R-spondin1, a novel intestinotrophic mitogen, ameliorates experimental colitis in mice.
OBJECTIVE
R-spondin 1 (Rspo1) is a novel epithelial mitogen that stimulates the growth of mucosa in both the small and large intestine.


METHODS
We investigated the therapeutic potential of Rspo1 in ameliorating experimental colitis induced by dextran sulfate sodium (DSS) or trinitrobenzene sulfonic acid (TNBS) as well as nonsteroidal anti-inflammatory drug-induced colitis in interleukin (IL)-10-deficient mice.


RESULTS
Therapeutic administration of recombinant Rspo1 protein reduced the loss of body weight, diarrhea, and rectal bleeding in a mouse model of acute or chronic DSS-induced colitis. Histologic evaluation revealed that Rspo1 improved mucosal integrity in both villus and/or crypt compartments in the small intestine and colon by stimulating crypt cell growth and mucosal regeneration in DSS-treated mice. Moreover, Rspo1 significantly reduced DSS-induced myeloperoxidase activity and inhibited the overproduction of proinflammatory cytokines, including tumor necrosis factor-alpha, IL-1alpha, IL-6, interferon-gamma, and granulocyte-macrophage colony-stimulating factor, in mouse intestinal tissue, indicating that Rspo1 may reduce DSS-induced inflammation by preserving the mucosal barrier function. Likewise, Rspo1 therapy also alleviated TNBS-induced interstitial inflammation and mucosal erosion in the mouse colon. Furthermore, Rspo1 substantially decreased the histopathologic severity of chronic enterocolitis by repairing crypt epithelium and simultaneously suppressing inflammatory infiltration in piroxicam-exposed IL-10(-/-) mice. Endogenous Rspo1 protein was localized to villus epithelium and crypt Paneth cells in mouse small intestine.


CONCLUSIONS
Our results show that Rspo1 may be clinically useful in the therapeutic treatment of inflammatory bowel disease by stimulating crypt cell growth, accelerating mucosal regeneration, and restoring intestinal architecture.
Zhao
Jingsong
J
Department of Research, Nuvelo, Inc, San Carlos, California, USA. jzhao@nuvelo.com
de Vera
Josephine
J
Narushima
Seiko
S
Beck
Eric X
EX
Palencia
Servando
S
Shinkawa
Pauline
P
Kim
Kyung-Ah
KA
Liu
Yi
Y
Levy
Michael D
MD
Berg
Daniel J
DJ
Abo
Arie
A
Funk
Walter D
WD
D000208:Acute Disease; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000633:toxicity; D049109:Cell Proliferation / Q000187:drug effects; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D003106:Colon / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D016264:Dextran Sulfate / Q000633:toxicity; D004195:Disease Models, Animal; D005260:Female; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000187:drug effects / Q000473:pathology; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008934:Mitogens / Q000627:therapeutic use*; D010894:Piroxicam / Q000633:toxicity; D010952:Plasma Substitutes / Q000633:toxicity; D011994:Recombinant Proteins / Q000627:therapeutic use; D012720:Severity of Illness Index; D019699:Thrombospondins / Q000627:therapeutic use*; D016896:Treatment Outcome; D014302:Trinitrobenzenesulfonic Acid / Q000633:toxicity
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D008934:Mitogens; D010952:Plasma Substitutes; C518903:RSPO1 protein, mouse; D011994:Recombinant Proteins; D019699:Thrombospondins; D010894:Piroxicam; D014302:Trinitrobenzenesulfonic Acid; D016264:Dextran Sulfate