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Overcoming Radiation Induced Oral Fibrosis Through The Down Regulation Of Wnt Signaling Using Bmp-7 Inhibitors
Nicholas Guardino, B.S., Michelle Griffin, MD, PhD, Amanda Spielman, BS, Darren Abbas, MD, Megan King, BS, Jennifer Parker, BS, Derrick Wan, MD, Michael Longaker, MD.
Stanford School of Medicine, Menlo Park, CA, USA.

PURPOSE:Oral scarring is a common debilitating side effect of head and neck radiation therapy. With no effective treatment patients suffer long-term pain, taste dysfunction, and infection from radiation induced oral fibrosis. Previous work has suggested that Wnt signaling may contribute to radiation scaring in the oral mucosa. We have developed a preclinical in vivo murine model to study the effects of radiation damage on the oral mucosa. Our study evaluates the effects of Wnt pathway inhibitors to reduce scarring in the oral mucosa following irradiation. METHODS:Adult C57Bl/6 mice (6-8-week-old) (n = 6) were randomized to one of three conditions: 1. Treated with 30 Gy external beam irradiation to the oral mucosa delivered as six fractionated doses of 5Gy over a period of 12 days (irradiation group), 2. Irradiation to the oral mucosa with simultaneous treatment with a Bone Morphogenetic Protein 7 (BMP-7) inhibitor (BMP-7) (treatment group), and 3. No irradiation and no treatment (control group). Mice were euthanized at 4 weeks post irradiation for histological and flow cytometry analysis. Oral sections underwent immunofluorescent staining for fibrosis (e.g., collagen type I/col-I, alpha smooth muscle actin/a-SMA), vascularization (CD31 staining), inflammation (F4/80 antigen), and Wnt signaling (e.g., axin2, Wnt1) markers and were imaged on a confocal microscope. RESULTS:Histological analysis by H&E staining confirmed dermal thickening and increased collagen content in the irradiated group compared to the control group (p < 0.05), confirming the reproducibility of the murine model to induce oral fibrosis. BMP-7 inhibitor treatment decreased the dermal and epidermal thickening observed in the irradiated group (p < 0.05). The treatment group also demonstrated reduced dermal fibrosis with decreased col-I and a-SMA staining compared to the irradiation group (p < 0.05). Flow cytometry analysis further showed reduced numbers of profibrotic fibroblasts (CD26+) in the treatment compared to the irradiation group (p < 0.05). Immunofluorescence staining confirmed significantly high levels of Wnt pathway protein signaling (Axin2, Wnt1) in the irradiation group compared to the treatment and control group (p < 0.05). Mice receiving the BMP-7 inhibitor also demonstrated improved vascularization as shown by CD31 staining and a decreased inflammatory infiltrate evidenced by F4/80 macrophage staining (p < 0.05). CONCLUSION:
Our novel murine model suggests that canonical Wnt signaling may be responsible for oral scarring post irradiation. Targeting Wnt signaling through BMP-7 inhibitors may be an effective method to reduce the burden of radiation induced oral fibrosis.


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