title: Targeting mRNA stability arrests inflammatory bone loss.
abstract: Many proinflammatory cytokines contain adenylate-uridylate-rich elements (AREs) within the 3'-untranslated region (UTR) that confer rapid mRNA destabilization. During the inflammatory response, cytokine mRNA are stabilized via complex interactions with RNA-binding proteins controlled by phosphorylation via multiple signaling pathways including the mitogen-activated protein kinases (MAPKs). In the absence of inflammation, a key cytokine-regulating RNA-binding protein, tristetraprolin (TTP), shuttles mRNA transcripts to degradation machinery in order to maintain low levels of inflammatory cytokines. Using this general model of mRNA decay, over expression of TTP was evaluated in an experimental model of inflammatory bone loss to determine whether altering cytokine mRNA stability has an impact in pathological bone resorption. Using adenoviral-delivered TTP, significant reductions of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and prostaglandin (PG)E(2) were observed in vitro through a mechanism consistent with targeting mRNA stability. In vivo analysis indicates a significant protective effect from inflammation-induced bone loss and inflammatory infiltrate in animals overexpressing TTP compared with reporter controls. These findings provide experimental evidence that mRNA stability is a valid therapeutic target in inflammatory bone loss.
authors.affiliation: Department of Periodontics and Oral Medicine, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Chetan S
authors.initials: CS
authors.lastname: Patil
authors.forename: Min
authors.initials: M
authors.lastname: Liu
authors.forename: Wenpu
authors.initials: W
authors.lastname: Zhao
authors.forename: Derek D
authors.initials: DD
authors.lastname: Coatney
authors.forename: Fei
authors.initials: F
authors.lastname: Li
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: VanTubergen
authors.forename: Nisha J
authors.initials: NJ
authors.lastname: D'Silva
authors.forename: Keith L
authors.initials: KL
authors.lastname: Kirkwood
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001851:Bone Diseases, Metabolic / Q000628:therapy*; D002460:Cell Line; D015232:Dinoprostone / Q000378:metabolism; D015316:Genetic Therapy; D006367:HeLa Cells; D006801:Humans; D007249:Inflammation / Q000628:therapy*; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D020871:RNA Stability / Q000235:genetics*; D051381:Rats; D051816:Tristetraprolin / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D015850:Interleukin-6; D051816:Tristetraprolin; D014409:Tumor Necrosis Factor-alpha; D015232:Dinoprostone