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Amendment history: Erratum (August 2003) Osteopontin: a bridge between and the immune system

Ellen M. Gravallese

J Clin Invest. 2003;112(2):147-149. https://doi.org/10.1172/JCI19190.

Commentary

The molecular mechanisms underlying the putative role of osteopontin in the chronic inflammatory disease are unclear. A study in a murine model of arthritis now demonstrates that a specific antibody directed against the exposed osteopontin SLAYGLR is capable of preventing inflammatory infiltration in arthritic joints.

Find the latest version: https://jci.me/19190/pdf 1. Berry, M.J., Banu, L., and Larsen, P.R. 1991. Type of human type 2 deiodinase: a novel ubiquitin- 11. Ohh, M., and Kaelin, W.G., Jr. 1999. The von Hip- I iodothyronine deiodinase is a selenocysteine- proteasomal mediated mechanism for regula- pel-Lindau tumour suppressor : new per- containing enzyme. Nature. 349:438–440. tion of hormone activation. Mol. Endocrinol. spectives. Mol. Med. Today. 5:257–263. 2. Davey, J.C., Becker, K.B., Schneider, M.J., St. Ger- 14:1697–1708. 12. Li, Z., et al. 2002. Ubiquitination of a novel deu- main, D.L., and Galton, V.A. 1995. Cloning of a 7. Ravid, T., Doolman, R., Avner, R., Harats, D., biquitinating enzyme requires direct binding to cDNA for the type II iodothyronine deiodinase. and Roitelman, R. 2000. The ubiquitin-protea- von Hippel-Lindau tumor suppresor protein. J. Biol. Chem. 270:26786–26789. some pathway mediates the regulated degrada- J. Biol. Chem. 277:4656–4662. 3. Bianco, A.C., Salvatore, D., Gereben, B., Berry, tion of mammalian 3-hydroxy-3-methylglu- 13. Li, Z., et al. 2002. Identification of a deubiquiti- M.J., and Larsen, P.R. 2002. Biochemistry, cellu- taryl-coenzyme A reductase. J. Biol. Chem. nating enzyme subfamily as substrates of the von lar and molecular biology, and physiological roles 275:35840–35847. Hippel-Lindau tumor suppressor. Biochem. Bio- of the iodothyronine selenodeiodinases. Endocr. 8. Curcio-Morelli, C., et al. 2003. Deubiquitination of phys. Res. Commun. 294:700–709. Rev. 23:38–89. type 2 iodothyronine deiodinase by von Hippel–Lin- 14. De Groot, L.J. 1999. Dangerous dogmas in medi- 4. Baqui, M.M.A., Gereben, B., Harney, J.W., Larsen, dau protein–interacting deubiquitinating enzymes cine: the nonthyroidal illness syndrome. J. Clin. P.R., and Bianco, A.C. 2000. Distinct subcellular regulates thyroid hormone activation. J. Clin. Invest. Endocrinol. Metab. 84:151–164. localization of transiently expressed types 1 and 112:189–196. doi:10.1172/JCI200318348. 15. Crantz, F.R., Silva, J.E., and Larsen, P.R. 1982. An 2 iodothyronine deiodinases as determined by 9. Berry, M.J., Maia, A.L., Kieffer, J.D., Harney, J.W., analysis of the sources and quantity of 3,5,3′-tri- immunofluorescence confocal microscopy. and Larsen, P.R. 1992. Substitution of cysteine iodothyronine specifically bound to nuclear Endocrinology. 141:4309–4312. for selenocysteine in type I iodothyronine deiod- receptors in rat cerebral cortex and cerebellum. 5. Bianco, A.C., and Silva, J.E. 1987. Intracellular inase reduces the catalytic efficiency of the pro- Endocrinology. 110:367–375. conversion of thyroxine to triiodothyronine is tein but enhances its translation. Endocrinology. 16. Campos-Barros, A., et al. 1996. Phenolic and required for the optimal thermogenic function of 131:1848–1852. tyrosyl ring iodothyronine deiodination and thy- brown adipose tissue. J. Clin. Invest. 79:295–300. 10. Latif, F., et al. 1993. Identification of the von roid hormone concentrations in the human cen- 6. Gereben, B., Goncalves, C., Harney, J.W., Larsen, Hippel-Lindau disease tumor suppressor gene. tral nervous system. J. Clin. Endocrinol. Metab. P.R., and Bianco, A.C. 2000. Selective proteolysis Science. 260:1317–1320. 81:2179–2185.

Osteopontin: a bridge between bone The role of OPN in bone and in the immune system and the immune system OPN is a phosphorylated secreted by activated , Ellen M. Gravallese leukocytes, and activated T lympho- cytes, and present in extracellular flu- Beth Israel Deaconess Medical Center, Harvard Institutes of Medicine, Boston, ids, at sites of inflammation, and in the Massachusetts, USA ECM of (5, 6). This mediates important cell- The molecular mechanisms underlying the putative role of osteopontin matrix and cell-cell interactions. OPN is in the chronic inflammatory disease rheumatoid arthritis are unclear. A abundant in bone, where it facilitates study in a murine model of arthritis now demonstrates that a specific the attachment of to the antibody directed against the exposed osteopontin epitope SLAYGLR bone matrix via an interaction with cell (see the related article beginning on page 181) is capable of preventing surface αvβ3 and CD44, the inflammatory cell infiltration in arthritic joints. hyaluronic acid receptor (7). OPN–/– mice have a subtle bone phenotype, J. Clin. Invest. 112:147–149 (2003). doi:10.1172/JCI200319190. with delayed and impaired bone resorp- tion (7). In the immune system, OPN In recent years a number of studies interaction between dendritic cells plays a role in , leading to have linked factors involved in in- and T cells in the immune system the migration of macrophages and den- flammation to those critical for and is the critical regulatory system dritic cells to sites of inflammation. bone physiology and remodeling. for under physio- Activation of T lymphocytes results in One well described story is that of logic conditions (1, 2). The RANKL/ an increase in OPN transcription, hence the receptor-activator of NF-κB lig- OPG system is also likely to play an its alternative designation as Eta-1. and (RANKL)/osteoprotegerin (OPG) important role in several forms of Weber et al. have demonstrated that system, which plays a role in the pathologic bone loss, including that OPN is a T lymphocyte suppressor fac- seen in , certain forms of tor and that it enhances B lymphocyte Address correspondence to: Ellen M. , and inflammatory arthritis Ig production and proliferation (8). In Gravallese, Beth Israel Deaconess Medical (3). There is mounting evidence for addition, OPN is an important cyto- Center, Harvard Institutes of Medicine, Room 241, 4 Blackfan Circle, Boston, the role of another cytokine, osteo- kine mediating Th1 immunity (9). Massachusetts 02115, USA. pontin (OPN; “bone-bridging” pro- OPN interacts with a variety of cell Phone: (617) 667-0717; Fax: (617) 975-5299; tein), also known as early acti- surface receptors, including the αvβ3, E-mail: [email protected]. vation gene-1 (Eta-1), in providing a αvβ5, αvβ1, α4β1, α8β1, and α9β1 inte- Conflict of interest: The author has declared link between the immune system and grins, as well as CD44. Binding of OPN that no conflict of interest exists. Nonstandard abbreviations used: receptor- bone. In this issue of the JCI, to these cell surface receptors stimulates activator of NF-κB ligand (RANKL); Yamamoto et al. (4) provide impor- , migration, and specific osteoprotegerin (OPG); osteopontin (OPN); tant new evidence indicating a role signaling functions. The major integrin- early T cell activation gene-1 (Eta-1); for OPN in the pathogenesis of binding site in OPN is the arginine- rheumatoid arthritis (RA); collagen-induced arthritis (CIA); collagen antibody–induced inflammatory arthritis and associat- glycine-aspartate (RGD) integrin-bind- arthritis (CAIA). ed joint destruction. ing motif, which is required for the

The Journal of Clinical Investigation | July 2003 | Volume 112 | Number 2 147 adherence of many cell types to OPN. In vitro studies were performed to (14) in which OPN was deleted by However, other sequences within OPN demonstrate that the M5 Ab blocked homologous recombination of strain have also been shown to mediate cell the formation of -like cells 129–derived cells, and backcrossed into adherence. For example, cleavage of induced from –derived a CIA- and CAIA-susceptible strain for human OPN by exposes the precursors by treatment with RANKL 12 generations. These authors then in- SVVYGLR sequence (SLAYGLR in the and M-CSF. In addition, this antibody duced CIA and CAIA in the OPN-defi- mouse), promoting the adherence of blocked the induction of release cient mice and in littermates and de- cells expressing α9 and α4 . from bone by monstrated no effect of OPN deficiency (PTH) and IL-1α in vitro (4). It has been in either form of murine arthritis. They Potential role for OPN previously demonstrated that PTH- concluded that prior observations in in the pathogenesis induced bone resorption is dependent OPN-deficient mice showing protec- of inflammatory arthritis on OPN (12). These results suggest that tion from arthritis may have resulted Several prior studies have suggested an one role of the M5 Ab in joint protec- from the deletion of polymorphic genes important role for OPN in the patho- tion could be the blockade of osteoclast linked to OPN from strain 129, rather genesis of inflammatory arthritis. OPN differentiation and function in vivo. A than from the deletion of OPN itself. mRNA and protein have been demon- limitation of this study is that bone These authors provided a list of several strated to be expressed in synovial tis- destruction was not directly assessed in other genes within the deleted locus sues from patients with rheumatoid the in vivo animal studies presented, that could be important for arthritis arthritis (RA), predominantly by fibro- and tartrate-resistant acid phosphatase– pathogenesis. blastic cells, and at sites of pannus inva- positive osteoclast-like cells were not The study of Yamamoto et al. (4) sion into cartilage (10). In murine col- quantitated in mice with and without certainly adds to our understanding lagen-induced arthritis (CIA), OPN was M5 Ab treatment. In addition, since M5 of the mechanisms by which OPN detected in synovial tissues and at sites Ab treatment inhibits joint inflamma- contributes to the pathogenesis of of osteoclast-mediated bone resorption, tion in this animal model, protection inflammatory arthritis. Given the where its expression colocalized to sites from joint destruction may be a second- clear and important role of OPN in of αvβ3 integrin expression (11). OPN ary phenomenon related to the general inflammatory processes and bone has thus been implicated in the process decrease in inflammation. Therefore a remodeling, it will be of considerable of joint destruction in arthritis. direct role of OPN in bone erosion in interest to resolve some of the remain- In their report in this issue of JCI, this model could not be determined. ing controversies regarding the role of Yamamoto et al. (4) studied CIA and an Given the important role of OPN in OPN in this disease. animal model of RA known as collagen bone remodeling, such studies would be 1. Kong, Y.Y., et al. 1999. OPGL is a key regulator of antibody–induced arthritis (CAIA). of great interest. Nonetheless, the effects osteoclastogenesis, lymphocyte development and Arthritis was induced by the transfer of on the clinical and histologic parame- lymph-node organogenesis. Nature. 397:315–323. anti–type II collagen antibodies in ters studied provide convincing addi- 2. Simonet, W.S., et al. 1997. Osteoprotegerin: a novel secreted protein involved in the regulation C57BL/6 mice boosted with an intra- tional evidence for a role of OPN in of bone density. Cell. 89:309–319. peritoneal injection of LPS. These au- arthritic inflammation, and specifically 3. Pettit, A.R., and Gravallese, E.M. 2003. Osteopro- thors report that splenic monocytes for its role in the recruitment of inflam- tegerin. In Targeted therapies in rheumatology. P.E. Lipsky and J.S. Smolen, editors. Martin Dunitz. from arthritic mice expressing α4 and matory cells to arthritic joints. London, United Kingdom/New York, New York, α9 integrins demonstrated enhanced USA. 359–377. 4. Yamamoto, N., et al. 2003. Essential role of the migration toward thrombin-cleaved Arthritis in the setting cryptic epitope SLAYGLR within osteopontin in a OPN compared with splenic monocytes of OPN deficiency murine model of rheumatoid arthritis. J. Clin. from nonarthritic mice. Of note is the Based on this information, one might Invest. 112:181–188. doi:10.1172/JCI200317778. 5. Denhardt, D.T., and Noda, M. 1998. Osteopontin fact that the ratio of the thrombin- expect that arthritis would be signifi- expression and function: role in bone remodel- cleaved form of OPN to noncleaved cantly attenuated in mice deficient in ing. J. Cell. Biochem. Suppl. 30/31:92–102. 6. Murry, C.E., Giachelli, C.M., Schwartz, S.M., and OPN was previously shown to be signif- OPN. In fact this has been demonstrat- Vracko, R. 1994. Macrophages express osteopon- icantly increased in the plasma and syn- ed in a CAIA model of RA (13) similar tin during repair of myocardial necrosis. Am. J. ovial fluid of patients with RA compared to that used in the study presented in Pathol. 145:1450–1462. 7. Chellaiah, M.A., et al. 2003. Osteopontin defi- with plasma from healthy controls and this issue of JCI (4). OPN-deficient mice ciency produces osteoclast dysfunction due to from patients with osteoarthritis (11). were found to have marked attenuation reduced CD44 surface expression. Mol. Biol. Cell. 14:173–189. Furthermore, treatment of mice with an of joint swelling and articular cartilage 8. Weber, G.F., Ashkar, S., Glimcher, M.J., and Cantor, antibody (M5 Ab) directed against the destruction compared with arthritic H. 1996. Receptor-ligand interaction between sequence SLAYGLR, exposed by throm- wild-type mice and had no increase in CD44 and osteopontin (Eta-1). Science. 71:509–512. 9. Jansson, M., Panoutsakopoulou, V., Baker, J., Klein, bin cleavage of murine OPN, inhibited urinary levels of deoxypyridinoline, a L., and Cantor, H. 2002. Attenuated experimental synovitis and inflammatory cell infiltra- marker of bone destruction (13). These autoimmune encephalomyelitis in Eta-1/osteo- tion into the joints of treated mice com- data support a role for OPN in both the pontin-deficient mice. J. Immunol. 168:2096–2099. 10. Petrow, P.K., et al. 2000. Expression of osteopontin pared with those of arthritic control inflammatory and the joint-destructive messenger RNA and protein in rheumatoid mice (4). M5 Ab treatment also resulted processes in arthritis. Interestingly, arthritis: effects of osteopontin on the release of collagenase 1 from articular in protection from cartilage destruction however, these results were called into and synovial . Arthritis Rheum. in this murine model of RA. question in a recent report in Science 43:1597–1605.

148 The Journal of Clinical Investigation | July 2003 | Volume 112 | Number 2 11. Ohshima, S., et al. 2002. Expression of osteopon- 12. Ihara, H., et al. 2001. Parathyroid hormone-induced Natl. Acad. Sci. U. S. A. 99:4556–4561. tin at sites of bone erosion in a murine experi- bone resorption does not occur in the absence of 14. Blom, T., Franzen, A., Heinegard, D., and Holm- mental arthritis model of collagen-induced osteopontin. J. Biol. Chem. 276:13065–13071. dahl, R. 2003. Technical comments: comment on arthritis: possible involvement of osteopontin in 13. Yumoto, K., et al. 2002. Osteopontin deficiency “The influence of the proinflammatory cytokine, bone destruction in arthritis. Arthritis Rheum. protects joints against destruction in anti-type II osteopontin, on autoimmune demyelinating dis- 46:1094–1101. collagen antibody-induced arthritis in mice. Proc. ease.” Science. 299:1845a.

Salicylic acid: an old dog, new tricks, at sites of nonbacterial thrombotic endocarditis (15) and the series of and staphylococcal disease reports by Clawson et al. on the interac- tion of S. aureus with purified platelets Mathias Herrmann (16). In the early 1990s, experiments with surface-activated platelets suggest- Department of Bacteriology and Hygiene, Institute of Medical Microbiology and Hygiene, ed to our group the importance of fib- University of Saarland, Homburg/Saar, Germany rinogen and S. aureus clumping factor in the bacteria-platelet interaction (17). Aspirin has been shown to cause a reduction in the virulence of Staphylo- These observations were subsequently coccus aureus–associated endocarditis. A new study (see the related article confirmed and extended by use of a low- beginning on page 222) reveals that salicylic acid, the major metabolite of platelet-binding mutant expressing a aspirin, acts at the level of transcription to downregulate the production of mutated ClfA protein (18) that displays fibrinogen, fibronectin, and α-hemolysin — virulence factors necessary for diminished virulence in an endocarditis bacterial replication in host tissues and, now, potential therapeutic targets. model (19), and by identification of the secreted fibrinogen-binding J. Clin. Invest. 112:149–151 (2003). doi:10.1172/JCI200319143. Coa and Efb in phage-display panning assays (20) (Figure 1). One hundred and twenty years after its battery of pathogenicity factors (7), While these observations pointed initial description as the pathogen that allowing for specific bacterial attach- toward complex but, according to their causes sepsis and abscesses (1), Staphylo- ment. This can be followed by cellular adhesive function, rather propatho- coccus aureus remains a dangerous organ- invasion and subsequent tissue degra- genic events at the bacteria-endocardi- ism. Staphylococcal endocarditis is on dation. Several lines of evidence clearly um interface, the role of platelets had the rise (2) and still causes significant indicate that the interaction with host to be reevaluated after the discovery mortality (3). The methicillin-resistant proteins and platelets is instrumental in that they function as specialized S. aureus (MRSA) epidemic has entered a the development of disease. A plethora inflammatory cells (21) in response to new era due to the spread of MRSA into of bacterial factors — either wall bound secretion of antimicrobial . In the community (4) and acquisition of (8) or secreted (9, 10) — mediate binding fact, paradoxically, hyperexpression of new resistance cassettes with the poten- of and attachment to ECM molecules α-toxin by S. aureus results in dimin- tial for genetic transfer (5). The advent such as fibronectin, fibrinogen, colla- ished virulence in experimental endo- of fully vancomycin-resistant, methi- gen, and vWF. Work with deletion carditis, possibly because of the release cillin-resistant clinical isolates (6) has mutants and complemented heterolo- of platelet microbicidal proteins (22). further weakened the available arma- gous hosts has demonstrated the par- The attributed role of platelets in the mentarium against this pathogen. ticular role of adhesins that recognize disease process that results in endovas- fibronectin (such as fibronectin-binding cular infection has prompted a number Importance of staphylococcal protein A) and fibrinogen (such as of researchers to interfere with platelet attachment and invasion in clumping factor A, ClfA), allowing for function for prevention or treatment of endovascular disease cellular invasion and production of endocarditis. Acetylsalicylic acid (ASA, S. aureus is a nonmotile microorganism experimental endocarditis (11, 12), and aspirin) has been used in vitro and in a with a particular propensity to colonize gfp reporter assays from endocarditis number of experimental models to biologic or artificial substrates using a models clearly indicate that activation reduce vegetation sizes and to mitigate of global regulators that coordinate the course of disease (23–25). Similar Address correspondence to: Mathias adhesin and toxin expression, such as effects have also been observed by Herrmann, Department of Bacteriology and agr and sar, occurs in vivo (13, 14). Kupferwasser et al. (26). However, when Hygiene, Institute of Microbiology and they studied its metabolite, salicylic acid Hygiene, Building 43, Kirrberger Street, Distinctive effects of acetylsalicylic (SAL), in parallel to ASA, they made the 66421 Homburg/Saar, Germany. Phone: 49-6841-162-3900; acid and salicylic acid on platelets interesting observation that pretreat- Fax: 49-6841-162-3985; E-mail: and bacteria ment of bacteria with SAL reduced [email protected]. A particular role of platelets in the attachment to the valvular epithelium Conflict of interest: The author has declared pathogenesis of staphylococcal endo- to an even greater extent than adminis- that no conflict of interest exists. carditis has been suggested since the tration of ASA. This observation was Nonstandard abbreviations used: clumping factor A (ClfA); acetylsalicylic acid (ASA); early observation by Durack of bacterial accompanied by the in vitro finding that salicylic acid (SAL). interaction with fibrin-platelet matrices SAL-pretreated S. aureus cells bound to

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