The clinical relevance of OSM in inflammatory diseases: a comprehensive review

Abstract

Oncostatin M (OSM) is a pleiotropic cytokine involved in a variety of inflammatory responses such as wound healing, liver regeneration, and bone remodeling. As a member of the interleukin-6 (IL-6) family of cytokines, OSM binds the shared receptor gp130, recruits either OSMRβ or LIFRβ, and activates a variety of signaling pathways including the JAK/STAT, MAPK, JNK, and PI3K/AKT pathways. Since its discovery in 1986, OSM has been identified as a significant contributor to a multitude of inflammatory diseases, including arthritis, inflammatory bowel disease, lung and skin disease, cardiovascular disease, and most recently, COVID-19. Additionally, OSM has also been extensively studied in the context of several cancer types including breast, cervical, ovarian, testicular, colon and gastrointestinal, brain,lung, skin, as well as other cancers. While OSM has been recognized as a significant contributor for each of these diseases, and studies have shown OSM inhibition is effective at treating or reducing symptoms, very few therapeutics have succeeded into clinical trials, and none have yet been approved by the FDA for treatment. In this review, we outline the role OSM plays in a variety of inflammatory diseases, including cancer, and outline the previous and current strategies for developing an inhibitor for OSM signaling.

Keywords: cancer; cytokine; drug development; inflammatory diseases; metastasis; oncostatin M (OSM); oncostatin M receptor beta (OSMRβ); therapeutics.

Figure 1

OSM activates multiple signaling cascades. (A) OSM binds to gp130 and then recruits LIFRβ to form a type I complex (LIFR). (B) OSM binds to gp130 and then recruits its major receptor complex subunit OSMRβ to form a type II complex. (C) Visual representation of the signaling pathways used by OSM type II complex. Created with BioRender.com.

Figure 2

OSM structure and receptor binding sites. (A) OSM is a four α-helical bundle protein consisting of helices A (red; aa 10 –37), B (green; aa 66-90), C (purple; aa 106-131), and D (blue; aa 159-185) (truncated X-ray crystallography PDB:1EVS). (B) Site-directed mutagenesis experiments have identified two separate binding sites responsible for receptor-ligand interactions. Site II is located near the N-terminal region in helices A and C, and three amino acids (Gly-16, Gly-20, Asn-124) have been identified as crucial for OSM interaction with gp130. Site III is located in the A- B loop with a small portion of the D helix (dark purple) that is responsible for binding of OSM to LIFRβ and OSMRβ. Substitution experiments with OSM and LIF revealed that Lys-163, and Phe-160 are required to bind to both receptor complexes, but Tyr-34, Gln-38, Gly-39 and Leu-45 are specifically needed for interactions with OSMRβ.