Bone pseudoarthrosis is a debilitating defect of bone healing. Both fracture and pseudoarthrosis represent the epiphenomena of an underlying, localized congenital disorder of skeletal tissues that alters the process of bone growth and remodeling and jeopardizes both the development of a mechanically sound internal structure and the process of bone repair. The etiopathology of pseudoarthrosis remains to be defined for the establishment of adapted therapies. Bone healing involves four main cell types: mesenchymal stem cells (MSCs), chondrocytes, osteoblasts and osteoclasts. To date, evidence suggests that lack of Nf1 in bone forming cells is responsible for NF1 (neurofibromatosis) pseudoarthrosis, but the cell types involved remain unidentified. The challenges today are to identify the cell types whose function is impaired in NF1 pseudoarthrosis, to characterize the defects associated with loss of function of Nf1 in this cell type, and based on this knowledge to propose adapted strategies to correct these defects. In this proposal, we ask whether Nf1 haplo-insufficiency or Nf1 loss of function in three specific bone cell types, chondrocytes, osteoblasts or their common precursor, MSCs, impairs bone healing. To address this question, we propose to use Nf1+/- mice and conditional mouse models lacking one or both copies of Nf1 specifically in MSCs, chondrocytes or osteoblasts in bone repair studies. With these mouse models in hand, it will possible to determine whether one or two copies of Nf1 is required for the formation of a cartilaginous callus by chondrocytes or for the calcification and remodeling of this callus by osteoblasts following fracture (Specific Aim I and II). We also designed studies aimed at characterizing a new therapeutic approach for treating bone pseudoarthrosis, based on our previous work (R21AR053978-01) and the ERK inhibitory property of PD19830 and lovastatin to correct the defects of Nf1-/- osteoblasts (Specific Aim III). The studies proposed in this application aim at characterizing novel pathways and genes regulating bone remodeling and repair, with the long-term goals of better understanding skeleton diseases and proposing adapted therapies. We expect our studies 1) to characterize the role of Nf1 at specific stages of bone repair in specific bone cell types, 2) to characterize novel therapeutic targets and strategies to identify the most appropriate treatment for this syndrome and 3) to provide new mouse models that can be used as pre-clinical tools.

Public Health Relevance

The studies proposed in this application aim at characterizing the molecular defects of NF1 bone pseudoarthrosis by the generation of new mouse models, subsequently used as pre-clinical models to test the corrective effect of various pharmacological agents on bone healing.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR055966-04
Application #
8290410
Study Section
Skeletal Biology Structure and Regeneration Study Section (SBSR)
Program Officer
Wang, Fei
Project Start
2009-07-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
4
Fiscal Year
2012
Total Cost
$328,244
Indirect Cost
$114,404
Name
Vanderbilt University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
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Karolak, Matthew R; Yang, Xiangli; Elefteriou, Florent (2015) FGFR1 signaling in hypertrophic chondrocytes is attenuated by the Ras-GAP neurofibromin during endochondral bone formation. Hum Mol Genet 24:2552-64
de la Croix Ndong, Jean; Stevens, David M; Vignaux, Guillaume et al. (2015) Combined MEK inhibition and BMP2 treatment promotes osteoblast differentiation and bone healing in Nf1Osx -/- mice. J Bone Miner Res 30:55-63
de la Croix Ndong, Jean; Makowski, Alexander J; Uppuganti, Sasidhar et al. (2014) Asfotase-? improves bone growth, mineralization and strength in mouse models of neurofibromatosis type-1. Nat Med 20:904-10
Wang, Weixi; Nyman, Jeffry S; Ono, Koichiro et al. (2011) Mice lacking Nf1 in osteochondroprogenitor cells display skeletal dysplasia similar to patients with neurofibromatosis type I. Hum Mol Genet 20:3910-24
Wang, Weixi; Nyman, Jeffry S; Moss, Heather E et al. (2010) Local low-dose lovastatin delivery improves the bone-healing defect caused by Nf1 loss of function in osteoblasts. J Bone Miner Res 25:1658-67