Oncostatin M: Risks and Benefits of a Novel Therapeutic Target for Atherosclerosis.

BACKGROUND: Cardiovascular disease (CVD) is a leading cause of death worldwide. It is predicted that approximately 23.6 million people will die from CVDs annually by 2030. Therefore, there is a great need for an effective therapeutic approach to combat this disease. The European Cardiovascular Target Discovery (CarTarDis) consortium identified Oncostatin M (OSM) as a potential therapeutic target for atherosclerosis. The benefits of modulating OSM - an interleukin (IL)-6 family cytokine - have since been studied for multiple indications. However, as decades of high attrition rates have stressed, the success of a drug target is determined by the fine balance between benefits and the risk of adverse events. Safety issues should therefore not be overlooked. OBJECTIVE: In this review, a risk/benefit analysis is performed on OSM inhibition in the context of atherosclerosis treatment. First, OSM signaling characteristics and its role in atherosclerosis are described. Next, an overview of in vitro, in vivo, and clinical findings relating to both the benefits and risks of modulating OSM in major organ systems is provided. Based on OSM's biological function and expression profile as well as drug intervention studies, safety concerns of inhibiting this target have been identified, assessed, and ranked for the target population. CONCLUSION: While OSM may be of therapeutic value in atherosclerosis, drug development should also focus on de-risking the herein identified major safety concerns: tissue remodeling, angiogenesis, bleeding, anemia, and NMDA- and glutamate-induced neurotoxicity. Close monitoring and/or exclusion of patients with various comorbidities may be required for optimal therapeutic benefit.

Oncostatin M reduces atherosclerosis development in APOE*3Leiden.CETP mice and is associated with increased survival probability in humans.

OBJECTIVE: Previous studies indicate a role for Oncostatin M (OSM) in atherosclerosis and other chronic inflammatory diseases for which inhibitory antibodies are in development. However, to date no intervention studies with OSM have been performed, and its relation to coronary heart disease (CHD) has not been studied. APPROACH AND RESULTS: Gene expression analysis on human normal arteries (n = 10) and late stage/advanced carotid atherosclerotic arteries (n = 127) and in situ hybridization on early human plaques (n = 9) showed that OSM, and its receptors, OSM receptor (OSMR) and Leukemia Inhibitory Factor Receptor (LIFR) are expressed in normal arteries and atherosclerotic plaques. Chronic OSM administration in APOE*3Leiden.CETP mice (n = 15/group) increased plasma E-selectin levels and monocyte adhesion to the activated endothelium independently of cholesterol but reduced the amount of inflammatory Ly-6CHigh monocytes and atherosclerotic lesion size and severity. Using aptamer-based proteomics profiling assays high circulating OSM levels were shown to correlate with post incident CHD survival probability in the AGES-Reykjavik study (n = 5457). CONCLUSIONS: Chronic OSM administration in APOE*3Leiden.CETP mice reduced atherosclerosis development. In line, higher serum OSM levels were correlated with improved post incident CHD survival probability in patients, suggesting a protective cardiovascular effect.