JNK inhibitor CC-930 reduces fibrosis in a murine model of Nf1-deficient fracture repair

Publication date: Available online 13 February 2018Source: Journal of Applied BiomedicineAuthor(s): Nikita Deo, Jad El-Hoss, Mille Kolind, Kathy Mikulec, Lauren Peacock, David G. Little, Aaron SchindelerAbstractTibial pseudarthrosis often features deficient bone formation, excessive bone resorption, and extensive pathological fibrosis, particularly in individuals with Neurofibromatosis type I (NF1). It was hypothesized that overactive NF1-Ras-JNK signalling may underlie the pathological fibrosis, and that this could be treated via a JNK antagonist. CC-930, a small molecule JNK inhibitor, was trialed in closed fractures in wild type mice CC-930 (25 mg/kg/twice daily) was dosed throughout fracture healing (D2–21) and during the latter stages of repair (D11–21). All fractures healed by D21, regardless of treatment, with some of the CC-930 (D11–21) treatment group showing early bridging. CC-930 (D11–21) was tested in an Nf1-null fracture model where Nf1 was inactivated by Ad-Cre virus injection in Nf1flox/flox mice; these mice also possessed a Cre-responsive tdTomato transgene. CC-930 resulted in a significant decrease in non-unions (93% vehicle vs. 64% CC-930, p < 0.01). Local treatment with the bone anabolic rhBMP-2 (10 μg) increased union and callus bone volume, but also increased the fibrotic tissue at the fracture site. Fractures treated with a combination of rhBMP-2 (10 μg) and CC-930 were all partially or fully bridged by D21 (p < 0.01 vs. veh...
Source: Journal of Applied Biomedicine - Category: Biotechnology Source Type: research