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Both Full-Length and Protease-Cleaved Products of Osteopontin Are Elevated in Infectious Diseases

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Both Full-Length and Protease-Cleaved Products of Osteopontin Are Elevated in Infectious Diseases biomedicines Review Both Full-Length and Protease-Cleaved Products of Osteopontin Are Elevated in Infectious Diseases Toshio Hattori 1,* , Hiroko Iwasaki-Hozumi 1 , Gaowa Bai 1 , Haorile Chagan-Yasutan 1,2, Ashwnini Shete 3 , Elizabeth Freda Telan 4, Atsushi Takahashi 1, Yugo Ashino 5 and Takashi Matsuba 6 1 Research Institute of Health and Welfare, Kibi International University, Takahashi 716-8508, Japan; [email protected] (H.I.-H.); [email protected] (G.B.); [email protected] (H.C.-Y.); [email protected] (A.T.) 2 Mongolian Psychosomatic Medicine Department, International Mongolian Medicine Hospital of Inner Mongolia, Hohhot 010065, China 3 ICMR-National AIDS Research Institute, 73 G-Block, MIDC, Bhosari, Pune 411026, India; [email protected] 4 STD AIDS Cooperative Central Laboratory, San Lazaro Hospital, Manila 1003, Philippines; [email protected] 5 Department of Respiratory Medicine, Sendai City Hospital, Sendai 982-8502, Japan; [email protected] 6 Department of Animal Pharmaceutical Science, School of Pharmaceutical Science, Kyusyu University of Health and Welfare, Nobeoka 882-8508, Japan; [email protected] * Correspondence: [email protected]; Tel./Fax: +81-866-22-9469 Citation: Hattori, T.; Abstract: Circulating full-length osteopontin (FL-OPN) is elevated in plasma from patients with Iwasaki-Hozumi, H.; Bai, G.; various infectious diseases, such as adult T-cell leukemia, Mycobacterium tuberculosis (TB), hepatitis Chagan-Yasutan, H.; Shete, A.; Telan, virus infection, leptospirosis, acquired immune deficiency syndrome (AIDS), AIDS/TB, and coron- E.F.; Takahashi, A.; Ashino, Y.; avirus disease 2019 (COVID-19). Proteolysis of OPN by thrombin, matrix metalloproteases, caspase Matsuba, T. Both Full-Length and 8/3, cathepsin D, plasmin, and enterokinase generates various cleaved OPNs with a variety of Protease-Cleaved Products of bioactivities by binding to different target cells. Moreover, OPN is susceptible to gradual proteolysis. Osteopontin Are Elevated in During inflammation, one of the cleaved fragments, N-terminal thrombin-cleaved OPN (trOPN or Infectious Diseases. Biomedicines 2021, 168 9, 1006. https://doi.org/ OPN-Arg [OPN-R]), induces dendritic cell (DC) adhesion. Further cleavage by carboxypeptidase 168 167 10.3390/biomedicines9081006 B2 or carboxypeptidase N removes Arg from OPN-R to OPN-Leu (OPN-L). Consequently, OPN-L decreases DC adhesion. In particular, the differences in plasma level over time are observed Academic Editor: between FL-OPN and its cleaved OPNs during inflammation. We found that the undefined OPN Giuseppe Cappellano levels (mixture of FL-OPN and cleaved OPN) were elevated in plasma and reflected the pathology of TB and COVID-19 rather than FL-OPN. These infections are associated with elevated levels of Received: 2 July 2021 various proteases. Inhibition of the cleavage or the activities of cleaved products may improve the Accepted: 9 August 2021 outcome of the therapy. Research on the metabolism of OPN is expected to create new therapies Published: 13 August 2021 against infectious diseases. Publisher’s Note: MDPI stays neutral Keywords: osteopontin; infectious disease; tuberculosis; adult T-cell leukemia; human immunodefi- with regard to jurisdictional claims in ciency virus; dengue virus; hepatitis C virus; leptospirosis; proteases; matrix metalloproteinase published maps and institutional affil- iations. 1. Introduction Osteopontin (OPN) is a phosphoprotein and is secreted by transformed cell lines from Copyright: © 2021 by the authors. several mammalian species in the 58,000-Da molecular-weight range [1]. Subsequently, Licensee MDPI, Basel, Switzerland. This article is an open access article OPN was shown to be secreted by activated macrophages and T-lymphocytes abundantly. distributed under the terms and Furthermore, a cleaved 45 kDa product and a 70 kDa species secreted from T cells were conditions of the Creative Commons identified [2]. It was also found that OPN belongs to matricellular proteins characterized Attribution (CC BY) license (https:// by the direct binding to other matrix proteins, triggering of their specific surface receptors, creativecommons.org/licenses/by/ and binding to proteases, growth factors, and cytokines (which modulates their activities). 4.0/). OPN also modulates several processes, like cell adhesion and migration, extracellular Biomedicines 2021, 9, 1006. https://doi.org/10.3390/biomedicines9081006 https://www.mdpi.com/journal/biomedicines Biomedicines 2021, 9, x FOR PEER REVIEW 2 of 27 surface receptors, and binding to proteases, growth factors, and cytokines (which modu- lates their activities). OPN also modulates several processes, like cell adhesion and migra- tion, extracellular matrix (ECM) deposition, cell survival, and proliferation [3,4]. Detection of various forms of OPN influencing these functions was sought by an enzyme-linked immunosorbent assay (ELISA) system using antibodies against synthetic peptides [5]. OPN is known to be cleaved by various proteases, and, among them, thrombin cleavage maybe important, because they localize together in various inflammations (Figure 1) [6,7]. The cleaved fragments maintain OPN adhesive function and expose new active domains Biomedicines 2021, 9, 1006 that may impart new activities. Thrombin cleavage leads to exposure of the SVVYGLR2 of 28 cryptic domain that induces cell adhesion and migration by binding to integrins α4 and α9 in vitro [8]. Using the combination of antibodies, namely, O-17 specific to the N-termi- 17 31 matrixnus of (ECM)OPN (Ile deposition,–Gln ) and cell 34E3 survival, specific and to proliferation N-terminal [ 3thrombin-cleaved,4]. Detection of various OPN (trOPN) forms 162 168 ofepitope OPN influencing(Ser –Arg these), exposed functions by thrombin was sought digestion, by an it enzyme-linked was possible to immunosorbent measure trOPN assay[9]. Thereafter, (ELISA) system plasma using full-length antibodies OPN against(FL-OPN) synthetic and trOPN peptides levels [5 were]. OPN measured is known using to bea commercial cleaved by variousELISA kit proteases, (Immuno-Biological and, among Laboratories, them, thrombin Gunma, cleavage Japan) maybe and important,another kit because(R&D Systems, they localize Minneapolis, together MN, in various USA) that inflammations detect both FL-OPN (Figure1 )[and6 ,the7]. cleaved The cleaved prod- fragmentsucts, though maintain their epitopes OPN adhesive were unde functionfined (Ud-OPN) and expose (Figure new active1) [10,11]. domains that may impartThese new studies activities. enabled Thrombin the development cleavage leads of new to exposure treatment of based the SVVYGLR on metabolism cryptic of domainOPN. It thatwas inducesproposed cell that adhesion antibody and agains migrationt thrombin by binding cryptic toepitope integrins of OPNα4 andinhibitsα9 inmetastasis vitro [8]. Usingas well the as combinationtumor growth of antibodies,in a mouse namely,model of O-17 adult specific T-cell toleukemia the N-terminus (ATL) [12] of OPNand (Ileattenuates17–Gln31 liver) and inflammation 34E3 specific toin N-terminal a non-alcoholic thrombin-cleaved steatohepatitis OPN mouse (trOPN) model epitope [13]. (SerFurthermore,162–Arg168 ),new exposed derivatives by thrombin of brefelam digestion,ide, aromatic it was amide possible isolated to measure from the trOPN Dictyoste- [9]. Thereafter,lium cellular plasma slime full-lengthmodel, were OPN reported (FL-OPN) to inhibit andtrOPN OPN synthesis levels were in THP-1 measured cells using [14]. aIn commercialthis review, ELISA we mention kit (Immuno-Biological the biological activities Laboratories, of FL-OPN Gunma, and its Japan) cleaved and products another and kit (R&Dthe summary Systems, of Minneapolis, clinical studies MN, USA)measuring that detect them bothand FL-OPNimplicated and novel the cleaved roles of products, OPN in thoughinfectious their diseases. epitopes were undefined (Ud-OPN) (Figure1)[10,11]. FigureFigure 1. 1.ELISA ELISA system system employed employed to to measure measure osteopontin osteopontin (OPN). (OPN). (A ().A Amino). Amino acid acid sequence sequence of theof the epitope epitope of theof the antibodies antibod- usedies used for the for assay.the assay. (B). Antibodies(B). Antibodies used used for the for ELISAthe ELISA kits. kits. Abbreviations Abbreviations are FL-OPN,are FL-OPN, full-length full-leng OPN;th OPN; trOPN, trOPN, thrombin- throm- cleavedbin-cleaved OPN; OPN; and Ud-OPN, and Ud-OPN, undefined undefined OPN. OPN. 2. OPNThese Proteolysis studies enabled and Bioa thectivities development of Cleaved of new OPNs treatment based on metabolism of OPN. It wasOPN proposed undergoes that antibody numerous against posttranslational thrombin cryptic modifications, epitope of OPNsuch inhibitsas serine/threonine metastasis asphosphorylation, well as tumor growth sulfation, in a mouse glycosylation, model of adult glutamination, T-cell leukemia and (ATL) proteolytic [12] and processing, attenuates liverwhich inflammation significantly in contribute a non-alcoholic to the steatohepatitis functions of OPN. mouse Proteolytic model [13 ].processing Furthermore, either new in- derivativescreases or reduces of brefelamide, the ability aromatic of OPN amide to bind isolated to target from receptors. the Dictyostelium Thus, smallcellular differences slime model,in the cleavage were reported pattern to result inhibit in OPN a substantia synthesisl effect in THP-1 on the cells functions [14]. In of this OPN. review, To date, we mentionthrombin the [15–17], biological matrix
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