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+;Nf1flox/− and Col2.3Cre+;Nf1flox/−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.
Highlights
Bone integrity is maintained by the balance between osteoclasts originated from hematopoietic stem cells and mesenchymalderived osteoblasts
Our study provides strong evidence of a non-cell autonomous mechanism for the skeletal manifestations of neurofibromatosis type 1 (NF1) and demonstrates that the hematopoietic microenvironment is instrumental for bone loss and impaired fracture healing process
To confirm 3.9 kb Periostin fragment promoter mediated Cre expression in adult mesenchymal stem/ progenitor cells (MSCs) and skeletal tissues, PeriCre+ mice were intercrossed with transgenic reporter mice that have LacZ sequence knocked into the Rosa26 locus
Summary
Bone integrity is maintained by the balance between osteoclasts originated from hematopoietic stem cells and mesenchymalderived osteoblasts. The development of the osteoblast and osteoclast lineages is tightly coupled [1]. Imbalances in coupling of the two lineages leads to defective skeletal development [2] as well as abnormal hematopoiesis [3,4]. Clinical studies have found that individuals with NF1 are at significant risk for generalized loss of bone mass (osteopenia and osteoporosis) [21,22,23,24,25,26] as well as focal skeletal abnormalities [25,27,28,29]. Non-union of spontaneous fractures, called pseudoarthrosis, is debilitating and frequently affects the distal tibia. Despite a range of orthopedic procedures attempting to facilitate fracture healing, the typical clinical outcome is non-union of the fracture and amputation of the affected limbs
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