Testing a Novel Therapy to Treat NF1-Related Skeletal Defects
Abstract
Neurofibromatosis type 1 (NF1) is a tumor-predisposing syndrome that affects multiple organ systems. With regard to the skeletal system, individuals with NF1 may have osteopenia (weak bones) or may develop scoliosis. In children, the most debilitating skeletal abnormality is congenital tibial dysplasia (bowing of the lower leg). Treatment may involve bracing to support the bowed leg in hopes of preventing fracture. Unfortunately, the tibia often fractures. Unlike typical fractures, tibia fractures in NF1 often fail to heal despite numerous surgeries over several years. Often, the persistent fracture requires amputation. At a cellular level, the fracture persists, at least in part, because the bone marrow stem cells that typically turn into bone-forming osteoblast cells are unable to do so. Thus, the fracture often fails to heal or, if it does heal, is prone to re-fracture and eventual amputation. At present, there are no proven therapies to improve fracture healing in these children. The goals of our research are to understand why stem cells fail to mature into osteoblasts following fracture, identify potential new therapies, and test whether these therapies improve skeletal development and fracture healing. Our proposed study will test whether a newly discovered protein improves osteoblast formation, and thus skeletal development, in the setting of NF1. This protein, called Osteolectin, is known to be sufficient to convert stem cells into bone-forming osteoblasts. The potential of Osteolectin as a therapy was also recently tested in mice, with promising results. When injected under the skin of mice, Osteolectin improved bone quality and, surprisingly, prevented bone loss in a mouse model of osteoporosis. Furthermore, in a separate experiment, Osteolectin therapy successfully reversed osteoporosis in mice. Consequently, Osteolectin is the most promising new potential therapy for conditions marked by bone deficiency, and we are encouraged to assess its potential to improve NF1-related skeletal disease. Our research group has pioneered the study of bone cells from NF1 patients. We study tissues that are removed at the time of surgery to understand the reasons why bone stem cells fail to become osteoblasts. Using this approach, we have shown in detail how cells from an NF1 tibia fracture are different, and our results have begun to provide clues as to why these cells do not form osteoblasts. Our unique capabilities and resources enable us to directly test novel therapies using cells from human patients. For this study, we will test whether Osteolectin therapy causes cells from a tibia fracture to properly form osteoblasts. Furthermore, we will test whether Osteolectin reverses abnormalities that occur in a commonly used mouse model of NF1 skeletal disease. If successful, Osteolectin may be an eventual therapeutic option for improving bone healing following fracture in individuals with NF1. Clinical applications for such a therapy extend far beyond tibia fracture, possibly addressing scoliosis and osteopenia (bone weakness). Together with the University of Texas (UT) Southwestern Medical Center’s Center for Translational Medicine and the UT Southwestern BioCenter, we will bring together the resources and expertise needed to translate promising therapies from the laboratory to the clinic, which will usher in a new outlook on the treatment and management of skeletal manifestations associated with NF1.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810817
Entities
People
- Jonathan J. Rios
Organizations
- United States Army
- University of Texas Southwestern Medical Center