Since its first description more than 20 years ago osteopontin has emerged as an active player in many physiological and pathological processes, including biomineralization, tissue remodeling and inflammation. As an extracellular matrix protein and proinflammatory cytokine osteopontin is thought to facilitate the recruitment of monocytes/macrophages and to mediate cytokine secretion in leukocytes. Modulation of immune cell response by osteopontin has been associated with various inflammatory diseases and may play a pivotal role in the development of adipose tissue inflammation and insulin resistance. Here we summarize recent findings on the role of osteopontin in metabolic disorders, particularly focusing on diabetes and obesity.

https://uknowledge.uky.edu/cgi/viewcontent.cgi?article=1002&context=heart_facpub

Osteopontin: A novel regulator at the cross roads of inflammation, obesity and diabetes.

The multiple functions and mechanisms of osteopontin.

The expression of osteopontin (OPN), CD44 variants, and integrins has been correlated with tumorigenesis and metastasis. Here we show that these proteins cooperate to enhance cell motility. First, we demonstrate that several different CD44 variants bind to OPN in an arginine-glycineaspartic acid-independent manner, but that the standard form of CD44 does not. These CD44 variants bind to both the amino- and COOH-terminal portions of OPN independently of the arginine-glycine-aspartic acid sequence, suggesting that multiple domains on OPN can be bound by the CD44 variants. Antibodies directed against the integrin beta1 subunit are able to inhibit this binding. The binding of CD44 variants to OPN is significantly augmented by both anti-CD44s and anti-CD44v antibodies. This augmentation by anti-CD44 antibodies is OPN specific and, again, can be blocked by anti-beta1 antibodies. Finally, we show that OPN binding by CD44 variants/beta1-containing integrins promotes cell spreading, motility, and chemotactic behavior.

CD44 variants but not CD44s cooperate with _1-containing′ integrins′ to permit cells to osteopontin independently of arginine-′ glycine-aspartic acid, thereby stimulating cell motility and′ chemotaxis.

Sepsis refers to severe systemic inflammation in response to invading pathogens. An overwhelming immune response, as mediated by the release of various inflammatory mediators, can lead to shock, multiple organ damage, and even death. Cytokines, proteases, lipid mediators, gaseous substances, vasoactive peptides, and cell stress markers play key roles in sepsis pathophysiology. Various adhesion molecules and chemokines sequester and activate neutrophils into the target organs, further augmenting inflammation and tissue damage. Although the anti-inflammatory substances counterbalance proinflammatory mediators, prolonged immune modulation may cause host susceptibility to concurrent infections, thus reflecting enormous challenge toward developing effective clinical therapy against sepsis. To understand the complex interplay between pro- and anti-inflammatory phenomenon in sepsis, there is still an unmet need to study newly characterized mediators. In addition, revealing the current trends of novel mediators will upgrade our understanding on their signal transduction, cross-talk, and synergistic and immunomodulating roles during sepsis. This review highlights the latest discoveries of the mediators in sepsis linking to innate and adaptive immune systems, which may lead to resolution of many unexplored queries.

https://jlb.onlinelibrary.wiley.com/doi/pdf/10.1189/jlb.0912437

Current trends in inflammatory and immunomodulatory mediators in sepsis

Emerging avenues linking inflammation and cancer

Osteopontin (OPN) is a matricellular protein that mediates diverse biological functions. OPN is involved in normal physiological processes and is implicated in the pathogenesis of a variety of disease states, including atherosclerosis, glomerulonephritis, cancer, and several chronic inflammatory diseases. Through interactions with several integrins, OPN mediates cell migration, adhesion, and survival in many cell types. OPN also functions as a Th1 cytokine, promotes cell-mediated immune responses, and plays a role in chronic inflammatory and autoimmune diseases. Besides its function in inflammation, OPN is also a regulator of biomineralization and a potent inhibitor of vascular calcification.

/pdf/the-role-of-osteopontin-in-inflammatory-processes-4m3cf9nx43.pdf

The role of osteopontin in inflammatory processes

Osteopontin (OPN) is highly expressed by macrophages and plays a key role in the pathology of several chronic inflammatory diseases including atherosclerosis and the foreign body reaction. However, the molecular mechanism behind OPN regulation of macrophage functions is not well understood. OPN is a secreted molecule and interacts with several integrins via two domains: the RGD sequence binding to α(v) -containing integrins, and the SLAYGLR sequence binding to α(4) β(1), α(4) β(7), and α(9) β(1) integrins. Here we determined the role of OPN in macrophage survival, chemotaxis, and activation state. For survival studies, OPN treated-bone marrow derived macrophages (BMDMs) were challenged with growth factor withdrawal and neutralizing integrin antibodies. We found that survival in BMDMs is mediated primarily through the α(4) integrin. In chemotaxis studies, we observed that migration to OPN was blocked by neutralizing α(4) and α(9) integrin antibodies. Further, OPN did not affect macrophage activation as measured by IL-12 production. Finally, the relative contributions of the RGD and the SLAYGLR functional domains of OPN to leukocyte recruitment were evaluated in an in vivo model. We generated chimeric mice expressing mutated forms of OPN in myeloid-derived leukocytes, and found that the SLAYGLR functional domain of OPN, but not the RGD, mediates macrophage accumulation in response to thioglycollate-elicited peritonitis. Collectively, these data indicate that α(4) and α(9) integrins interacting with OPN via the SLAYGLR domain play a key role in macrophage biology by regulating migration, survival, and accumulation.

Osteopontin mediates macrophage chemotaxis via α4 and α9 integrins and survival via the α4 integrin.

Macrophages play a central role in guiding proper organ and tissue development, physiological healing, and in maintaining tissue homeostasis. Further, they are one of the major cell components of the inflammatory response. During healing, macrophages assume a temporal series of distinct phenotypes that guide tissue repair and restoration of tissue homeostasis. Macrophages then decline and the restored tissue is macrophage free. Dysfunction or imbalance in macrophage phenotypes results in compromised healing that is thought to be the root cause of inflammatory diseases. Implanted biomedical devices elicit a robust inflammatory response driven largely by dysfunctional macrophages, which show a significant shift in their physiological behavior. They do not progress through the temporal series of phenotypes and do not decline with time, rather remain with the biomedical device for the life of it (the bad). At the host-device interface macrophages fuse to create large cells, foreign body giant cells. These giant cells are believed to damage the biomedical device at a structural and functional level (the ugly). Significant effort has been put forward to understand the processes leading to the dysfunctional macrophage response to biomedical devices, as well as to design novel approaches to guide the macrophages through the temporal series of phenotypes of physiological healing (the good). In this chapter, the current understanding of the developmental origin of macrophages, their functions in physiological processes, and dysfunction in response to the foreign body will be presented and discussed, as well as approaches to guide them toward resolution of the foreign body-elicited inflammatory response.

Susan Amanda Lund

Papers

The role of osteopontin in inflammatory processes

Osteopontin mediates macrophage chemotaxis via α4 and α9 integrins and survival via the α4 integrin.

Macrophages: The Bad, the Ugly, and the Good in the Inflammatory Response to Biomaterials