Hyperactive transforming growth factor-β1 signaling potentiates skeletal defects in a neurofibromatosis type 1 mouse model

Steven D. Rhodes, Xiaohua Wu, Yongzheng He, Shi Chen, Hao Yang, Karl W. Staser, Jiapeng Wang, Ping Zhang, Chang Jiang, Hiroki Yokota, Ruizhi Dong, Xianghong Peng, Xianlin Yang, Sreemala Murthy, Mohamad Azhar, Khalid Mohammad, Mingjiang Xu, Theresa Guise, Feng Chun Yang

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Dysregulated transforming growth factor beta (TGF-β) 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-β1 signaling pivotally underpins osseous defects in Nf1flox/-;Col2.3Cre mice, a model which closely recapitulates the skeletal abnormalities found in the human disease. Compared to controls, we show that serum TGF-β1 levels are fivefold to sixfold increased both in Nf1flox/-;Col2.3Cre mice and in a cohort of NF1 patients. Nf1-deficient osteoblasts, the principal source of TGF-β1 in bone, overexpress TGF-β1 in a gene dosage-dependent fashion. Moreover, Nf1-deficient osteoblasts and osteoclasts are hyperresponsive to TGF-β1 stimulation, potentiating osteoclast bone resorptive activity while inhibiting osteoblast differentiation. These cellular phenotypes are further accompanied by p21-Ras-dependent hyperactivation of the canonical TGF-β1-Smad 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-β1 expression levels and reduced Smad phosphorylation in response to TGF-β1 stimulation. As an in vivo proof of principle, we demonstrate that administration of the TGF-β receptor 1 (TβRI) kinase inhibitor, SD-208, can rescue bone mass deficits and prevent tibial fracture nonunion in Nf1flox/-;Col2.3Cre mice. In sum, these data demonstrate a pivotal role for hyperactive TGF-β1 signaling in the pathogenesis of NF1-associated osteoporosis and pseudarthrosis, thus implicating the TGF-β signaling pathway as a potential therapeutic target in the treatment of NF1 osseous defects that are refractory to current therapies.

Original languageEnglish
Pages (from-to)2476-2489
Number of pages14
JournalJournal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
Volume28
Issue number12
DOIs
StatePublished - Dec 2013

Fingerprint

Neurofibromatosis 1
Transforming Growth Factors
Transforming Growth Factor beta
Osteoblasts
Pseudarthrosis
Osteoclasts
Bone and Bones
Osteoporosis
Loeys-Dietz Syndrome
Camurati-Engelmann Syndrome
Neurofibromin 1
Proto-Oncogene Proteins p21(ras)
Phenotype
Marfan Syndrome
Tibial Fractures
Gene Dosage
Guanosine
Phosphotransferases
Therapeutics
Phosphorylation

Keywords

  • fracture nonunion
  • neurofibromatosis type 1
  • osteoporosis
  • smad
  • tgf-β
  • Transforming growth factor-beta

ASJC Scopus subject areas

  • Orthopedics and Sports Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Hyperactive transforming growth factor-β1 signaling potentiates skeletal defects in a neurofibromatosis type 1 mouse model. / Rhodes, Steven D.; Wu, Xiaohua; He, Yongzheng; Chen, Shi; Yang, Hao; Staser, Karl W.; Wang, Jiapeng; Zhang, Ping; Jiang, Chang; Yokota, Hiroki; Dong, Ruizhi; Peng, Xianghong; Yang, Xianlin; Murthy, Sreemala; Azhar, Mohamad; Mohammad, Khalid; Xu, Mingjiang; Guise, Theresa; Yang, Feng Chun.

In: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research, Vol. 28, No. 12, 12.2013, p. 2476-2489.

Research output: Contribution to journalArticle

Rhodes, SD, Wu, X, He, Y, Chen, S, Yang, H, Staser, KW, Wang, J, Zhang, P, Jiang, C, Yokota, H, Dong, R, Peng, X, Yang, X, Murthy, S, Azhar, M, Mohammad, K, Xu, M, Guise, T & Yang, FC 2013, 'Hyperactive transforming growth factor-β1 signaling potentiates skeletal defects in a neurofibromatosis type 1 mouse model', Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research, vol. 28, no. 12, pp. 2476-2489. https://doi.org/10.1002/jbmr.1992
Rhodes, Steven D. ; Wu, Xiaohua ; He, Yongzheng ; Chen, Shi ; Yang, Hao ; Staser, Karl W. ; Wang, Jiapeng ; Zhang, Ping ; Jiang, Chang ; Yokota, Hiroki ; Dong, Ruizhi ; Peng, Xianghong ; Yang, Xianlin ; Murthy, Sreemala ; Azhar, Mohamad ; Mohammad, Khalid ; Xu, Mingjiang ; Guise, Theresa ; Yang, Feng Chun. / Hyperactive transforming growth factor-β1 signaling potentiates skeletal defects in a neurofibromatosis type 1 mouse model. In: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2013 ; Vol. 28, No. 12. pp. 2476-2489.
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AU - Wu, Xiaohua

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AU - Chen, Shi

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AU - Staser, Karl W.

AU - Wang, Jiapeng

AU - Zhang, Ping

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AU - Yang, Xianlin

AU - Murthy, Sreemala

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