Proteolytic processing of osteopontin by PHEX and accumulation of osteopontin fragments in Hyp mouse bone, the murine model of X-linked hypophosphatemia

Journal of Bone and Mineral Research

Volumn 28, Issue 3, 2013, Pages 688-699

  Barros, Nilana M T ^a   Hoac, Betty ^b   Neves, Raquel L ^a   Addison, William N ^c   Assis, Diego M ^a   Murshed, Monzur ^b,d   Carmona, Adriana K ^a   McKee, Marc D ^b,e  

^a FEDERAL UNIVERSITY OF SÃO PAULO   (Brazil)

^b MCGILL UNIVERSITY   (Canada)

^c HARVARD SCHOOL OF DENTAL MEDICINE   (United States)

^d MCGILL UNIVERSITY   (Canada)

^e MCGILL UNIVERSITY   (Canada)

Author keywords

BONE ENZYMES; MINERALIZATION; OSTEOPONTIN; PHEX; X LINKED HYPOPHOSPHATEMIA

Indexed keywords

BONE SIALOPROTEIN; OSTEOPONTIN; PHOSPHATE REGULATING NEUTRAL ENDOPEPTIDASE;

AMINO TERMINAL SEQUENCE; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; ELECTRON MICROSCOPY; ENZYME ACTIVITY; FEMUR; GEL ELECTROPHORESIS; HYDROLYSIS; IMMUNOHISTOCHEMISTRY; MALE; MASS SPECTROMETRY; MOUSE; NONHUMAN; OSTEOMALACIA; POLYACRYLAMIDE GEL ELECTROPHORESIS; PROTEIN DEGRADATION; PROTEIN MOTIF; PROTEIN PROCESSING; TIBIA; WESTERN BLOTTING; WILD TYPE; X LINKED HYPOPHOSPHATEMIC RICKETS;

AMINO ACID SEQUENCE; ANIMALS; BLOTTING, WESTERN; BONE AND BONES; DISEASE MODELS, ANIMAL; ELECTROPHORESIS, POLYACRYLAMIDE GEL; HYPOPHOSPHATEMIC RICKETS, X-LINKED DOMINANT; IMMUNOHISTOCHEMISTRY; MASS SPECTROMETRY; MICE; MOLECULAR SEQUENCE DATA; OSTEOPONTIN; PHEX PHOSPHATE REGULATING NEUTRAL ENDOPEPTIDASE; PROTEOLYSIS;

EID: 84873962431     PISSN: 08840431     EISSN: 15234681     Source Type: Journal    
DOI: 10.1002/jbmr.1766     Document Type: Article

References (90)

1. Francis F, Hennig S, Korn B, Reinhardt R, de Jong P, Poustka A, Lehrach H, Rowe PSN, Goulding JN, Summerfield T, Mountford R, Read AP, Popowska E, Pronicka E, Davies KE, O'Riordan JLH, Econs MJ, Nesbitt T, Drezner MK, Oudet C, Pannetier S, Hanauer A, Strom TM, Meindl A, Lorenz B, Cagnoli B, Mohnike KL, Murken J, Meitinger T., A gene (PEX) with homologies to endopeptidases is mutated in patients with X-linked hypophosphatemic rickets. Nat Genet. 1995; 11 (2): 130-6.
2. Turner AJ, Tanzawa K., Mammalian membrane metallopeptidases: NEP, ECE, KELL, and PEX. FASEB J. 1997; 11 (5): 355-64.
3. Oefner C, D'Arcy A, Hennig M, Winkler FK, Dale GE., Structure of human neutral endopeptidase (neprilysin) complexed with phosphoramidon. J Mol Biol. 2000; 296 (2): 341-9.
4. Econs MJ, Francis F., Positional cloning of the PEX gene: new insights into the pathophysiology of X-linked hypophosphatemic rickets. Am J Physiol. 1997; 273 (4): F489-98.
5. Tenenhouse HS., X-linked hypophosphataemia: a homologous disorder in humans and mice. Nephrol Dial Transplant. 1999; 14 (2): 333-41.
6. Liu S, Tang W, Fang J, Ren J, Li H, Xiao Z, Quarles LD., Novel regulators of Fgf23 expression and mineralization in Hyp bone. Mol Endocrinol. 2009; 23 (9): 1505-18.
7. Onishi T, Umemura S, Shintani S, Ooshima T., Phex mutation causes overexpression of FGF23 in teeth. Arch Oral Biol. 2008; 53 (2): 99-104.
8. Farrow EG, White KE., Recent advances in renal phosphate handling. Nat Rev Nephrol. 2010; 6 (4): 207-17.
9. Martin A, Liu S, David V, Li H, Karydis A, Feng JQ, Quarles LD., Bone proteins PHEX and DMP1 regulate fibroblastic growth factor Fgf23 expression in osteocytes through a common pathway involving FGF receptor (FGFR) signaling. FASEB J. 2011; 25 (8): 2551-62.
10. Boukpessi T, Gaucher C, Léger T, Salmon B, Faouder JL, Willig C, Rowe PS, Garabédian M, Meilhac O, Chaussain C., Abnormal presence of the matrix extracellular phosphoglycoprotein-derived acidic serine- and aspartate-rich motif peptide in human hypophosphatemic dentin. Am J Pathol. 2010; 177 (2): 803-12.
11. Boukpessi T, Septier D, Bagga S, Garabedian M, Goldberg M, Chaussain-Miller C., Dentin alteration of deciduous teeth in human hypophosphatemic rickets. Calcif Tissue Int. 2006; 79 (5): 294-300.
12. Bresler D, Bruder J, Mohnike K, Fraser WD, Rowe PSN., Serum MEPE-ASARM-peptides are elevated in X-linked rickets (HYP): implications for phosphaturia and rickets. J Endocrinol. 2004; 183 (3): R1-R9.
13. Addison WN, Masica DL, Gray JJ, McKee MD., Phosphorylation-dependent inhibition of mineralization by osteopontin ASARM peptides is regulated by PHEX cleavage. J Bone Miner Res. 2010; 25 (4): 695-705.
14. Addison WN, Nakano Y, Loisel T, Crine P, McKee MD., MEPE-ASARM peptides control extracellular matrix mineralization by binding to hydroxyapatite: an inhibition regulated by PHEX cleavage of ASARM. J Bone Miner Res. 2008; 23 (10): 1638-49.
15. Jono S, Peinado C, Giachelli CM., Phosphorylation of osteopontin is required for inhibition of vascular smooth muscle cell calcification. J Biol Chem. 2000; 275 (26): 20197-203.
16. Christensen B, Nielsen MS, Haselmann KF, Petersen TE, Sørensen ES., Post-translationally modified residues of native human osteopontin are located in clusters: identification of 36 phosphorylation and five O-glycosylation sites and their biological implications. Biochem J. 2005; 390 (1): 285-92.
17. Christensen B, Petersen TE, Sørensen ES., Post-translational modification and proteolytic processing of urinary osteopontin. Biochem J. 2008; 411 (1): 53-61.
18. Gericke A, Qin C, Spevak L, Fujimoto Y, Butler WT, Sørensen ES, Boskey AL., Importance of phosphorylation for osteopontin regulation of biomineralization. Calcif Tissue Int. 2005; 77 (1): 45-54.
19. Addison WN, Azari F, Sørensen ES, Kaartinen MT, McKee MD., Pyrophosphate inhibits mineralization of osteoblast cultures by binding to mineral, up-regulating osteopontin, and inhibiting alkaline phosphatase activity. J Biol Chem. 2007; 282 (21): 15872-83.
20. Qin C, Baba O, Butler WT., Post-translational modifications of sibling proteins and their roles in osteogenesis and dentinogenesis. Crit Rev Oral Biol Med. 2004; 15 (3): 126-36.
21. Martin A, David V, Laurence JS, Schwarz PM, Lafer EM, Hedge A-M, Rowe PSN., Degradation of MEPE, DMP1, and release of SIBLING ASARM-peptides (minhibins): ASARM-peptide(s) are directly responsible for defective mineralization in HYP. Endocrinology. 2008; 149 (4): 1757-72.
22. Qin C, D'Souza R, Feng JQ., Dentin matrix protein 1 (DMP1): new and important roles for biomineralization and phosphate homeostasis. J Dent Res. 2007; 86 (12): 1134-41.
23. Gericke A, Qin C, Sun Y, Redfern R, Redfern D, Fujimoto Y, Taleb H, Butler WT, Boskey AL., Different forms of DMP1 play distinct roles in mineralization. J Dent Res. 2010; 89 (4): 355-9.
24. Maciejewska I, Cowan C, Svoboda K, Butler WT, D'Souza R, Qin C., The NH2-terminal and COOH-terminal fragments of dentin matrix protein 1 (DMP1) localize differently in the compartments of dentin and growth plate of bone. J Histochem Cytochem. 2009; 57 (2): 155-66.
25. von Marschall Z, Fisher LW., Dentin matrix protein-1 isoforms promote differential cell attachment and migration. J Biol Chem. 2008; 283 (47): 32730-40.
26. Fisher LW, Fedarko NS., Six genes expressed in bones and teeth encode the current members of the SIBLING family of proteins. Connect Tissue Res. 2003; 44: 33-40.
27. Kawasaki K., The SCPP gene family and the complexity of hard tissues in vertebrates. Cells Tissues Organs. 2011; 194 (2-4): 108-12.
28. Kawasaki K, Weiss KM., Evolutionary genetics of vertebrate tissue mineralization: the origin and evolution of the secretory calcium-binding phosphoprotein family. J Exp Zool B Mol Dev Evol. 2006; 306B (3): 295-316.
29. Kawasaki K, Weiss KM., SCPP gene evolution and the dental mineralization continuum. J Dent Res. 2008; 87 (6): 520-31.
30. McKee MD, Nanci A., Postembedding colloidal-gold immunocytochemistry of noncollagenous extracellular matrix proteins in mineralized tissues. Microsc Res Tech. 1995; 31 (1): 44-62.
31. McKee MD, Nanci A., Osteopontin at mineralized tissue interfaces in bone, teeth, and osseointegrated implants: ultrastructural distribution and implications for mineralized tissue formation, turnover, and repair. Microsc Res Tech. 1996; 33 (2): 141-64.
32. Boskey AL, Maresca M, Ullrich W, Doty SB, Butler WT, Prince CW., Osteopontin-hydroxyapatite interactions in vitro: inhibition of hydroxyapatite formation and growth in a gelatin-gel. Bone Miner. 1993; 22 (2): 147-59.
33. McKee MD, Nanci A., Osteopontin and the bone remodeling sequence. Colloidal-gold immunocytochemistry of an interfacial extracellular matrix protein. Ann NY Acad Sci. 1995; 760: 177-89.
34. Boskey AL, Spevak L, Paschalis E, Doty SB, McKee MD., Osteopontin deficiency increases mineral content and mineral crystallinity in mouse bone. Calcif Tissue Int. 2002; 71 (2): 145-54.
35. Campos M, Couture C, Hirata IY, Juliano MA, Loisel TP, Crine P, Juliano L, Boileau G, Carmona AK., Human recombinant endopeptidase PHEX has a strict S1' specificity for acidic residues and cleaves peptides derived from fibroblast growth factor-23 and matrix extracellular phosphoglycoprotein. Biochem J. 2003; 373 (Pt 1): 271-9.
36. Barros NMT, Nascimento FD, Oliveira V, Juliano MA, Juliano L, Loisel T, Nader HB, Boileau G, Tersariol ILS, Carmona AK., The critical interaction of the metallopeptidase PHEX with heparan sulfate proteoglycans. Int J Biochem Cell Biol. 2008; 40 (12): 2781-92.
37. Boileau G, Tenenhouse HS, Desgroseillers L, Crine P., Characterization of PHEX endopeptidase catalytic activity: identification of parathyroid-hormone- related peptide107-139 as a substrate and osteocalcin, PPi and phosphate as inhibitors. Biochem J. 2001; 355 (Pt 3): 707-13.
38. Goldberg HA, Sodek J., Purification of mineralized tissue-associated osteopontin. Methods Cell Sci. 1994; 16 (3): 211-5.
39. Shevchenko A, Tomas H, Havlis J, Olsen JV, Mann M., In-gel digestion for mass spectrometric characterization of proteins and proteomes. Nat Protoc. 2006; 1 (6): 2856-60.
40. Consortium TU., Reorganizing the protein space at the Universal Protein Resource (UniProt). Nucleic Acids Res. 2012; 40 (D1): D71-5.
41. Wasiak S, Legendre-Guillemin V, Puertollano R, Blondeau F, Girard M, de Heuvel E, Boismenu D, Bell AW, Bonifacino JS, McPherson PS., Enthoprotin: a novel clathrin-associated protein identified through subcellular proteomics. J Cell Biol. 2002; 158 (5): 855-62.
42. Keller A, Nesvizhskii AI, Kolker E, Aebersold R., Empirical statistical model to estimate the accuracy of peptide identifications made by MS/MS and database search. Anal Chem. 2002; 74 (20): 5383-92.
43. Nesvizhskii AI, Keller A, Kolker E, Aebersold R., A statistical model for identifying proteins by tandem mass spectrometry. Anal Chem. 2003; 75 (17): 4646-58.
44. Sabbagh Y, Boileau G, Campos M, Carmona AK, Tenenhouse HS., Structure and function of disease-causing missense mutations in the PHEX gene. J Clin Endocrinol Metab. 2003; 88 (5): 2213-22.
45. Beck L, Karaplis AC, Amizuka N, Hewson AS, Ozawa H., Targeted inactivation of Npt2 in mice leads to severe renal phosphate wasting, hypercalciuria, and skeletal abnormalities. Proc Natl Acad Sci USA. 1998; 95 (9): 5372-7.
46. Rowe PSN, Kumagai Y, Gutierrez G, Garrett IR, Blacher R, Rosen D, Cundy J, Navvab S, Chen D, Drezner MK, Quarles LD, Mundy GR., MEPE has the properties of an osteoblastic phosphatonin and minhibin. Bone. 2004; 34 (2): 303-19.
47. Onishi T, Okawa R, Ogawa T, Shintani S, Ooshima T., Phex mutation causes the reduction of npt2b mRNA in teeth. J Dent Res. 2007; 86 (2): 158-62.
48. Addison WN, McKee MD., ASARM mineralization hypothesis: a bridge to progress. J Bone Miner Res. 2010; 25 (5): 1191-2.
49. Du L, Desbarats M, Viel J, Glorieux FH, Cawthorn C, Ecarot B., cDNA cloning of the murine Pex gene implicated in X-linked hypophosphatemia and evidence for expression in bone. Genomics. 1996; 36 (1): 22-8.
50. Beck L, Soumounou Y, Martel J, Krishnamurthy G, Gauthier C, Goodyer CG, Tenenhouse HS., Pex/PEX tissue distribution and evidence for a deletion in the 3' region of the Pex gene in X-linked hypophosphatemic mice. J Clin Invest. 1997; 99 (6): 1200-9.
51. Guo R, Quarles LD., Cloning and sequencing of human PEX from a bone cDNA library: evidence for its developmental stage-specific regulation in osteoblasts. J Bone Miner Res. 1997; 12 (7): 1009-17.
52. Ruchon AF, Marcinkiewicz M, Siegfried G, Tenenhouse HS, DesGroseillers L, Crine P, Boileau G., Pex mRNA is localized in developing mouse osteoblasts and odontoblasts. J Histochem Cytochem. 1998; 46 (4): 459-68.
53. Ruchon AF, Tenenhouse HS, Marcinkiewicz M, Siegfried G, Aubin JE, DesGroseillers L, Crine P, Boileau G., Developmental expression and tissue distribution of Phex protein: effect of the Hyp mutation and relationship to bone markers. J Bone Miner Res. 2000; 15 (8): 1440-50.
54. Zoidis E, Zapf J, Schmid C., Phex cDNA cloning from rat bone and studies on phex mRNA expression: tissue-specificity, age-dependency, and regulation by insulin-like growth factor (IGF) I in vivo. Mol Cell Endocrinol. 2000; 168 (1-2): 41-51.
55. Thompson DL, Sabbagh Y, Tenenhouse HS, Roche PC, Drezner MK, Salisbury JL, Grande JP, Poeschla EM, Kumar R., Ontogeny of Phex/PHEX protein expression in mouse embryo and subcellular localization in osteoblasts. J Bone Miner Res. 2002; 17 (2): 311-20.
56. Yamazaki Y, Okazaki R, Shibata M, Hasegawa Y, Satoh K, Tajima T, Takeuchi Y, Fujita T, Nakahara K, Yamashita T, Fukumoto S., Increased circulatory level of biologically active full-length FGF-23 in patients with hypophosphatemic rickets/osteomalacia. J Clin Endocrinol Metab. 2002; 87 (11): 4957-60.
57. Jonsson KB, Zahradnik R, Larsson T, White KE, Sugimoto T, Imanishi Y, Yamamoto T, Hampson G, Koshiyama H, Ljunggren O, Oba K, Yang IM, Miyauchi A, Econs MJ, Lavigne J, Juppner H., Fibroblast growth factor 23 in oncogenic osteomalacia and X-linked hypophosphatemia. N Engl J Med. 2003; 348 (17): 1656-63.
58. Larsson T, Marsell R, Schipani E, Ohlsson C, Ljunggren O, Tenenhouse HS, Juppner H, Jonsson KB., Transgenic mice expressing fibroblast growth factor 23 under the control of the alpha1(I) collagen promoter exhibit growth retardation, osteomalacia, and disturbed phosphate homeostasis. Endocrinology. 2004; 145 (7): 3087-94.
59. White KE, Carn G, Lorenz-Depiereux B, Benet-Pages A, Strom TM, Econs MJ., Autosomal-dominant hypophosphatemic rickets (ADHR) mutations stabilize FGF-23. Kidney Int. 2001; 60 (6): 2079-86.
60. White KE, Jonsson KB, Carn G, Hampson G, Spector TD, Mannstadt M, Lorenz-Depiereux B, Miyauchi A, Yang IM, Ljunggren O, Meitinger T, Strom TM, Juppner H, Econs MJ., The autosomal dominant hypophosphatemic rickets (ADHR) gene is a secreted polypeptide overexpressed by tumors that cause phosphate wasting. J Clin Endocrinol Metab. 2001; 86 (2): 497-500.
61. White KE, Evans WE, O'Riordan JLH, Speer MC, Econs MJ, Lorenz-Depiereux B, Grabowski M, Meitinger T, Strom TM., Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23. Nat Genet. 2000; 26 (3): 345-8.
62. Lipman ML, Panda D, Bennett HP, Henderson JE, Shane E, Shen Y, Goltzman D, Karaplis AC., Cloning of human PEX cDNA. Expression, subcellular localization, and endopeptidase activity. J Biol Chem. 1998; 273 (22): 13729-37.
63. Liu S, Guo R, Simpson LG, Xiao Z-S, Burnham CE, Quarles LD., Regulation of fibroblastic growth factor 23 expression but not degradation by PHEX. J Biol Chem. 2003; 278 (39): 37419-26.
64. Benet-Pages A, Lorenz-Depiereux B, Zischka H, White KE, Econs MJ, Strom TM., FGF23 is processed by proprotein convertases but not by PHEX. Bone. 2004; 35 (2): 455-62.
65. Quarles LD., FGF23, PHEX, and MEPE regulation of phosphate homeostasis and skeletal mineralization. Am J Physiol Endocrinol Metab. 2003; 285 (1): E1-9.
66. Bowe AE, Finnegan R, Jan de Beur SM, Cho J, Levine MA, Kumar R, Schiavi SC., FGF-23 inhibits renal tubular phosphate transport and is a PHEX substrate. Biochem Biophys Res Commun. 2001; 284 (4): 977-81.
67. Rowe PSN, Matsumoto N, Jo OD, Shih RNJ, O'Connor J, Roudier MP, Bain S, Liu S, Harrison J, Yanagawa N., Correction of the mineralization defect in hyp mice treated with protease inhibitors CA074 and pepstatin. Bone. 2006; 39 (4): 773-86.
68. Rowe PS, de Zoysa PA, Dong R, Wang HR, White KE, Econs MJ, Oudet CL., MEPE, a new gene expressed in bone marrow and tumors causing osteomalacia. Genomics. 2000; 67 (1): 54-68.
69. Baht GS, Hunter GK, Goldberg HA., Bone sialoprotein-collagen interaction promotes hydroxyapatite nucleation. Matrix Biol. 2008; 27 (7): 600-8.
70. Fisher LW, Torchia DA, Fohr B, Young MF, Fedarko NS., Flexible structures of SIBLING proteins, bone sialoprotein, and osteopontin. Biochem Biophys Res Commun. 2001; 280 (2): 460-5.
71. Harmey D, Johnson KA, Zelken J, Camacho NP, Hoylaerts MF, Noda M, Terkeltaub R, Millan JL., Elevated skeletal osteopontin levels contribute to the hypophosphatasia phenotype in Akp2(-/-) mice. J Bone Miner Res. 2006; 21 (9): 1377-86.
72. Gao YA, Agnihotri R, Vary CPH, Liaw L., Expression and characterization of recombinant osteopontin peptides representing matrix metalloproteinase proteolytic fragments. Matrix Biol. 2004; 23 (7): 457-66.
73. Agnihotri R, Crawford HC, Haro H, Matrisian LM, Havrda MC, Liaw L., Osteopontin, a novel substrate for matrix metalloproteinase-3 (stromelysin-1) and matrix metalloproteinase-7 (matrilysin). J Biol Chem. 2001; 276 (30): 28261-7.
74. Dean RA, Overall CM., Proteomics discovery of metalloproteinase substrates in the cellular context by iTRAQ labeling reveals a diverse MMP-2 substrate degradome. Mol Cell Proteomics. 2007; 6 (4): 611-23.
75. Senger DR, Perruzzi CA, Papadopoulos A, Tenen DG., Purification of a human milk protein closely similar to tumor-secreted phosphoproteins and osteopontin. Biochim Biophys Acta. 1989; 996 (1-2): 43-8.
76. Kim H-J, Lee H-J, Jun J-I, Oh Y, Choi S-G, Kim H, Chung C-W, Kim I-K, Park I-S, Chae H-J, Kim H-R, Jung Y-K., Intracellular cleavage of osteopontin by caspase-8 modulates hypoxia/reoxygenation cell death through p53. Proc Natl Acad Sci USA. 2009; 106 (36): 15326-31.
77. Christensen B, Schack L, Klaning E, Sorensen ES., Osteopontin is cleaved at multiple sites close to its integrin-binding motifs in milk and is a novel substrate for plasmin and cathepsin D. J Biol Chem. 2010; 285 (11): 7929-37.
78. Sodek J, Ganss B, McKee MD., Osteopontin. Crit Rev Oral Biol Med. 2000; 11 (3): 279-303.
79. Yuan B, Takaiwa M, Clemens TL, Feng JQ, Kumar R, Rowe PS, Xie Y, Drezner MK., Aberrant Phex function in osteoblasts and osteocytes alone underlies murine X-linked hypophosphatemia. J Clin Invest. 2008; 118 (2): 722-34.
80. Sheen CR, Pilarowski GOW, Wang W, Millan JL., Molecular characterisation of the Hyp deletion and an improved assay for its detection. Bone. 2012; 50 (3): 592-5.
81. Meyer RA Jr, Meyer MH, Gray RW., Parabiosis suggests a humoral factor is involved in X-linked hypophosphatemia in mice. J Bone Miner Res. 1989; 4 (4): 493-500.
82. Nesbitt T, Coffman TM, Griffiths R, Drezner MK., Crosstransplantation of kidneys in normal and Hyp mice. Evidence that the Hyp mouse phenotype is unrelated to an intrinsic renal defect. J Clin Invest. 1992; 89 (5): 1453-9.
83. Ecarot B, Glorieux FH, Desbarats M, Travers R, Labelle L., Defective bone formation by Hyp mouse bone cells transplanted into normal mice: evidence in favor of an intrinsic osteoblast defect. J Bone Miner Res. 1992; 7 (2): 215-20.
84. Lajeunesse D, Meyer RA Jr, Hamel L., Direct demonstration of a humorally-mediated inhibition of renal phosphate transport in the Hyp mouse. Kidney Int. 1996; 50 (5): 1531-8.
85. Xiao ZS, Crenshaw M, Guo R, Nesbitt T, Drezner MK, Quarles LD., Intrinsic mineralization defect in Hyp mouse osteoblasts. Am J Physiol. 1998; 275 (4 Pt 1): E700-8.
86. Shih NR, Jo OD, Yanagawa N., Effects of PHEX antisense in human osteoblast cells. J Am Soc Nephrol. 2002; 13 (2): 394-9.
87. Senger DR, Perruzzi CA., Cell migration promoted by a potent GRGDS-containing thrombin-cleavage fragment of osteopontin. Biochim Biophys Acta. 1996; 1314 (1-2): 13-24.
88. Liaw L, Crawford HC., Functions of the extracellular matrix and matrix degrading proteases during tumor progression. Braz J Med Biol Res. 1999; 32 (7): 805-12.
89. Scatena M, Liaw L, Giachelli CM., Osteopontin: a multifunctional molecule regulating chronic inflammation and vascular disease. Arterioscler Thromb Vasc Biol. 2007; 27 (11): 2302-9.
90. Yokasaki Y, Sheppard D., Mapping of the cryptic integrin-binding site in osteopontin suggests a new mechanism by which thrombin can regulate inflammation and tissue repair. Trends Cardiovasc Med. 2000; 10 (4): 155-9.