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Vet Pathol 46:124-137 (2009)
© 2009 American College of Veterinary Pathologists
ANIMAL MODELS OF HUMAN DISEASE

Mice Overexpressing Murine Oncostatin M (OSM) Exhibit Changes in Hematopoietic and Other Organs that Are Distinct from Those of Mice Overexpressing Human OSM or Bovine OSM

T.S.-C. Juan, B. Bolon, R. A. Lindberg, Y. Sun, G. Van and F. A. Fletcher

Departments of Functional Genomics (TS-CJ, YS, FAF1); Pathology (BB,,2 GV); and Metabolic Disease (RAL), Amgen Inc., Thousand Oaks, CA

Abstract

Oncostatin M (OSM) and leukemia inhibitory factor (LIF) belong to the interleukin-6 family of cytokines. The authors' previous in vitro work demonstrated that in mouse cells mouse OSM (mOSM) signals through a heterodimeric receptor complex incorporating the mOSM-specific receptor mOSMRβ while human OSM (hOSM) and bovine OSM (bOSM) use the mouse LIF receptor mLIFRβ rather than mOSMRβ. These in vitro data suggest that prior studies in mouse systems with hOSM or bOSM (the usual molecules used in early studies) reflect LIF rather than OSM biology. The current work assessed whether or not this divergence in actions among these three OSMs also occurs in vivo in mouse models. Adult female (C57BL/6J x DBA/2J) F1 mice were engineered to stably overexpress mOSM, hOSM, or bOSM by retrovirus-mediated gene transfer (n = 10 or more per group). After 4 weeks, molecular and hematologic profiles and anatomic phenotypes in multiple organs were assessed by standard techniques. Animals overexpressing either hOSM or bOSM had an identical phenotype resembling that associated with LIF activation, including significant hematologic abnormalities (anemia, neutrophilia, lymphopenia, eosinopenia, and thrombocytosis); weight loss; profound enlargement (lymph node, spleen) and/or structural reorganization (lymph node, spleen, thymus) of lymphoid organs; and severe osteosclerosis. In contrast, mice overexpressing mOSM did not develop hematologic changes, weight loss, or osteosclerosis and exhibited more modest and anatomically distinct restructuring of lymphoid organs. These data indicate that activities imputed to OSM and the mOSMRβ signaling pathway using in vitro and in vivo mouse experimental systems are unique to mOSM.

Key words: Cytokine; cytokine receptor; gene transfer; leukemia inhibitory factor; mice, transgenic; species specificity.

Request reprints from Dr Todd Juan, MS 29-2-B, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320 (USA). E-mail: tjuan{at}amgen.com


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