title: Oncostatin M Confers Neuroprotection against Ischemic Stroke.
abstract: Cell-surface receptors provide potential targets for the translation of bench-side findings into therapeutic strategies; however, this approach for the treatment of stroke is disappointing, at least partially due to an incomplete understanding of the targeted factors. Previous studies of oncostatin M (OSM), a member of the gp130 cytokine family, have been limited, as mouse models alone may not strongly resemble the human condition enough. In addition, the precise function of OSM in the CNS remains unclear. Here, we report that human OSM is neuroprotective in vivo and in vitro by recruiting OSMRβ in the setting of ischemic stroke. Using gain- and loss-of-function approaches, we demonstrated that decreased neuronal OSMRβ expression results in deteriorated stroke outcomes but that OSMRβ overexpression in neurons is cerebroprotective. Moreover, administering recombinant human OSM to mice before the onset of I/R showed that human OSM can be protective in rodent models of ischemic stroke. Mechanistically, OSM/OSMRβ activate the JAK2/STAT3 prosurvival signaling pathway. Collectively, these data support that human OSM may represent a promising drug candidate for stroke treatment.
  
  
  CONCLUSIONS
  OSM, a member of the gp130 cytokine family, regulates neuronal function and survival. OSM engages a second receptor, either LIFRα or OSMRβ, before recruiting gp130. However, it is not clear whether OSM/OSMRβ signaling is involved in neuroprotection in the setting of ischemic stroke. Recent studies show that, compared with mouse disease models, the OSM receptor system in rats more closely resembles that in humans. In the present study, we use genetic manipulations of OSMRβ in both mouse and rat stroke models to demonstrate that OSMRβ in neurons is critical for neuronal survival during cerebral ischemic/reperfusion. Interestingly, administration of human OSM also leads to improved stroke outcomes. Therefore, OSM may represent a promising drug candidate for stroke treatment.
authors: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, PR China.
authors: Sen
authors: S
authors: Guo
authors: Department of Cardiology, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing 100730, PR China, National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, PR China.
authors: Zuo-Zhi
authors: ZZ
authors: Li
authors: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, PR China, College of Life Sciences, Wuhan University, Wuhan 430072, PR China.
authors: Jun
authors: J
authors: Gong
authors: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, PR China.
authors: Mei
authors: M
authors: Xiang
authors: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, PR China.
authors: Peng
authors: P
authors: Zhang
authors: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, PR China.
authors: Guang-Nian
authors: GN
authors: Zhao
authors: Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan 430060, PR China.
authors: Mingchang
authors: M
authors: Li
authors: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, PR China.
authors: Ankang
authors: A
authors: Zheng
authors: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, PR China.
authors: Xueyong
authors: X
authors: Zhu
authors: Wuhan Center for Magnetic Resonance, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences, Wuhan 430060, PR China.
authors: Hao
authors: H
authors: Lei
authors: Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo 113-0032, Japan, and.
authors: Tanaka
authors: T
authors: Minoru
authors: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, PR China, Animal Experiment Center/Animal Biosafety Level-III Laboratory, Wuhan University, Wuhan 430060, PR China lihl@whu.edu.cn.
authors: Hongliang
authors: H
authors: Li
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D053683:Oncostatin M / Q000096:biosynthesis*; D053681:Oncostatin M Receptor beta Subunit / Q000096:biosynthesis*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D020521:Stroke / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*
chemical_list: D053681:Oncostatin M Receptor beta Subunit; D053683:Oncostatin M
keywords: OSM; OSMRβ; cerebral ischemia; gene therapy; neuroprotection