Tibial pseudarthrosis causes substantial morbidity in patients with neurofibromatosis type 1 (NF1). We studied tibial pseudarthrosis tissue from patients with NF1 and found elevated levels of b-catenin compared to unaffected bone. To elucidate the role of b-catenin in fracture healing, we used a surgically induced tibial fracture model in conditional knockout (KO) Nfl (Nf1 flox/flox ) mice. When treated with a Cre-expressing adenovirus (Ad-Cre), there was a localized knockdown of Nf1 in the healing fracture and a subsequent development of a fibrous pseudarthrosis. Consistent with human data, elevated b-catenin levels were found in the murine fracture sites. The increased fibrous tissue at the fracture site was rescued by local treatment with a Wingless-type MMTV integration site (Wnt) antagonist, Dickkopf-1 (Dkk1). The murine pseudarthrosis phenotype was also rescued by conditional b-catenin gene inactivation. The number of colony-forming unit osteoblasts (CFU-Os), a surrogate marker of undifferentiated mesenchymal cells able to differentiate to osteoblasts, correlated with the capacity to form bone at the fracture site. Our findings indicate that the protein level of b-catenin must be precisely regulated for normal osteoblast differentiation. An up-regulation of b-catenin in NF1 causes a shift away from osteoblastic differentiation resulting in a pseudarthrosis in vivo. These results support the notion that pharmacological modulation of b-catenin can be used to treat pseudarthrosis in patients with NF1.-Ghadakzadeh, S., Kannu, P., Whetstone, H., Howard A., Alman, B. A. b-catenin modulation in neurofibromatosis type 1 bone repair: therapeutic implications. FASEB J. 30, 3227-3237 (2016). www.fasebj.orgNeurofibromatosis type 1 (NF1) is an autosomal dominant disorder characterized by activated RAS signaling and mutations that dysregulate the NF1 protein (neurofibromin). NF1-related skeletal abnormalities are an important cause of morbidity with osteoporosis, scoliosis, and tibial dysplasia affecting more than half of affected individuals. Tibial dysplasia typically starts with anterolateral tibial bowing, characteristically progressing to a fracture that will not heal, termed a pseudarthrosis. Normal fracture healing is characterized by the deposition of new bone from osteoblasts, followed by a period of remodeling in which osteoclasts are active. At the tibial pseudarthrosis fracture site, however, is fibrous hamartoma tissue contain cells that do not undergo osteoblastic differentiation form. There is also an increase in osteoclastogenic activity at the fracture site, when compared to the healing in a normal fractured tibia (1-4). Because tibial pseudarthrosis is refractive to medical treatment, the only management options are surgical. For those continuing to experience chronic pain and impaired mobility, an amputation may be required if other treatments are not effective.Germline heterozygous mutations of NF1 cause NF1. In some but not all NF1-related tibial pseudarthrosis, a second hit to the NF1 gen...