Differential osteopontin functions: The role of osteopontin isoforms

Abstract

We would like to thank Dr. Fujita for the positive comments. We agree that a sensitivity of 67% and specificity of 96% would be useful as a test used in the clinic. 1 In regard to cost, we also agree that this is a very important consideration, along with complexity of the test and feasibility for a clinical laboratory to perform the test. These were considerations that we contemplated throughout the development of the project. For example, at an earlier stage of the project, we experimented with a quicker, but more expensive, method to extract extracellular vesicles. We decided to utilize, thoroughly test, and eventually implement ultracentrifugation for simplicity and cost reasons.Early diagnosis of cholangiocarcinoma, as accurately pointed out by Dr. Fujita, is the cornerstone of survival. Though the sensitivity of the microRNA (miR) panel for all comers is not dramatically different than the sensitivity of cancer antigen 19-9 (CA19-9), we noted that the panel is more sensitive than CA19-9 for early cancers. There is hope that further testing of the panel in larger cohorts will validate this finding and that the panel will prove its utility in detecting early cancers.Some of the miR species on the panel (in particular, miR-191 and 2486-3p) have been associated with cancer in the past. 2,3 However, our findings are limited to the presence of these miR species in extracellular vesicles in bile. It would be of interest to further the study of these miR species to unravel their mechanistic involvement in cancers of the liver. In addition, as Dr. Fujita indicated, a study to look at these miR species in bile from patients with other small lesions (such as small hepatocellular carcinomas) would further shed light into the utility of the reported panel in differentiating the etiology of small liver masses found at imaging.

Liver stiffness correlates with serum osteopontin and TAZ expression in human liver cirrhosis

“…iOPN is a cytoskeletal protein that plays a significant role in the regulation of the intracellular protein functions, while sOPN acts as a cytokine . Also, it is proposed that iOPN contributes to protection and sOPN is involved in promotion of the disease . The last but not the least possible reason is that OPN expression is predominant in areas with active fibrogenesis and where myofibroblasts are accumulated, as confirmed by the histological analysis .…”

“…The second reason may be due to the fact that OPN is altered by posttranscriptional modification, splicing, and cleavage . Two isoforms of OPN, intercellular OPN (iOPN) and secreted OPN (sOPN), exert distinct functions, despite similarities in the molecular structure . iOPN is a cytoskeletal protein that plays a significant role in the regulation of the intracellular protein functions, while sOPN acts as a cytokine .…”

Animal Models of Alcoholic Liver Disease: Pathogenesis and Clinical Relevance

“…Another study suggested that OPN may protect against chronic alcoholic liver injury by blocking the gut-derived LPS and TNF-α in the liver 34 . These discrepancies could be explained, in part, by differences in the models being studied (i.e., varying degrees of severity, duration, gender) and possibly by the different forms of OPNs (i.e., the intracellular OPN isoform [iOPN] and the extracellular/soluble cytokine [sOPN]) 35 .…”

Advancements in the Alcohol-Associated Liver Disease Model

“…Additionally, alcohol intake induces ER stress followed by the production of proinflammatory mediators and DAMPs that activate the nuclear translocation of cyclic AMP response element-binding protein H (CREBH) and nCREBH [ 10 ]. Another consequence of ER stress is the activation of lipogenic pathways in hepatocytes, particularly through SREBPs, followed by the upregulation of the predominant form of FSP27-β [ 109 , 110 ]. The interaction of FSP27 with lipid droplet membrane proteins promotes lipid droplet formation and steatosis.…”