β-Catenin modulation in neurofibromatosis type 1 bone repair: therapeutic implications.
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 β-catenin compared to unaffected bone. To elucidate the role of β-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 β-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 β-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 β-catenin must be precisely regulated for normal osteoblast differentiation. An up-regulation of β-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 β-catenin can be used to treat pseudarthrosis in patients with NF1.-Ghadakzadeh, S., Kannu, P., Whetstone, H., Howard A., Alman, B. A. β-catenin modulation in neurofibromatosis type 1 bone repair: therapeutic implications.
Division of Developmental and Stem Cell Biology, University of Toronto, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada;
Saber
S
Ghadakzadeh
Division of Developmental and Stem Cell Biology, University of Toronto, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada; Bone Health Centre, Hospital for Sick Children, Toronto, Ontario, Canada;
Peter
P
Kannu
Division of Developmental and Stem Cell Biology, University of Toronto, Toronto, Ontario, Canada;
Heather
H
Whetstone
Bone Health Centre, Hospital for Sick Children, Toronto, Ontario, Canada; Division of Orthopaedic Surgery, Hospital for Sick Children, Toronto, Ontario, Canada; and.
Andrew
A
Howard
Division of Developmental and Stem Cell Biology, University of Toronto, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada; Department of Orthopaedic Surgery, Duke University, Durham, North Carolina, USA ben.alman@duke.edu.
Benjamin A
BA
Alman
D000818:Animals; D001696:Biomechanical Phenomena; D017102:Fracture Healing / Q000502:physiology; D050723:Fractures, Bone / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009456:Neurofibromatosis 1 / Q000150:complications / Q000235:genetics / Q000378:metabolism*; D010010:Osteoclasts; D011542:Pseudarthrosis / Q000378:metabolism / Q000628:therapy; D015398:Signal Transduction; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
D051176:beta Catenin
Wnt signaling; fracture nonunion; neurofibromin; osteoblast differentiation; tibial congenital pseudarthrosis