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• W2014097308 abstract "Osteopontin, a major noncollagenous bone protein, is an in vitro and in vivo substrate of tissue transglutaminase, which catalyzes formation of cross-linked protein aggregates. The roles of the enzyme and the polymeric osteopontin are presently not fully understood. In this study we provide evidence that transglutaminase treatment significantly increases the binding of osteopontin to collagen. This was tested with an enzyme-linked immunosorbent assay. The results also show that this increased interaction is clearly calcium-dependent and specific to osteopontin. In dot blot overlay assay 1 μg of collagen type I was able to bind 420 ng of in vitro prepared and purified polymeric osteopontin and only 83 ng of monomeric osteopontin, indicating that the transglutaminase treatment introduces a 5-fold amount of osteopontin onto collagen. Assays using a reversed situation showed that the collagen binding of the polymeric form of osteopontin appears to be dependent on its conformation in solution. Circular dichroism analysis of monomeric and polymeric osteopontin indicated that transglutaminase treatment induces a conformational change in osteopontin, probably exposing motives relevant to its interactions with other extracellular molecules. This altered collagen binding property of osteopontin may have relevance to its biological functions in tissue repair, bone remodeling, and collagen fibrillogenesis. Osteopontin, a major noncollagenous bone protein, is an in vitro and in vivo substrate of tissue transglutaminase, which catalyzes formation of cross-linked protein aggregates. The roles of the enzyme and the polymeric osteopontin are presently not fully understood. In this study we provide evidence that transglutaminase treatment significantly increases the binding of osteopontin to collagen. This was tested with an enzyme-linked immunosorbent assay. The results also show that this increased interaction is clearly calcium-dependent and specific to osteopontin. In dot blot overlay assay 1 μg of collagen type I was able to bind 420 ng of in vitro prepared and purified polymeric osteopontin and only 83 ng of monomeric osteopontin, indicating that the transglutaminase treatment introduces a 5-fold amount of osteopontin onto collagen. Assays using a reversed situation showed that the collagen binding of the polymeric form of osteopontin appears to be dependent on its conformation in solution. Circular dichroism analysis of monomeric and polymeric osteopontin indicated that transglutaminase treatment induces a conformational change in osteopontin, probably exposing motives relevant to its interactions with other extracellular molecules. This altered collagen binding property of osteopontin may have relevance to its biological functions in tissue repair, bone remodeling, and collagen fibrillogenesis. Tissue transglutaminase (TG) 1The abbreviations used are: TG, transglutaminase; OPN, osteopontin; HPLC, high performance liquid chromatography; PAGE, polyacrylamide gel electrophoresis; MALDI-TOF, matrix-assisted laser desorption ionization-time of flight; ELISA, enzyme-linked immunosorbent assay; BSA, bovine serum albumin; BAG-75, bone acidic glycoprotein-75; FPLC, fast protein liquid chromatography. 1The abbreviations used are: TG, transglutaminase; OPN, osteopontin; HPLC, high performance liquid chromatography; PAGE, polyacrylamide gel electrophoresis; MALDI-TOF, matrix-assisted laser desorption ionization-time of flight; ELISA, enzyme-linked immunosorbent assay; BSA, bovine serum albumin; BAG-75, bone acidic glycoprotein-75; FPLC, fast protein liquid chromatography. (EC 2.3.2.13) is a widely distributed intra- and extracellular calcium-dependent enzyme, which catalyzes the formation of high molecular mass complexes of its substrate proteins by creating isopeptide cross-links from glutamine and lysine residues and releasing ammonia (1Greenberg C.S. Birckbichler P.J. Rice R.H. FASEB J. 1991; 5: 3071-3077Crossref PubMed Scopus (927) Google Scholar, 2Aeschlimann D. Paulsson M. Thromb. Haemostasis. 1994; 71: 402-415Crossref PubMed Scopus (491) Google Scholar). TG is suggested to be involved in matrix maturation and stabilize the tissue with cross-links that are resistant to normal proteolysis (1Greenberg C.S. Birckbichler P.J. Rice R.H. FASEB J. 1991; 5: 3071-3077Crossref PubMed Scopus (927) Google Scholar, 2Aeschlimann D. Paulsson M. Thromb. Haemostasis. 1994; 71: 402-415Crossref PubMed Scopus (491) Google Scholar). TG is closely related to wound healing which suggests a role for it in tissue remodeling and repair (3Upchurch H.F. Conway E. Patterson Jr., M.K. Maxwell M. J. Cell. Physiol. 1991; 149: 375-382Crossref PubMed Scopus (141) Google Scholar, 4Bowness J.M. Tarr A.H. Wong T. Biochim. Biophys. Acta. 1988; 967: 234-240Crossref PubMed Scopus (54) Google Scholar). Immunohistochemical data have also demonstrated the presence of TG in mineralizing cartilage and bone (5Aeschlimann D. Wetterwald A. Fleisch H. Paulsson M. J. Cell Biol. 1993; 120: 1461-1470Crossref PubMed Scopus (166) Google Scholar, 6Aeschlimann D. Kaupp O. Paulsson M. J. Cell Biol. 1995; 129: 881-892Crossref PubMed Scopus (182) Google Scholar) and the enzyme is thought to participate in matrix cross-linking before the tissue undergoes calcification (5Aeschlimann D. Wetterwald A. Fleisch H. Paulsson M. J. Cell Biol. 1993; 120: 1461-1470Crossref PubMed Scopus (166) Google Scholar, 6Aeschlimann D. Kaupp O. Paulsson M. J. Cell Biol. 1995; 129: 881-892Crossref PubMed Scopus (182) Google Scholar). The number of proteins serving as glutaminyl substrates for TG is restricted indicating the physiological importance of its functions (1Greenberg C.S. Birckbichler P.J. Rice R.H. FASEB J. 1991; 5: 3071-3077Crossref PubMed Scopus (927) Google Scholar). The roles of TG and the actions of its enzymatic products, meaning high molecular weight proteins, are still unclear.Osteopontin (OPN), a prominent and potentially multifunctional acidic phosphoglycoprotein (7Butler W.T. Connect. Tissue Res. 1989; 23: 123-136Crossref PubMed Scopus (484) Google Scholar, 8Denhardt D.T. Guo X. FASEB J. 1993; 7: 1475-1482Crossref PubMed Scopus (1001) Google Scholar), is a substrate of TG (9Prince C.W. Dickie D. Krumdieck C.L. Biochem. Biophys. Res. Commun. 1991; 177: 1205-1210Crossref PubMed Scopus (115) Google Scholar, 10Sørensen E.S. Rasmussen L.K. Møller L. Jensen P.H. Højrup P. Petersen T.E. Biochem. J. 1994; 304: 13-16Crossref PubMed Scopus (72) Google Scholar, 11Beninati S. Senger D.R. Cordella-Miele E. Mukherjee A.B. Chackalaparampil I. Shanmugam V. Singh K. Mukherjee B.B. J. Biochem. 1994; 115: 675-682Crossref PubMed Scopus (82) Google Scholar). OPN is a major product of bone forming cells, osteoblasts, but is not specific to bone. It is also synthesized in other types of tissues and found in,e.g. inner ear, brain, kidney (7Butler W.T. Connect. Tissue Res. 1989; 23: 123-136Crossref PubMed Scopus (484) Google Scholar), and atherosclerotic plaques (13Fitzpatrick L.A. Severson A. Edwards W.D. Ingram R.T. J. Clin. Invest. 1994; 94: 1597-1604Crossref PubMed Google Scholar, 14Giachelli C.M. Bae N. Almeida M. Denhardt D.T. Alpers C.E. Schwartz S.M. J. Clin. Invest. 1993; 92: 1686-1696Crossref PubMed Scopus (589) Google Scholar), and it is also secreted into milk (12Sørensen E.S. Petersen T.E. J. Dairy Res. 1993; 60: 189-197Crossref PubMed Scopus (120) Google Scholar) and urine (15Shiraga H. Min W. VanDusen W.J. Clayman M.D. Miner D. Terrell C.H. Sherbotie J.R. Foreman J.W. Przysiecki C. Neilson E.G. Hoyer J.R. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 426-430Crossref PubMed Scopus (386) Google Scholar). Its production is also related to immunity, infection, and cancer (8Denhardt D.T. Guo X. FASEB J. 1993; 7: 1475-1482Crossref PubMed Scopus (1001) Google Scholar). Osteoblasts express OPN at an early developmental stage of bone formation (16Mark M.P. Prince C.W. Oosawa T. Gay S. Bronckers A.L.J.J. Butler W.T. J. Histochem. Cytochem. 1987; 35: 707-715Crossref PubMed Scopus (169) Google Scholar, 17Mark M.P. Butler W.T. Prince C.W. Finkelman R.D. Ruch J.-V. Differentation. 1988; 37: 123-136Crossref PubMed Scopus (198) Google Scholar). In bone, OPN is deposited into unmineralized matrix prior to calcification and thereon localized at various tissue interfaces, e.g. cement lines, lamina limitans, and between collagen fibrils of fully matured hard tissues (18McKee M.D. Nanci A. Microsc. Res. Tech. 1996; 33: 141-164Crossref PubMed Scopus (296) Google Scholar). Recent knock-out mice experiments by Liaw et al. (19Liaw L. Birk D.E. Ballas C.B. Whitsitt J.S. Davidson J.M. Hogan B.L.M. J. Clin. Invest. 1998; 101: 1468-1478Crossref PubMed Google Scholar) indicate that OPN, more specifically, functions in tissue repair, matrix organization, and collagen fibrillogenesis.The role of polymeric OPN, resulting from cross-linking by TG, is unknown. We have previously demonstrated that osteocalcin inhibits TG activity in vitro as measured by cross-linking of osteopontin (20Kaartinen M.T. Pirhonen A. Linnala-Kankkunen A. Mäenpää P.H. J. Biol. Chem. 1997; 272: 22736-22741Crossref PubMed Scopus (72) Google Scholar). Since recent gene knock-out experiments have demonstrated that osteocalcin is an inhibitor of bone formation (21Ducy P. Desbois C. Boyce B. Pinero G. Story B. Dunstan C. Smith E. Bonadio J. Goldstein S. Gundberg C. Bradley A. Karsenty G. Nature. 1996; 382: 448-452Crossref PubMed Scopus (1365) Google Scholar), our results suggest that TG activity and the OPN aggregates may be involved in enhancement of biomineralization or matrix maturation that precedes it. In this study the collagen binding properties of polymeric and monomeric OPN were investigated since this feature could be pivotal for the maturation and organization of the bone matrix as well as for the mineralization event. The collagen types examined were the fiber forming collagens, types I and II, III and V, which are synthesized in,e.g. bone, cartilage, and vascular smooth muscle cells (22Liu S.H. Yang R.-S. Al-shaikh R. Lane J.M. Clin. Orthop. Relat. Res. 1995; 318: 265-278PubMed Google Scholar), and type IV, which is a basement membrane collagen (23Yurchenco P.D. O′Rear J.J. Methods Enzymol. 1994; 245: 489-518Crossref PubMed Scopus (54) Google Scholar). We provide evidence that OPN, as a high molecular weight complex form, exhibits significantly increased binding ability to all tested collagens. This may result from an altered conformation of the OPN after polymerization as observed by circular dichroism measurements. A more stabile structure and amplified collagen binding property, after treating OPN with an enzyme that is intimately involved in tissue repair, brings further support to OPN′s role as a tissue remodeling protein and gives an insight into the functions of the polymeric OPN.DISCUSSIONWe have previously reported that the TG-catalyzed cross-linking of OPN is inhibited in vitro by osteocalcin (20Kaartinen M.T. Pirhonen A. Linnala-Kankkunen A. Mäenpää P.H. J. Biol. Chem. 1997; 272: 22736-22741Crossref PubMed Scopus (72) Google Scholar). In light of the finding that osteocalcin apparently functions as a mineralization inhibitor in the mouse model (21Ducy P. Desbois C. Boyce B. Pinero G. Story B. Dunstan C. Smith E. Bonadio J. Goldstein S. Gundberg C. Bradley A. Karsenty G. Nature. 1996; 382: 448-452Crossref PubMed Scopus (1365) Google Scholar), the TG-mediated protein aggregation event might have an advantageous effect on mineralization or matrix maturation that precedes it. The results of this study demonstrated that OPN aggregates exhibited a property of increased binding to collagen as compared with the monomeric form. Another acidic phosphorylated TG-substrate, casein, did not posses this property, indicating the specificity of collagen binding of TG-treated OPN. TG treatment appeared to introduce a 5-fold amount of OPN onto collagens, but predominantly when OPN and its polymer were in solution. This might indicate that a specific conformation, achieved in solution, might be required for binding. This elevated collagen binding property of polymeric OPN can result from: 1) its increased affinity for and association with collagen fibrils, therefore resulting in more rapid coating of collagen during the incubation; 2) or the polymer may have more binding sites on collagen resulting in a more efficient coating. Both could be explained by a conformational change observed in the CD experiments. Alteration in the OPN conformation of the monomer unit and/or several OPN molecules packed together could expose or create motives relevant to its interactive properties with collagen. Most interestingly, in comparison with other types of collagens, collagen type V appeared to have a very distinctive and different behavior. It seemed to bind the polymeric OPN even in the absence of calcium, but only when the polymer was in solution. Soluble collagen type V also seemed to have the greatest affinity for immobilized monomeric OPN. This might not only reflect a special function of collagen type V in extracellular matrix maturation (or bone formation) sequence, but also demonstrates the difference between the two forms of OPN.OPN′s in vitro behavior with TG clearly shows that OPN is a substrate of this enzyme. OPN functioning also as an in vivosubstrate is supported by several studies. The transglutaminase reactive acceptor glutamines are well conserved in all known OPN sequences, indicating the significance of the motif to its functions (27Sørensen E.S. Petersen T.E. Ann. N. Y. Acad. Sci. 1995; 760: 363-366Crossref PubMed Scopus (15) Google Scholar). OPN polymers have been found in different physiological sources such as bone (10Sørensen E.S. Rasmussen L.K. Møller L. Jensen P.H. Højrup P. Petersen T.E. Biochem. J. 1994; 304: 13-16Crossref PubMed Scopus (72) Google Scholar), secreted by smooth muscle cells (28Giachelli C.M. Liaw L. Murry C.E. Schwartz S.M. Almeida M. Ann. N. Y. Acad. Sci. 1995; 760: 109-126Crossref PubMed Scopus (173) Google Scholar), and in milk as shown by our study. The observation that TG has been found to be active in bone in areas undergoing mineralization (5Aeschlimann D. Wetterwald A. Fleisch H. Paulsson M. J. Cell Biol. 1993; 120: 1461-1470Crossref PubMed Scopus (166) Google Scholar, 6Aeschlimann D. Kaupp O. Paulsson M. J. Cell Biol. 1995; 129: 881-892Crossref PubMed Scopus (182) Google Scholar) where also OPN has been localized in high concentrations (29McKee M.D. Glimcher M.J. Nanci A. Anat. Rec. 1992; 234: 479-492Crossref PubMed Scopus (141) Google Scholar), gives us a reason to believe that TG and OPN are able to interact in these areas. Indeed, Sørensen et al. (10Sørensen E.S. Rasmussen L.K. Møller L. Jensen P.H. Højrup P. Petersen T.E. Biochem. J. 1994; 304: 13-16Crossref PubMed Scopus (72) Google Scholar) have shown with Western blotting that EDTA extracts of bovine bone contain high-molecular mass OPN complexes. Functional or basic biochemical studies of OPN aggregates have not been performed earlier and the functions of these complexes have only been speculative.Based on the results of this study, we suggest that the TG-mediated cross-linking of OPN may be directed to enhance the “glue-like” adhesion properties required in the processes that need collagen binding, e.g. in the adherence of different tissue interfacial structures (new and old bone), collagen fibrillogenesis, and wound healing. The enhanced adhesive property would be highly important for a protein postulated to function as a “mortar between bricks” (18McKee M.D. Nanci A. Microsc. Res. Tech. 1996; 33: 141-164Crossref PubMed Scopus (296) Google Scholar). Although OPN is predominantly localized between collagen fibrils in fully matured hard tissue (29McKee M.D. Glimcher M.J. Nanci A. Anat. Rec. 1992; 234: 479-492Crossref PubMed Scopus (141) Google Scholar), the reports on its affinity for collagens have shown evidence of no or only moderate attachment (7Butler W.T. Connect. Tissue Res. 1989; 23: 123-136Crossref PubMed Scopus (484) Google Scholar, 30Chen Y. Bal B.S. Gorski J.P. J. Biol. Chem. 1992; 267: 24871-24878Abstract Full Text PDF PubMed Google Scholar). The results of our study suggest that OPN has a significant affinity for collagens, but predominantly as a polymeric form. TG has been recently characterized as a biological glue for cartilage-cartilage interfaces (31Jürgensen K. Aeschlimann D. Cavin V. Genge M. Hunziker E.B. J. Bone Joint Surg. 1997; 79: 185-193Crossref PubMed Scopus (75) Google Scholar). Therefore, OPN as a TG substrate could be an essential component of the “glue” and the polymerization indeed a prerequisite for its functioning as an adhesive protein.Since isopeptide bonds produced by TG are resistant to normal proteolysis (1Greenberg C.S. Birckbichler P.J. Rice R.H. FASEB J. 1991; 5: 3071-3077Crossref PubMed Scopus (927) Google Scholar, 2Aeschlimann D. Paulsson M. Thromb. Haemostasis. 1994; 71: 402-415Crossref PubMed Scopus (491) Google Scholar), the polymeric OPN may substantially contribute to the overall integrity and strength of the extracellular matrix where it is present. This kind of strenghtening might be required, for example, in wound healing. In bone, it is also possible that the binding of OPN to collagen could be further stabilized by additional cross-linking by TG since covalent collagen-phosphoprotein complexes have been foundin vivo in bone (32Curley-Joseph J. Veis A. J. Dent. Res. 1979; 58: 1625-1633Crossref PubMed Scopus (41) Google Scholar) and several collagens have been identified as substrates of TG (2Aeschlimann D. Paulsson M. Thromb. Haemostasis. 1994; 71: 402-415Crossref PubMed Scopus (491) Google Scholar, 33Kleman J.-P. Aeschlimann D. Paulsson M. van der Rest M. Biochemistry. 1995; 34: 13768-13775Crossref PubMed Scopus (103) Google Scholar). Osteonectin (6Aeschlimann D. Kaupp O. Paulsson M. J. Cell Biol. 1995; 129: 881-892Crossref PubMed Scopus (182) Google Scholar) and fibronectin (11Beninati S. Senger D.R. Cordella-Miele E. Mukherjee A.B. Chackalaparampil I. Shanmugam V. Singh K. Mukherjee B.B. J. Biochem. 1994; 115: 675-682Crossref PubMed Scopus (82) Google Scholar) are also TG substrates indicating the presence of non-collagenous protein-protein cross-links in the extracellular matrix.In addition to the plausable adhesive and matrix-stabilizing (or matrix organizing) properties of the polymeric OPN/TG activity, a collagen-bound acidic cross-link network could also provide suitable bedding for mineral growth in bone (34Boskey A.L. Clin. Orthop. Relat. Res. 1992; 281: 244-274PubMed Google Scholar, 35Glimcher M.J. Phil. Trans. R. Soc. Lond. B. 1984; 304: 479-508Crossref PubMed Google Scholar, 36Glimcher M.J. Anat. Rec. 1989; 224: 139-153Crossref PubMed Scopus (260) Google Scholar). Calcification of the matrix follows matrix deposition and maturation in the bone formation sequence, distinguishing it from other types of extracellular matrices. It has been shown that collagen per se is not able to calcify (37Endo A. Glimcher M. Connect. Tissue Res. 1989; 21: 179-196Crossref PubMed Scopus (42) Google Scholar). To accumulate and crystallize calcium and phosphate into hydroxyapatite, collagens seem to require other charged molecules on their surface (37Endo A. Glimcher M. Connect. Tissue Res. 1989; 21: 179-196Crossref PubMed Scopus (42) Google Scholar). Bone phosphoproteins have been postulated to function as such molecules (34Boskey A.L. Clin. Orthop. Relat. Res. 1992; 281: 244-274PubMed Google Scholar). Indeed, phosphoproteins have been observed to initiate in vitro mineral formation when bound to collagen (37Endo A. Glimcher M. Connect. Tissue Res. 1989; 21: 179-196Crossref PubMed Scopus (42) Google Scholar) and to inhibit crystal growth in vitro when in solution (38Romberg R.W. Werness P.G. Riggs B.L. Mann K.G. Biochemistry. 1986; 25: 1176-1180Crossref PubMed Scopus (245) Google Scholar, 39Boskey A.L. Maresca M. Ullrich W. Doty S.B. Butler W.T. Prince C.W. Bone Miner. 1993; 22: 147-159Abstract Full Text PDF PubMed Scopus (382) Google Scholar, 40Hunter G.K. Kyle C.L. Goldberg H.A. Biochem. J. 1994; 300: 723-728Crossref PubMed Scopus (368) Google Scholar). OPN, as a phosphoprotein, could function as an initiator when bound to collagen as a polymeric form or provide a protein scaffold together with collagen for other bone matrix macromolecules, such as bone sialoprotein, to bind and initiate calcification. The calcium binding properties of OPN were not specifically altered after polymerization (data not shown). However, OPN is known as a high capacity calcium binder (30Chen Y. Bal B.S. Gorski J.P. J. Biol. Chem. 1992; 267: 24871-24878Abstract Full Text PDF PubMed Google Scholar).A protein aggregation event may have an important role in bone formation, maturation, and calcification in general. Gorski et al. (41Gorski J.P. Kremer E.A. Chen Y. Ryan S. Fullenkamp C. Delviscio J. Jensen K. McKee M.D. J. Cell. Biochem. 1997; 64: 547-564Crossref PubMed Scopus (25) Google Scholar, 42Gorski J.P. Calcif. Tissue Int. 1992; 50: 391-396Crossref PubMed Scopus (205) Google Scholar) have reported that bone acidic glycoprotein-75 (BAG-75) undergoes a spontaneous Ca2+-induced polymerization, which increases its collagen binding activity. The aggregated forms of BAG-75 are resistant to reducing and denaturing conditions indicating their covalent nature, which suggests that intramolecular cross-links could be present. High molecular weight complexes of BAG-75 were detected in extracts of mineralizing calvarial explant cultures (41Gorski J.P. Kremer E.A. Chen Y. Ryan S. Fullenkamp C. Delviscio J. Jensen K. McKee M.D. J. Cell. Biochem. 1997; 64: 547-564Crossref PubMed Scopus (25) Google Scholar). More interestingly, newly synthesized BAG-75 from these cultures was present entirely in large macromolecular complexes, whereas non-mineralizing ROS 17/2.8 cultures produced only monomeric BAG-75 (41Gorski J.P. Kremer E.A. Chen Y. Ryan S. Fullenkamp C. Delviscio J. Jensen K. McKee M.D. J. Cell. Biochem. 1997; 64: 547-564Crossref PubMed Scopus (25) Google Scholar). Other kinds of enzymatic modulation have also recently been reported to have an effect on bone matrix protein interaction property. Sasaki et al. (43Sasaki T. Göhring W. Mann K. Maurer P. Hohenester E. Knäuper V. Murphy G. Timpl R. J. Biol. Chem. 1997; 272: 9237-9243Abstract Full Text Full Text PDF PubMed Scopus (139) Google Scholar) demonstrated,e.g. that cleavage of osteonectin by metalloproteinases results in a 7–20-fold increase in its binding to collagens.Those results together with ours suggest that biological functions of bone matrix proteins may largely depend on their post-translational modifications, conformational alterations, and surrounding ion concentrations, and that especially a covalent aggregation event may have a pivotal role for tissue maturation and development. In light of our findings, we suggest that TG activity could result in an altered function of OPN resulting from altered conformation accompanied with amplified collagen binding property. Instead of monomeric OPN, the complex form of OPN might be the OPN that is involved in collagen fibrillogenesis, matrix maturation, and possibly mineralization. Importantly, the function of OPN could therefore be regulated by TG expression and tissue distribution during different stages of tissue remodeling or bone formation. Tissue transglutaminase (TG) 1The abbreviations used are: TG, transglutaminase; OPN, osteopontin; HPLC, high performance liquid chromatography; PAGE, polyacrylamide gel electrophoresis; MALDI-TOF, matrix-assisted laser desorption ionization-time of flight; ELISA, enzyme-linked immunosorbent assay; BSA, bovine serum albumin; BAG-75, bone acidic glycoprotein-75; FPLC, fast protein liquid chromatography. 1The abbreviations used are: TG, transglutaminase; OPN, osteopontin; HPLC, high performance liquid chromatography; PAGE, polyacrylamide gel electrophoresis; MALDI-TOF, matrix-assisted laser desorption ionization-time of flight; ELISA, enzyme-linked immunosorbent assay; BSA, bovine serum albumin; BAG-75, bone acidic glycoprotein-75; FPLC, fast protein liquid chromatography. (EC 2.3.2.13) is a widely distributed intra- and extracellular calcium-dependent enzyme, which catalyzes the formation of high molecular mass complexes of its substrate proteins by creating isopeptide cross-links from glutamine and lysine residues and releasing ammonia (1Greenberg C.S. Birckbichler P.J. Rice R.H. FASEB J. 1991; 5: 3071-3077Crossref PubMed Scopus (927) Google Scholar, 2Aeschlimann D. Paulsson M. Thromb. Haemostasis. 1994; 71: 402-415Crossref PubMed Scopus (491) Google Scholar). TG is suggested to be involved in matrix maturation and stabilize the tissue with cross-links that are resistant to normal proteolysis (1Greenberg C.S. Birckbichler P.J. Rice R.H. FASEB J. 1991; 5: 3071-3077Crossref PubMed Scopus (927) Google Scholar, 2Aeschlimann D. Paulsson M. Thromb. Haemostasis. 1994; 71: 402-415Crossref PubMed Scopus (491) Google Scholar). TG is closely related to wound healing which suggests a role for it in tissue remodeling and repair (3Upchurch H.F. Conway E. Patterson Jr., M.K. Maxwell M. J. Cell. Physiol. 1991; 149: 375-382Crossref PubMed Scopus (141) Google Scholar, 4Bowness J.M. Tarr A.H. Wong T. Biochim. Biophys. Acta. 1988; 967: 234-240Crossref PubMed Scopus (54) Google Scholar). Immunohistochemical data have also demonstrated the presence of TG in mineralizing cartilage and bone (5Aeschlimann D. Wetterwald A. Fleisch H. Paulsson M. J. Cell Biol. 1993; 120: 1461-1470Crossref PubMed Scopus (166) Google Scholar, 6Aeschlimann D. Kaupp O. Paulsson M. J. Cell Biol. 1995; 129: 881-892Crossref PubMed Scopus (182) Google Scholar) and the enzyme is thought to participate in matrix cross-linking before the tissue undergoes calcification (5Aeschlimann D. Wetterwald A. Fleisch H. Paulsson M. J. Cell Biol. 1993; 120: 1461-1470Crossref PubMed Scopus (166) Google Scholar, 6Aeschlimann D. Kaupp O. Paulsson M. J. Cell Biol. 1995; 129: 881-892Crossref PubMed Scopus (182) Google Scholar). The number of proteins serving as glutaminyl substrates for TG is restricted indicating the physiological importance of its functions (1Greenberg C.S. Birckbichler P.J. Rice R.H. FASEB J. 1991; 5: 3071-3077Crossref PubMed Scopus (927) Google Scholar). The roles of TG and the actions of its enzymatic products, meaning high molecular weight proteins, are still unclear. Osteopontin (OPN), a prominent and potentially multifunctional acidic phosphoglycoprotein (7Butler W.T. Connect. Tissue Res. 1989; 23: 123-136Crossref PubMed Scopus (484) Google Scholar, 8Denhardt D.T. Guo X. FASEB J. 1993; 7: 1475-1482Crossref PubMed Scopus (1001) Google Scholar), is a substrate of TG (9Prince C.W. Dickie D. Krumdieck C.L. Biochem. Biophys. Res. Commun. 1991; 177: 1205-1210Crossref PubMed Scopus (115) Google Scholar, 10Sørensen E.S. Rasmussen L.K. Møller L. Jensen P.H. Højrup P. Petersen T.E. Biochem. J. 1994; 304: 13-16Crossref PubMed Scopus (72) Google Scholar, 11Beninati S. Senger D.R. Cordella-Miele E. Mukherjee A.B. Chackalaparampil I. Shanmugam V. Singh K. Mukherjee B.B. J. Biochem. 1994; 115: 675-682Crossref PubMed Scopus (82) Google Scholar). OPN is a major product of bone forming cells, osteoblasts, but is not specific to bone. It is also synthesized in other types of tissues and found in,e.g. inner ear, brain, kidney (7Butler W.T. Connect. Tissue Res. 1989; 23: 123-136Crossref PubMed Scopus (484) Google Scholar), and atherosclerotic plaques (13Fitzpatrick L.A. Severson A. Edwards W.D. Ingram R.T. J. Clin. Invest. 1994; 94: 1597-1604Crossref PubMed Google Scholar, 14Giachelli C.M. Bae N. Almeida M. Denhardt D.T. Alpers C.E. Schwartz S.M. J. Clin. Invest. 1993; 92: 1686-1696Crossref PubMed Scopus (589) Google Scholar), and it is also secreted into milk (12Sørensen E.S. Petersen T.E. J. Dairy Res. 1993; 60: 189-197Crossref PubMed Scopus (120) Google Scholar) and urine (15Shiraga H. Min W. VanDusen W.J. Clayman M.D. Miner D. Terrell C.H. Sherbotie J.R. Foreman J.W. Przysiecki C. Neilson E.G. Hoyer J.R. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 426-430Crossref PubMed Scopus (386) Google Scholar). Its production is also related to immunity, infection, and cancer (8Denhardt D.T. Guo X. FASEB J. 1993; 7: 1475-1482Crossref PubMed Scopus (1001) Google Scholar). Osteoblasts express OPN at an early developmental stage of bone formation (16Mark M.P. Prince C.W. Oosawa T. Gay S. Bronckers A.L.J.J. Butler W.T. J. Histochem. Cytochem. 1987; 35: 707-715Crossref PubMed Scopus (169) Google Scholar, 17Mark M.P. Butler W.T. Prince C.W. Finkelman R.D. Ruch J.-V. Differentation. 1988; 37: 123-136Crossref PubMed Scopus (198) Google Scholar). In bone, OPN is deposited into unmineralized matrix prior to calcification and thereon localized at various tissue interfaces, e.g. cement lines, lamina limitans, and between collagen fibrils of fully matured hard tissues (18McKee M.D. Nanci A. Microsc. Res. 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