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Science (New York, N.Y.) Aug 2023Tumor microenvironments (TMEs) influence cancer progression but are complex and often differ between patients. Considering that microenvironment variations may reveal...
Tumor microenvironments (TMEs) influence cancer progression but are complex and often differ between patients. Considering that microenvironment variations may reveal rules governing intratumoral cellular programs and disease outcome, we focused on tumor-to-tumor variation to examine 52 head and neck squamous cell carcinomas. We found that macrophage polarity-defined by and (CS) expression but not by conventional M1 and M2 markers-had a noticeably strong prognostic association. CS macrophage polarity also identified a highly coordinated network of either pro- or antitumor variables, which involved each tumor-associated cell type and was spatially organized. We extended these findings to other cancer indications. Overall, these results suggest that, despite their complexity, TMEs coordinate coherent responses that control human cancers and for which CS macrophage polarity is a relevant yet simple variable.
Topics: Humans; Chemokine CXCL9; Head and Neck Neoplasms; Macrophages; Osteopontin; Prognosis; Squamous Cell Carcinoma of Head and Neck; Tumor Microenvironment; Cell Polarity
PubMed: 37535729
DOI: 10.1126/science.ade2292 -
Gastroenterology Jul 2023Nonalcoholic steatohepatitis (NASH) is characterized by steatosis, lobular inflammation, hepatocyte ballooning degeneration, and fibrosis, all of which increase the risk...
BACKGROUND & AIMS
Nonalcoholic steatohepatitis (NASH) is characterized by steatosis, lobular inflammation, hepatocyte ballooning degeneration, and fibrosis, all of which increase the risk of progression to end-stage liver disease. Osteopontin (OPN, SPP1) plays an important role in macrophage (MF) biology, but whether MF-derived OPN affects NASH progression is unknown.
METHODS
We analyzed publicly available transcriptomic datasets from patients with NASH, and used mice with conditional overexpression or ablation of Spp1 in myeloid cells and liver MFs, and fed them a high-fat, fructose, and cholesterol diet mimicking the Western diet, to induce NASH.
RESULTS
This study demonstrated that MFs with high expression of SPP1 are enriched in patients and mice with nonalcoholic fatty liver disease (NAFLD), and show metabolic but not pro-inflammatory properties. Conditional knockin of Spp1 in myeloid cells (Spp1) or in hepatic macrophages (Spp1) conferred protection, whereas conditional knockout of Spp1 in myeloid cells (Spp1) worsened NASH. The protective effect was mediated by induction of arginase-2 (ARG2), which enhanced fatty acid oxidation (FAO) in hepatocytes. Induction of ARG2 stemmed from enhanced production of oncostatin-M (OSM) in MFs from Spp1 mice. OSM activated STAT3 signaling, which upregulated ARG2. In addition to hepatic effects, Spp1 also protected through sex-specific extrahepatic mechanisms.
CONCLUSION
MF-derived OPN protects from NASH, by upregulating OSM, which increases ARG2 through STAT3 signaling. Further, the ARG2-mediated increase in FAO reduces steatosis. Therefore, enhancing the OPN-OSM-ARG2 crosstalk between MFs and hepatocytes may be beneficial for patients with NASH.
Topics: Animals; Female; Male; Mice; Diet, High-Fat; Diet, Western; Disease Models, Animal; Liver; Liver Cirrhosis; Macrophages; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Osteopontin
PubMed: 37028770
DOI: 10.1053/j.gastro.2023.03.228 -
Hepatology (Baltimore, Md.) Apr 2021Osteopontin (OPN) was first identified in 1986. The prefix osteo- means bone; however, OPN is expressed in other tissues, including liver. The suffix -pontin means... (Review)
Review
Osteopontin (OPN) was first identified in 1986. The prefix osteo- means bone; however, OPN is expressed in other tissues, including liver. The suffix -pontin means bridge and denotes the role of OPN as a link protein within the extracellular matrix. While OPN has well-established physiological roles, multiple "omics" analyses suggest that it is also involved in chronic liver disease. In this review, we provide a summary of the OPN gene and protein structure and regulation. We outline the current knowledge on how OPN is involved in hepatic steatosis in the context of alcoholic liver disease and non-alcoholic fatty liver disease. We describe the mechanisms whereby OPN participates in inflammation and liver fibrosis and discuss current research on its role in hepatocellular carcinoma and cholangiopathies. To conclude, we highlight important points to consider when doing research on OPN and provide direction for making progress on how OPN contributes to chronic liver disease.
Topics: Animals; Carcinoma, Hepatocellular; Disease Models, Animal; Extracellular Matrix; Gene Expression; Humans; Liver Cirrhosis; Liver Diseases, Alcoholic; Liver Neoplasms; Mice; Non-alcoholic Fatty Liver Disease; Osteopontin
PubMed: 32986864
DOI: 10.1002/hep.31582 -
Immunological Reviews Oct 2022Osteopontin (OPN) also known by its official gene designation secreted phosphoprotein-1 (SPP1) is a fascinating, multifunctional protein expressed in a number of cell... (Review)
Review
Osteopontin (OPN) also known by its official gene designation secreted phosphoprotein-1 (SPP1) is a fascinating, multifunctional protein expressed in a number of cell types that functions not only in intercellular communication, but also in the extracellular matrix (ECM). OPN/SPP1 possesses cytokine, chemokine, and signal transduction functions by virtue of modular structural motifs that provide interaction surfaces for integrins and CD44-variant receptors. In humans, there are three experimentally verified splice variants of OPN/SPP1 and CD44's ten exons are also alternatively spiced in a cell/tissue-specific manner, although very little is known about how this is regulated in the central nervous system (CNS). Post-translational modifications of phosphorylation, glycosylation, and localized cleavage by specific proteases in the cells and tissues where OPN/SPP1 functions, provides additional layers of specificity. However, the former make elucidating the exact molecular mechanisms of OPN/SPP1 function more complex. Flexibility in OPN/SPP1 structure and its engagement with integrins having the ability to transmit signals in inside-out and outside-in direction, is likely why OPN/SPP1 can serve as an early detector of inflammation and ongoing tissue damage in response to cancer, stroke, traumatic brain injury, pathogenic infection, and neurodegeneration, processes that impair tissue homeostasis. This review will focus on what is currently known about OPN/SPP1 function in the brain.
Topics: Cell Communication; Cytokines; Humans; Integrins; Ligands; Neuroinflammatory Diseases; Osteopontin; Peptide Hydrolases; Phosphoproteins
PubMed: 35451082
DOI: 10.1111/imr.13081 -
Archivum Immunologiae Et Therapiae... May 2021Organ transplantation represents the optimal therapeutic tool for patients with end-stage organ failure. Hematopoietic stem cell transplantation (HSCT) is likewise an... (Review)
Review
Organ transplantation represents the optimal therapeutic tool for patients with end-stage organ failure. Hematopoietic stem cell transplantation (HSCT) is likewise an effective therapy for a wide range of malignant and non-malignant diseases. Better understanding of transplantation immunology and the use of multi-modal immunosuppression protocols, can decrease the risk of graft failure and graft-versus-host disease (GVHD) after HSCT. Nevertheless, a major challenge of modern transplantology still seems to be finding non-invasive biomarkers for recipients selection, monitoring of allograft function, and diagnosis of rejection. Since proinflammatory cytokine osteopontin (OPN) is closely involved in regulating both adaptive and innate immune responses, as well as the pathogenesis of inflammatory and autoimmune diseases, it is likely to play an important role in organ and HSC transplantation. This review is to summarize recent advances in our knowledge about OPN function in the kidney, heart, liver, lung, and HSC transplantation. Most studies found that elevated OPN is associated with poorer graft function in kidney, heart, liver and lung recipients. Moreover, some reports suggested that this protein can play role in GVHD pathogenesis. However, due to relatively small number of similar studies, as well as some inconclusive results, future investigation in this field is needed to verify if OPN can serve as a biomarker of organ and HSC transplantation. The knowledge about such markers will promote our understanding of the mechanisms underlying graft dysfunction and posttransplant mortality. In addition, such knowledge may be helpful in the development of new treatment strategies and identification of recipients with increased risk of allograft failure.
Topics: Biomarkers; Graft Rejection; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Organ Transplantation; Osteopontin; Risk Assessment
PubMed: 34019147
DOI: 10.1007/s00005-021-00617-6 -
Nutrients May 2023Osteopontin (OPN) is a multifunctional protein found in all vertebrates. OPN is expressed in many different cell types, and is consequently found in most tissues and... (Review)
Review
Osteopontin (OPN) is a multifunctional protein found in all vertebrates. OPN is expressed in many different cell types, and is consequently found in most tissues and physiological secretions. OPN is involved in a multitude of biological processes, such as activation and regulation of the immune system; biomineralization; tissue-transformative processes, including growth and development of the gut and brain; interaction with bacteria; and many more. OPN is found in the highest concentrations in milk, where it is believed to initiate and regulate developmental, immunological and physiological processes in infants who consume milk. Processes for the isolation of bovine OPN for use in infant formula have been developed, and in recent years, many studies have investigated the effects of the intake of milk OPN. The purpose of this article is to review and compare existing knowledge about the structure and function of milk OPN, with a particular focus on the effects of milk OPN on human health and disease.
Topics: Infant; Humans; Animals; Cattle; Milk; Osteopontin; Infant Formula; Brain; Milk, Human
PubMed: 37299387
DOI: 10.3390/nu15112423 -
Computers in Biology and Medicine Jun 2023Osteoarthritis (OA) has become the most common degenerative disease in the world, which brings a serious economic burden to society and the country. Although...
Osteoarthritis (OA) has become the most common degenerative disease in the world, which brings a serious economic burden to society and the country. Although epidemiological studies have shown that the occurrence of osteoarthritis is associated with obesity, sex, and trauma, the biomolecular mechanisms for the development and progression of osteoarthritis remain ambiguous. Several studies have drawn a connection between SPP1 and osteoarthritis. SPP1 was first found to be highly expressed in osteoarthritic cartilage, and later more studies have shown that SPP1 is also highly expressed in subchondral bone and synovial in OA patients. However, the biological function of SPP1 remains unclear. Single-cell RNA sequencing (scRNA-seq) is a novel technique that reflects gene expression at the cellular level, making it better depict the state of different cells than ordinary transcriptome data. However, most of the existing chondrocyte scRNA-seq studies focus on the occurrence and development of OA chondrocytes and lack analysis of normal chondrocyte development. Therefore, to better understand the mechanism of OA, scRNA-seq analysis of a larger cell volume containing normal and osteoarthritic cartilage is of great importance. Our study identifies a unique cluster of chondrocytes characterized by high SPP1 expression. The metabolic and biological characteristics of these clusters were further investigated. Besides, in animal models, we found that the expression of SPP1 is spatially heterogeneous in cartilage. Overall, our work provides novel insight into the potential role of SPP1 in OA, which sheds light on understanding the role of SPP1 in OA, promoting the progress of the treatment and prevention in the field of OA.
Topics: Animals; Humans; Chondrocytes; Transcriptome; RNA; Cartilage, Articular; Osteoarthritis; Osteopontin
PubMed: 37141654
DOI: 10.1016/j.compbiomed.2023.106926 -
Frontiers in Endocrinology 2022Osteopontin (OPN) is a multifunctional noncollagenous matrix phosphoprotein that is expressed both intracellularly and extracellularly in various tissues. As a growth... (Review)
Review
Osteopontin (OPN) is a multifunctional noncollagenous matrix phosphoprotein that is expressed both intracellularly and extracellularly in various tissues. As a growth regulatory protein and proinflammatory immunochemokine, OPN is involved in the pathological processes of many diseases. Recent studies have found that OPN is widely involved in the aging processes of multiple organs and tissues, such as T-cell senescence, atherosclerosis, skeletal muscle regeneration, osteoporosis, neurodegenerative changes, hematopoietic stem cell reconstruction, and retinal aging. However, the regulatory roles and mechanisms of OPN in the aging process of different tissues are not uniform, and OPN even has diverse roles in different developmental stages of the same tissue, generating uncertainty for the future study and utilization of OPN. In this review, we will summarize the regulatory role and molecular mechanism of OPN in different tissues and cells, such as the musculoskeletal system, central nervous system, cardiovascular system, liver, and eye, during senescence. We believe that a better understanding of the mechanism of OPN in the aging process will help us develop targeted and comprehensive therapeutic strategies to fight the spread of age-related diseases.
Topics: Osteopontin; Liver; Retina; Central Nervous System
PubMed: 36619570
DOI: 10.3389/fendo.2022.1014853 -
Biomolecules Jul 2021Unprecedented advances in secondary prevention have greatly improved the prognosis of cardiovascular diseases (CVDs); however, CVDs remain a leading cause of death... (Review)
Review
Unprecedented advances in secondary prevention have greatly improved the prognosis of cardiovascular diseases (CVDs); however, CVDs remain a leading cause of death globally. These findings suggest the need to reconsider cardiovascular risk and optimal medical therapy. Numerous studies have shown that inflammation, pro-thrombotic factors, and gene mutations are focused not only on cardiovascular residual risk but also as the next therapeutic target for CVDs. Furthermore, recent clinical trials, such as the Canakinumab Anti-inflammatory Thrombosis Outcomes Study trial, showed the possibility of anti-inflammatory therapy for patients with CVDs. Osteopontin (OPN) is a matricellular protein that mediates diverse biological functions and is involved in a number of pathological states in CVDs. OPN has a two-faced phenotype that is dependent on the pathological state. Acute increases in OPN have protective roles, including wound healing, neovascularization, and amelioration of vascular calcification. By contrast, chronic increases in OPN predict poor prognosis of a major adverse cardiovascular event independent of conventional cardiovascular risk factors. Thus, OPN can be a therapeutic target for CVDs but is not clinically available. In this review, we discuss the role of OPN in the development of CVDs and its potential as a therapeutic target.
Topics: Acute Kidney Injury; Animals; Biomarkers; Cardio-Renal Syndrome; Cardiovascular Diseases; Humans; Mice; Osteopontin
PubMed: 34356671
DOI: 10.3390/biom11071047 -
The European Respiratory Journal Aug 2013
Topics: Biomarkers, Tumor; GPI-Linked Proteins; Humans; Mesothelioma; Osteopontin; Pleural Neoplasms
PubMed: 23904556
DOI: 10.1183/09031936.00064413