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The haploinsufficient hematopoietic microenvironment is critical to the pathological fracture repair in murine models of neurofibromatosis type 1
- Source :
- PLoS ONE, Vol 6, Iss 9, p e24917 (2011), PLoS ONE
- Publication Year :
- 2011
- Publisher :
- Public Library of Science (PLoS), 2011.
-
Abstract
- Germline mutations in the NF1 tumor suppressor gene cause neurofibromatosis type 1 (NF1), a complex genetic disorder with a high predisposition of numerous skeletal dysplasias including short stature, osteoporosis, kyphoscoliosis, and fracture non-union (pseudoarthrosis). We have developed murine models that phenocopy many of the skeletal dysplasias observed in NF1 patients, including reduced bone mass and fracture non-union. We also show that the development of these skeletal manifestations requires an Nf1 haploinsufficient background in addition to nullizygous loss of Nf1 in mesenchymal stem/progenitor cells (MSCs) and/or their progenies. This is replicated in two animal models of NF1, PeriCre(+);Nf1(flox/-) and Col2.3Cre(+);Nf1(flox/-) mice. Adoptive transfer experiments demonstrate a critical role of the Nf1+/- marrow microenvironment in the impaired fracture healing in both models and adoptive transfer of WT bone marrow cells improves fracture healing in these mice. To our knowledge, this is the first demonstration of a non-cell autonomous mechanism in non-malignant NF1 manifestations. Collectively, these data provide evidence of a combinatory effect between nullizygous loss of Nf1 in osteoblast progenitors and haploinsufficiency in hematopoietic cells in the development of non-malignant NF1 manifestations.
- Subjects :
- Pathology
Anatomy and Physiology
Mouse
lcsh:Medicine
Haploinsufficiency
Mice
0302 clinical medicine
Bone Density
Bone Marrow
Immune Physiology
Molecular Cell Biology
Bone Marrow and Stem Cell Transplantation
lcsh:Science
Musculoskeletal System
Fracture Healing
0303 health sciences
Multidisciplinary
Stem Cells
Animal Models
Hematology
medicine.anatomical_structure
Autosomal Dominant
Medicine
Cellular Types
Research Article
medicine.medical_specialty
congenital, hereditary, and neonatal diseases and abnormalities
Neurofibromatosis 1
Tumor suppressor gene
Immunology
030209 endocrinology & metabolism
Mice, Transgenic
Bone healing
Biology
03 medical and health sciences
Model Organisms
Genes, Neurofibromatosis 1
medicine
Genetics
Animals
Progenitor cell
Neurofibromatosis
Bone
neoplasms
Crosses, Genetic
Germ-Line Mutation
030304 developmental biology
Phenocopy
Clinical Genetics
Osteoblasts
lcsh:R
Mesenchymal Stem Cells
Human Genetics
Bone fracture
medicine.disease
Hematopoietic Stem Cells
beta-Galactosidase
eye diseases
nervous system diseases
Disease Models, Animal
Immune System
Clinical Immunology
lcsh:Q
Bone marrow
Neurofibromatosis Type 1
Developmental Biology
Subjects
Details
- Language :
- English
- ISSN :
- 19326203
- Volume :
- 6
- Issue :
- 9
- Database :
- OpenAIRE
- Journal :
- PLoS ONE
- Accession number :
- edsair.doi.dedup.....e4c92db38f573e67985a0d8dcb9d5c2c