"year":2023,"count":13},{"year":2024,"count":27},{"year":2025,"count":25},{"year":2026,"count":17}],"oa_status":"gold","license":"cc-by","oa_locations":[{"url":"http://www.jci.org/articles/view/152571/files/pdf","host_type":"journal"},{"url":"http://www.jci.org/articles/view/152571/files/pdf","host_type":"publisher"},{"url":"https://www.jci.org/articles/view/152571/files/pdf","host_type":"publisher"},{"url":"https://doi.org/10.1172/jci152571","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/35113812","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/8970679","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC8970679","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC8970679?pdf=render","host_type":"Europe_PMC"},{"url":"https://doi.org/10.1530/ey.19.5.1","host_type":""},{"url":"http://dx.doi.org/10.1172/JCI152571","host_type":""},{"url":"https://doaj.org/article/9348cb1c7256408f9c15e5c78a7a8c81","host_type":""}],"fields_of_study":["Connective tissue disorders research","Dermatological and Skeletal Disorders","TGF-β signaling in diseases","0301 basic medicine","0303 health sciences","03 medical and health sciences","Adult","Bone Density","Bone and Bones","Child","Humans","Lumbar Vertebrae","Osteogenesis Imperfecta","Transforming Growth Factor beta"],"mesh_terms":["Adult","Bone and Bones","Child","Humans","Lumbar Vertebrae","Osteogenesis Imperfecta","Bone Density","Transforming Growth Factor beta"],"keywords":["Osteogenesis imperfecta","SMAD","Signal transduction","Bone mineral","Phosphorylation","Bone remodeling","Bone morphogenetic protein","Bone density","Downregulation and upregulation","Drug therapy","Therapeutics","Clinical Trials","bone disease","Adult","Lumbar Vertebrae","R","Bone and Bones","Transforming Growth Factor beta","Medicine","Humans","Clinical Medicine","Child"],"sdg_mappings":[{"sdg_number":3,"sdg_label":"3. 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