{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T10:41:29Z","timestamp":1790419289205,"version":"4.1.0"},"reference-count":71,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2013,5,23]],"date-time":"2013-05-23T00:00:00Z","timestamp":1369267200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2013,12,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n               <jats:sec>\n                  <jats:title>\u2003<\/jats:title>\n                  <jats:p>Dysregulated transforming growth factor beta (TGF-\u03b2) signaling is associated with a spectrum of osseous defects as seen in Loeys-Dietz syndrome, Marfan syndrome, and Camurati-Engelmann disease. Intriguingly, neurofibromatosis type 1 (NF1) patients exhibit many of these characteristic skeletal features, including kyphoscoliosis, osteoporosis, tibial dysplasia, and pseudarthrosis; however, the molecular mechanisms mediating these phenotypes remain unclear. Here, we provide genetic and pharmacologic evidence that hyperactive TGF-\u03b21 signaling pivotally underpins osseous defects in Nf1flox\/\u2212;Col2.3Cre mice, a model which closely recapitulates the skeletal abnormalities found in the human disease. Compared to controls, we show that serum TGF-\u03b21 levels are fivefold to sixfold increased both in Nf1flox\/\u2212;Col2.3Cre mice and in a cohort of NF1 patients. Nf1-deficient osteoblasts, the principal source of TGF-\u03b21 in bone, overexpress TGF-\u03b21 in a gene dosage\u2013dependent fashion. Moreover, Nf1-deficient osteoblasts and osteoclasts are hyperresponsive to TGF-\u03b21 stimulation, potentiating osteoclast bone resorptive activity while inhibiting osteoblast differentiation. These cellular phenotypes are further accompanied by p21-Ras\u2013dependent hyperactivation of the canonical TGF-\u03b21\u2013Smad pathway. Reexpression of the human, full-length neurofibromin guanosine triphosphatase (GTPase)-activating protein (GAP)-related domain (NF1 GRD) in primary Nf1-deficient osteoblast progenitors, attenuated TGF-\u03b21 expression levels and reduced Smad phosphorylation in response to TGF-\u03b21 stimulation. As an in vivo proof of principle, we demonstrate that administration of the TGF-\u03b2 receptor 1 (T\u03b2RI) kinase inhibitor, SD-208, can rescue bone mass deficits and prevent tibial fracture nonunion in Nf1flox\/\u2212;Col2.3Cre mice. In sum, these data demonstrate a pivotal role for hyperactive TGF-\u03b21 signaling in the pathogenesis of NF1-associated osteoporosis and pseudarthrosis, thus implicating the TGF-\u03b2 signaling pathway as a potential therapeutic target in the treatment of NF1 osseous defects that are refractory to current therapies. \u00a9 2013 American Society for Bone and Mineral Research.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1002\/jbmr.1992","type":"journal-article","created":{"date-parts":[[2013,5,23]],"date-time":"2013-05-23T13:18:26Z","timestamp":1369315106000},"page":"2476-2489","source":"Crossref","is-referenced-by-count":54,"title":["Hyperactive Transforming Growth Factor-\u03b21 Signaling Potentiates Skeletal Defects in a Neurofibromatosis Type 1 Mouse Model"],"prefix":"10.1093","volume":"28","author":[{"given":"Steven D","family":"Rhodes","sequence":"first","affiliation":[{"name":"Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indiana University School of MedicineIndianapolisINUSA"},{"name":"Department of Anatomy and Cell BiologyIndiana University School of MedicineIndianapolisINUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohua","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of PediatricsIndiana University School of MedicineIndianapolisINUSA"},{"name":"Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indiana University School of MedicineIndianapolisINUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongzheng","family":"He","sequence":"additional","affiliation":[{"name":"Department of PediatricsIndiana University School of MedicineIndianapolisINUSA"},{"name":"Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indiana University School of MedicineIndianapolisINUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shi","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of PediatricsIndiana University School of MedicineIndianapolisINUSA"},{"name":"Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indiana University School of MedicineIndianapolisINUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of PediatricsIndiana University School of MedicineIndianapolisINUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karl W","family":"Staser","sequence":"additional","affiliation":[{"name":"Department of PediatricsIndiana University School of MedicineIndianapolisINUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiapeng","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of PediatricsIndiana University School of MedicineIndianapolisINUSA"},{"name":"Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indiana University School of MedicineIndianapolisINUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of PediatricsIndiana University School of MedicineIndianapolisINUSA"},{"name":"Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indiana University School of MedicineIndianapolisINUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chang","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Biomedical EngineeringIndiana University\u2013Purdue UniversityIndianapolisINUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroki","family":"Yokota","sequence":"additional","affiliation":[{"name":"Department of Biomedical EngineeringIndiana University\u2013Purdue UniversityIndianapolisINUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruizhi","family":"Dong","sequence":"additional","affiliation":[{"name":"Department of PediatricsIndiana University School of MedicineIndianapolisINUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianghong","family":"Peng","sequence":"additional","affiliation":[{"name":"Endocrinology and Metabolism, Department of Internal Medicine, Indiana University School of MedicineIndianapolisINUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianlin","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of PediatricsIndiana University School of MedicineIndianapolisINUSA"},{"name":"Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indiana University School of MedicineIndianapolisINUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sreemala","family":"Murthy","sequence":"additional","affiliation":[{"name":"Endocrinology and Metabolism, Department of Internal Medicine, Indiana University School of MedicineIndianapolisINUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamad","family":"Azhar","sequence":"additional","affiliation":[{"name":"Department of PediatricsIndiana University School of MedicineIndianapolisINUSA"},{"name":"Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indiana University School of MedicineIndianapolisINUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khalid S","family":"Mohammad","sequence":"additional","affiliation":[{"name":"Endocrinology and Metabolism, Department of Internal Medicine, Indiana University School of MedicineIndianapolisINUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingjiang","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Medical and Molecular GeneticsIndiana University School of MedicineIndianapolisINUSA"},{"name":"Department of PediatricsIndiana University School of MedicineIndianapolisINUSA"},{"name":"Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indiana University School of MedicineIndianapolisINUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theresa A","family":"Guise","sequence":"additional","affiliation":[{"name":"Endocrinology and Metabolism, Department of Internal Medicine, Indiana University School of MedicineIndianapolisINUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng-Chun","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of PediatricsIndiana University School of MedicineIndianapolisINUSA"},{"name":"Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indiana University School of MedicineIndianapolisINUSA"},{"name":"Department of Anatomy and Cell BiologyIndiana University School of MedicineIndianapolisINUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2013,5,23]]},"reference":[{"key":"2024020318332241200_jbmr1992-bib-0001","first-page":"2","article-title":"The classic. Ununited fractures in children. 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Long-term followup of 29 cases treated by microvascular bone transfer","author":"Gilbert","year":"1995","journal-title":"Clin Orthop Relat Res."},{"issue":"1","key":"2024020318332241200_jbmr1992-bib-0005","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1097\/01202412-200001000-00002","article-title":"Pathology of bone lesions associated with congenital pseudarthrosis of the leg","volume":"9","author":"Ippolito","year":"2000","journal-title":"J Pediatr Orthop B."},{"issue":"4","key":"2024020318332241200_jbmr1992-bib-0006","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1097\/01.bpb.0000271310.87997.ae","article-title":"Decreased bone mineral density in neurofibromatosis type 1: results from a pediatric cohort","volume":"27","author":"Dulai","year":"2007","journal-title":"J Pediatr Orthop."},{"issue":"1","key":"2024020318332241200_jbmr1992-bib-0007","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.jpeds.2006.10.048","article-title":"Bone mineral density 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lowest local values are located in the load-carrying parts of the body","volume":"16","author":"Kuorilehto","year":"2005","journal-title":"Osteoporos Int."},{"issue":"9","key":"2024020318332241200_jbmr1992-bib-0011","doi-asserted-by":"crossref","first-page":"1161","DOI":"10.1007\/s00198-005-1940-2","article-title":"Decreased bone mineral density in patients with neurofibromatosis 1","volume":"16","author":"Lammert","year":"2005","journal-title":"Osteoporos Int."},{"key":"2024020318332241200_jbmr1992-bib-0012","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1097\/00003086-200208000-00013","article-title":"Orthopaedic manifestations of neurofibromatosis in children: an update","author":"Vitale","year":"2002","journal-title":"Clin Orthop Relat Res."},{"issue":"4","key":"2024020318332241200_jbmr1992-bib-0013","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1136\/jmg.2008.061895","article-title":"Bone health and fracture rate in individuals with neurofibromatosis 1 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