Skeletal Complications in Neurofibromatosis Type 1: The Role of Neurofibromin Haploinsufficiency in Defective Skeletal Remodeling and Bone Healing in NF1
Abstract
A large proportion of patients with Neurofibromatosis Type 1 display skeletal abnormalities including scoliosis and pseudoarthrosis which are compounded by osteoporosis and poor bone healing. Corrective orthopaedic intervention often fails necessitating multiple revision surgeries followed by prolonged recovery periods. The cell types and pathway by which neurofibromin haploinsufficiency (Nf1 +/-) leads to dysregulation of bone remodeling and healing are unknown. The aim of this study is to identify the cell types expressing Nf1 in normal bone cell physiology and fracture healing. We demonstrate that in normal mouse bones neurofibromin is primarily expressed by cells of the osteoblast lineage. Neurofibromin expression was also induced during osteoblastic differentiation of MC3T3 cells. We found that during fracture repair neurofibromin expression increased in the early stage and was seen at sites of primary bone formation. Taken together these observations indicate that neurofibromin expression is primarily associated with bone-adherent osteoblast lineage cells with minimal expression in other cell types. In addition neurofibromin expression is induced during the formation of the mineralized callus in the endochondral-like formation stage of bone fracture healing. Neurofibromin haploinsufficiency may keep osteoblasts in an immature state. Immature osteoblasts produce large quantities of the osteoclastogenic cytokine RANKL. A high RANKL environment would shift the balance of bone metabolism in favor of bone resorption and may result in the bone-healing defect seen in NF1 patients.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jan 01, 2007
- Accession Number
- ADA468693
Entities
People
- Kevin P. Mchugh
Organizations
- Beth Israel Deaconess Medical Center