Hyperactive Ras/MAPK signaling is critical for tibial nonunion fracture in neurobromin-decient mice

Richa Sharma, Xiaohua Wu, Steven D. Rhodes, Shi Chen, Yongzheng He, Jin Yuan, Jiliang Li, Xianlin Yang, Xiaohong Li, Li Jiang, Edward T. Kim, David A. Stevenson, David Viskochil, Mingjiang Xu, Feng Chun Yang

Research output: Contribution to journalArticle

27 Scopus citations

Abstract

Neurobromatosis type 1 (NF1) is a common genetic disorder affecting 1 in 3500 individuals. Patients with NF1 are predisposed to de bilitating skeletal manifestations, including osteopenia/osteoporosis and long bone pseu-darthrosis (nonunion fracture).Hyperactivation of the Ras/mitogen-activated protein kinase (MAPK) pathway in NF1 is known to underlie aberrant proliferation and differentiation in cell lineages, including osteoclast progeni-tors andmesenchymal stemcells (MSCs) also known as osteoblast progenitors (pro-OBLs). Our current study demonstrates the hyper Ras/MAPKas a critical pathway underlying the pathogenesis of NF1-associated fracture repair decits. Nf1-decient pro-OBLs exhibit Ras/MAPK hyperactivation. Introduction of the NF1 GTPase acti-vating-related domain (NF1 GAP-related domain) in vitro is sufcient to rescue hyper Ras activity and enhance osteoblast (OBL) differentiation in Nf1-/- pro-OBLs and NF1 human (h) MSCs cultured from NF1 patients with skeletal abnormalities, including pseudarthrosis or scoliosis. Pharmacologic inhibition of mitogen-activated protein kinase kinase (MEK) signaling with PD98059 partially rescues aberrant Erk activation while enhancing OBL differentiation and expression of OBL markers, osterix and osteocalcin, in Nf1-decient murine pro-OBLs. Similarly,MEK inhibition enhancesOBL differentiation of hMSCs. In addition, PD98059 rescues aberrant osteoclastmaturation in Nf1 haploinsufcient bonemarrowmononuclear cells (BMMNCs). Importantly,MEKin-hibitor signicantly improves fracture healing in an NF1 murine model, Col2.3Cre;Nf1ox/2. Collectively, these data indicate the Ras/MAPK cascade as a critical pathway in the pathogenesis of bone loss and pseudarthrosis relatedtoNF1mutations.These studiesprovide evidence for targeting the MAPK pathway to improve bone mass and treat pseudarthrosis in NF1.

Original languageEnglish (US)
Article numberddt333
Pages (from-to)4818-4828
Number of pages11
JournalHuman molecular genetics
Volume22
Issue number23
DOIs
StatePublished - Dec 1 2013

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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    Sharma, R., Wu, X., Rhodes, S. D., Chen, S., He, Y., Yuan, J., Li, J., Yang, X., Li, X., Jiang, L., Kim, E. T., Stevenson, D. A., Viskochil, D., Xu, M., & Yang, F. C. (2013). Hyperactive Ras/MAPK signaling is critical for tibial nonunion fracture in neurobromin-decient mice. Human molecular genetics, 22(23), 4818-4828. [ddt333]. https://doi.org/10.1093/hmg/ddt333