R-Spondin1 protects mice from chemotherapy or radiation-induced oral mucositis through the canonical Wnt/beta-catenin pathway.
R-Spondin1 (RSpo1) is a novel secreted protein that augments canonical Wnt/beta-catenin signaling. We injected recombinant RSpo1 protein into transgenic Wnt reporter TOPGAL mice and have identified the oral mucosa as a target tissue for RSpo1. Administration of RSpo1 into normal mice triggered nuclear translocation of beta-catenin and resulted in increased basal layer cellularity, thickened mucosa, and elevated epithelial cell proliferation in tongue. We herein evaluated the therapeutic potential of RSpo1 in treating chemotherapy or radiotherapy-induced oral mucositis in several mouse models. Prophylactic treatment with RSpo1 dose-dependently overcame the reduction of basal layer epithelial cellularity, mucosal thickness, and epithelial cell proliferation in tongues of mice exposed to whole-body irradiation. RSpo1 administration also substantially alleviated tongue mucositis in the oral cavity of mice receiving concomitant 5-fluorouracil and x-ray radiation. Furthermore, RSpo1 significantly reduced the extent of tongue ulceration in mice receiving a single fraction, high dose head-only radiation in a dose-dependent manner. Moreover, combined therapy of RSpo1 and keratinocyte growth factor resulted in complete healing of tongue ulcers in mice subjected to snout-only irradiation. In conclusion, our results demonstrate RSpo1 to be a potent therapeutic agent for oral mucositis by enhancing basal layer epithelial regeneration and accelerating mucosal repair through up-regulation of Wnt/beta-catenin pathway.
Zhao
Jingsong
J
Department of Research, Nuvelo, Inc., 201 Industrial Road, Suite 310, San Carlos, CA 94070, USA. jingsongzhao@yahoo.com
Kim
Kyung-Ah
KA
De Vera
Josephine
J
Palencia
Servando
S
Wagle
Marie
M
Abo
Arie
A
D000818:Animals; D005786:Gene Expression Regulation; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D015603:Keratinocytes / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D009055:Mouth / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects*; D052016:Mucositis / Q000378:metabolism / Q000473:pathology*; D011994:Recombinant Proteins / Q000737:chemistry; D019699:Thrombospondins / Q000096:biosynthesis*; D013997:Time Factors; D014059:Tongue / Q000187:drug effects; D014456:Ulcer; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
C501127:Dkk1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; C518903:RSPO1 protein, mouse; D011994:Recombinant Proteins; D019699:Thrombospondins; D051153:Wnt Proteins; D051176:beta Catenin