Oncostatin M: Unraveling the Signaling Pathways and Implications in Health and Disease

OSM and OSM Receptor Complex

Oncostatin M (OSM), a vital IL-6 family member, was initially discovered in the U-937 human lymphoma cell line. The human OSM gene, located in chromosome 22q12.2, encodes a polypeptide of 252 amino acid residues, undergoing proteolytic processing to yield a mature 195 amino acid residue protein with a molecular weight of 28 kDa. OSM exhibits widespread in vivo expression, particularly in immune cells like T cells, monocytes/macrophages, and neutrophils.

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Fig. 1 Schematic diagram of the OSM receptor complex structure (Han L., et al. 2023).

The receptor complexes of OSM are heterodimers categorized into two types: type I and type II. Type I consists of gp130 and LIFRβ, while type II involves gp130 and OSMRβ. The two subunits of the OSM receptor complex exist separately in the resting state, and OSM initially forms a low-affinity heterodimer with gp130. Computational simulations identified key amino acid residues involved in OSM-OSMR binding. OSM and LIF can share the LIFR receptor due to structural similarities. The species-specific binding of OSM and the OSM receptor complex dictates unique downstream signaling pathways, emphasizing OSMR's role in enabling type II OSM receptor complexes to exert distinct biological functions.

OSM Signaling Transduction

The OSM receptor, akin to other IL-6 family receptors, exhibits transmembrane structures in both subunits. Upon OSM binding to the extracellular region, the intracellular region initiates recruitment and activation of Janus kinase (JAK) family. The OSM receptor complex, upon binding, activates JAK1 through gp130, leading to phosphorylation and dimerization of the downstream transcription factor STAT. Subsequently, STAT translocates to the nucleus, regulating target gene expression. OSM signaling also activates the RAS/MAPK, JNK/p38 MAPK, and PI3K/AKT pathways. Notably, the type II OSM receptor complex uniquely contains the OSMR subunit, distinguishing it from other IL-6 family cytokines. This distinction allows OSM to exert distinctive biological regulatory functions through the type II OSM receptor complex, which, like type I complexes, can activate JAK. However, the binding affinity of OSM's type II receptor complex with JAK1 or JAK2 is equivalent, while type I receptor complexes exhibit a higher affinity for JAK1.

The Physiological Functions of OSM Signaling

Haematopoiesis

OSM assumes a crucial role in haematopoiesis, intricately influencing the differentiation and maturation of blood cells. It actively contributes to the homeostasis of the hematopoietic system by orchestrating the production of various blood cell lineages, ensuring a balanced and functional blood cellular environment.

Bone Turnover

Within the domain of bone metabolism, OSM plays a significant role in regulating osteoblastic differentiation and impacting bone turnover. Its influence extends to the delicate balance between bone formation and resorption, thereby contributing to the overall health and integrity of the skeletal system.

Wound Repair

OSM emerges as a key player in tissue repair processes, particularly in wound healing. It actively contributes to this intricate biological phenomenon by modulating cellular responses critical for tissue regeneration and remodeling. This underscores OSM's importance in the broader context of physiological functions, where it aids in maintaining the structural and functional integrity of various tissues and organs.

The Role of OSM in Diseases

Cardiovascular Diseases

The role of OSM in cardiovascular diseases is substantial. Notably, there is an observable elevation of OSM levels in patients suffering from heart failure. The intricate involvement of OSM is highlighted by its dual function: on one hand, it plays a crucial role in promoting cardiomyocyte dedifferentiation following acute injury, thereby facilitating tissue repair; on the other hand, persistent OSM activity contributes to the development of heart failure. This dualistic nature underscores the complexity of OSM's impact on the cardiovascular system.

Atherosclerosis

OSM emerges as a key player in the progression of atherosclerosis, a condition characterized by the buildup of plaque in arteries. Its influence is evident in the stimulation of pro-inflammatory factors in vascular smooth muscle cells and fibroblasts, thereby actively contributing to the formation of arterial plaques. Remarkably, murine models reveal a correlation between OSMR deficiency and a reduction in atherosclerotic lesions. This correlation suggests the potential of OSM or OSMR as a therapeutic target for managing atherosclerosis.

Inflammatory Bowel Disease (IBD)

Within the realm of the gut, the connection between OSM and IBD unfolds. High levels of OSMR in intestinal fibroblasts and increased OSM expression in the inflamed intestinal tissues of IBD patients underscore the relevance of OSM in this context. Encouragingly, studies using mouse models demonstrate promising outcomes when OSM is deficient or neutralized, revealing a potential avenue for novel therapeutic interventions to alleviate the severity of colitis in IBD patients.

Fibrosis

OSM's ability to activate stromal cells and interact with components of the extracellular matrix positions it as a significant player in fibrotic diseases. Ongoing research delves into the contrasting effects observed in different organs: while OSM promotes pulmonary fibrosis, it exhibits protective qualities against hepatic fibrosis. The nuanced interplay between OSM and fibrosis underscores the importance of understanding the specific conditions and contexts in which OSM contributes to fibrotic pathogenesis.

Metabolic Disorders

OSM's influence on adipocytes and metabolism becomes evident in conditions related to obesity. Its role in steering mesenchymal progenitors towards osteoblastic differentiation at the expense of adipogenesis is noteworthy. Additionally, OSM induces dedifferentiation of mature adipocytes. In the context of obesity, heightened OSM expression correlates with adipose tissue inflammation, liver steatosis, and insulin resistance. This multifaceted influence highlights OSM as a factor in the intricate network regulating metabolic disorders associated with obesity.

Cancer

In many forms of cancer, OSM can act as a growth factor, stimulating the proliferation of cancer cells. In other forms, particularly breast cancer, OSM can inhibit tumor growth by reducing angiogenesis, the process by which tumors form new blood vessels to supply themselves with nutrients. This duality of function makes OSM a complex factor in oncology.

In conclusion, OSM, a cytokine secreted by cells, plays a crucial role in modulating JAK/STAT, RAS/MAPK, JNK/p38 MAPK, and PI3K/AKT signaling pathways. Its regulatory influence extends to key physiological processes, including cell proliferation, inflammation, immune response, and hematopoiesis. Notably, OSM is implicated in the pathogenesis of diverse diseases, underlining its significance in contributing to the development and progression of various health conditions.

References

1. Han L., et al. Multifaceted oncostatin M: novel roles and therapeutic potential of the oncostatin M signaling in rheumatoid arthritis. Frontiers in Immunology. 2023, 14.
2. West N. R., et al. The oncostatin M‐stromal cell axis in health and disease. Scandinavian Journal of Immunology. 2018, 88(3): e12694.