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Osteopontin, inflammation and myogenesis: influencing regeneration, fibrosis and size of skeletal muscle

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Journal of Cell Communication and Signaling Aims and scope

Abstract

Osteopontin is a multifunctional matricellular protein that is expressed by many cell types. Through cell-matrix and cell-cell interactions the molecule elicits a number of responses from a broad range of target cells via its interaction with integrins and the hyaluronan receptor CD44. In many tissues osteopontin has been found to be involved in important physiological and pathological processes, including tissue repair, inflammation and fibrosis. Post-natal skeletal muscle is a highly differentiated and specialised tissue that retains a remarkable capacity for regeneration following injury. Regeneration of skeletal muscle requires the co-ordinated activity of inflammatory cells that infiltrate injured muscle and are responsible for initiating muscle fibre degeneration and phagocytosis of necrotic tissue, and muscle precursor cells that regenerate the injured muscle fibres. This review focuses on the current evidence that osteopontin plays multiple roles in skeletal muscle, with particular emphasis on its role in regeneration and fibrosis following injury, and in determining the severity of myopathic diseases such as Duchenne muscular dystrophy.

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References

  • Allen RE, Sheehan SM, Taylor RG, Kendall TL, Rice GM (1995) Hepatocyte growth factor activates quiescent skeletal muscle satellite cells in vitro. J Cell Physiol 165:307–312

    Article  CAS  PubMed  Google Scholar 

  • Andreetta F, Bernasconi P, Baggi F, Ferro P, Oliva L, Arnoldi E, Cornelio F, Mantegazza R, Confalonieri P (2006) Immunomodulation of TGF-beta 1 in mdx mouse inhibits connective tissue proliferation in diaphragm but increases inflammatory response: implications for antifibrotic therapy. J Neuroimmunol 175:77–86

    Article  CAS  PubMed  Google Scholar 

  • Ashkar S, Weber GF, Panoutsakopoulou V, Sanchirico ME, Jansson M, Zawaideh S, Rittling SR, Denhardt DT, Glimcher MJ, Cantor H (2000) Eta-1 (osteopontin): an early component of type-1 (cell-mediated) immunity. Science 287:860–864

    Article  CAS  PubMed  Google Scholar 

  • Banerjee A, Apte UM, Smith R, Ramaiah SK (2006) Higher neutrophil infiltration mediated by osteopontin is a likely contributing factor to the increased susceptibility of females to alcoholic liver disease. J Pathol 208:473–485

    Article  CAS  PubMed  Google Scholar 

  • Barbosa-Souza V, Contin DK, Filho WB, de Araujo AL, Irazusta SP, da Cruz-Hofling MA (2011) Osteopontin, a chemotactic protein with cytokine-like properties, is up-regulated in muscle injury caused by Bothrops lanceolatus (fer-de-lance) snake venom. Toxicon 58:398–409

    Article  CAS  PubMed  Google Scholar 

  • Bello L, Piva L, Barp A, Taglia A, Picillo E, Vasco G, Pane M, Previtali SC, Torrente Y, Gazzerro E, Motta MC, Grieco GS, Napolitano S, Magri F, D’Amico A, Astrea G, Messina S, Sframeli M, Vita GL, Boffi P, Mongini T, Ferlini A, Gualandi F, Soraru G, Ermani M, Vita G, Battini R, Bertini E, Comi GP, Berardinelli A, Minetti C, Bruno C, Mercuri E, Politano L, Angelini C, Hoffman EP, Pegoraro E (2012) Importance of SPP1 genotype as a covariate in clinical trials in Duchenne muscular dystrophy. Neurology 79:159–162

    Article  PubMed Central  PubMed  Google Scholar 

  • Berman JS, Serlin D, Li X, Whitley G, Hayes J, Rishikof DC, Ricupero DA, Liaw L, Goetschkes M, O’Regan AW (2004) Altered bleomycin-induced lung fibrosis in osteopontin-deficient mice. Am J Physiol Lung Cell Mol Physiol 286:L1311–L1318

    Article  CAS  PubMed  Google Scholar 

  • Chambers AF, Wilson SM, Kerkvliet N, O’Malley FP, Harris JF, Casson AG (1996) Osteopontin expression in lung cancer. Lung Cancer 15:311–323

    Article  CAS  PubMed  Google Scholar 

  • Chen G, Birnbaum RS, Yablonka-Reuveni Z, Quinn LS (1994) Separation of mouse crushed muscle extract into distinct mitogenic activities by heparin affinity chromatography. J Cell Physiol 160:563–572

    Article  CAS  PubMed  Google Scholar 

  • Christensen B, Kazanecki CC, Petersen TE, Rittling SR, Denhardt DT, Sorensen ES (2007) Cell type-specific post-translational modifications of mouse osteopontin are associated with different adhesive properties. J Biol Chem 282:19463–19472

    Article  CAS  PubMed  Google Scholar 

  • Collins CA, Olsen I, Zammit PS, Heslop L, Petrie A, Partridge TA, Morgan JE (2005) Stem cell function, self-renewal, and behavioral heterogeneity of cells from the adult muscle satellite cell niche. Cell 122:289–301

    Article  CAS  PubMed  Google Scholar 

  • Deng B, Wehling-Henricks M, Villalta SA, Wang Y, Tidball JG (2012) IL-10 triggers changes in macrophage phenotype that promote muscle growth and regeneration. J Immunol 189:3669–3680

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Denhardt DT, Noda M, O’Regan AW, Pavlin D, Berman JS (2001) Osteopontin as a means to cope with environmental insults: regulation of inflammation, tissue remodeling, and cell survival. J Clin Invest 107:1055–1061

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Duvall CL, Taylor WR, Weiss D, Wojtowicz AM, Guldberg RE (2007) Impaired angiogenesis, early callus formation, and late stage remodeling in fracture healing of osteopontin-deficient mice. J Bone Miner Res 22:286–297

    Article  CAS  PubMed  Google Scholar 

  • Ervasti JM (2007) Dystrophin, its interactions with other proteins, and implications for muscular dystrophy. Biochim Biophys Acta 1772:108–117

    Article  CAS  PubMed  Google Scholar 

  • Florini JR, Ewton DZ, Magri KA (1991) Hormones, growth factors, and myogenic differentiation. Annu Rev Physiol 53:201–216

    Article  CAS  PubMed  Google Scholar 

  • Giachelli CM, Lombardi D, Johnson RJ, Murry CE, Almeida M (1998) Evidence for a role of osteopontin in macrophage infiltration in response to pathological stimuli in vivo. Am J Pathol 152:353–358

    CAS  PubMed Central  PubMed  Google Scholar 

  • Giacopelli F, Marciano R, Pistorio A, Catarsi P, Canini S, Karsenty G, Ravazzolo R (2004) Polymorphisms in the osteopontin promoter affect its transcriptional activity. Physiol Genomics 20:87–96

    Article  CAS  PubMed  Google Scholar 

  • Gimba ER, Tilli TM (2013) Human osteopontin splicing isoforms: known roles, potential clinical applications and activated signaling pathways. Cancer Lett 331:11–17

    Article  CAS  PubMed  Google Scholar 

  • Hashimoto M, Sun D, Rittling SR, Denhardt DT, Young W (2007) Osteopontin-deficient mice exhibit less inflammation, greater tissue damage, and impaired locomotor recovery from spinal cord injury compared with wild-type controls. J Neurosci 27:3603–3611

    Article  CAS  PubMed  Google Scholar 

  • Haslett JN, Sanoudou D, Kho AT, Bennett RR, Greenberg SA, Kohane IS, Beggs AH, Kunkel LM (2002) Gene expression comparison of biopsies from Duchenne muscular dystrophy (DMD) and normal skeletal muscle. Proc Natl Acad Sci U S A 99:15000–15005

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Hirata A, Masuda S, Tamura T, Kai K, Ojima K, Fukase A, Motoyoshi K, Kamakura K, Miyagoe-Suzuki Y, Takeda S (2003) Expression profiling of cytokines and related genes in regenerating skeletal muscle after cardiotoxin injection: a role for osteopontin. Am J Pathol 163:203–215

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Hoffman EP, Brown RH Jr, Kunkel LM (1987) Dystrophin: the protein product of the Duchenne muscular dystrophy locus. Cell 51:919–928

    Article  CAS  PubMed  Google Scholar 

  • Hoffman EP, Gordish-Dressman H, McLane VD, Devaney JM, Thompson PD, Visich P, Gordon PM, Pescatello LS, Zoeller RF, Moyna NM, Angelopoulos TJ, Pegoraro E, Cox GA, Clarkson PM (2013) Alterations in osteopontin modify muscle size in females in both humans and mice. Med Sci Sports Exerc 45:1060–1068

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Inoue M, Shinohara ML (2011) Intracellular osteopontin (iOPN) and immunity. Immunol Res 49:160–172

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Joulia D, Bernardi H, Garandel V, Rabenoelina F, Vernus B, Cabello G (2003) Mechanisms involved in the inhibition of myoblast proliferation and differentiation by myostatin. Exp Cell Res 286:263–275

    Article  CAS  PubMed  Google Scholar 

  • Kazanecki CC, Uzwiak DJ, Denhardt DT (2007) Control of osteopontin signaling and function by post-translational phosphorylation and protein folding. J Cell Biochem 102:912–924

    Article  CAS  PubMed  Google Scholar 

  • Koh A, da Silva AP, Bansal AK, Bansal M, Sun C, Lee H, Glogauer M, Sodek J, Zohar R (2007) Role of osteopontin in neutrophil function. Immunology 122:466–475

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Lescaudron L, Peltekian E, Fontaine-Perus J, Paulin D, Zampieri M, Garcia L, Parrish E (1999) Blood borne macrophages are essential for the triggering of muscle regeneration following muscle transplant. Neuromuscul Disord 9:72–80

    Article  CAS  PubMed  Google Scholar 

  • Liaw L, Almeida M, Hart CE, Schwartz SM, Giachelli CM (1994) Osteopontin promotes vascular cell adhesion and spreading and is chemotactic for smooth muscle cells in vitro. Circ Res 74:214–224

    Article  CAS  PubMed  Google Scholar 

  • Mori R, Shaw TJ, Martin P (2008) Molecular mechanisms linking wound inflammation and fibrosis: knockdown of osteopontin leads to rapid repair and reduced scarring. J Exp Med 205:43–51

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Mukherjee BB, Nemir M, Beninati S, Cordella-Miele E, Singh K, Chackalaparampil I, Shanmugam V, DeVouge MW, Mukherjee AB (1995) Interaction of osteopontin with fibronectin and other extracellular matrix molecules. Ann N Y Acad Sci 760:201–212

    Article  CAS  PubMed  Google Scholar 

  • Murani E, Muraniova M, Ponsuksili S, Schellander K, Wimmers K (2007) Identification of genes differentially expressed during prenatal development of skeletal muscle in two pig breeds differing in muscularity. BMC Dev Biol 7:109

    Article  PubMed Central  PubMed  Google Scholar 

  • Murani E, Ponsuksili S, Seyfert HM, Shi X, Wimmers K (2009) Dual effect of a single nucleotide polymorphism in the first intron of the porcine secreted phosphoprotein 1 gene: allele-specific binding of C/EBP beta and activation of aberrant splicing. BMC Mol Biol 10:96

    Article  PubMed Central  PubMed  Google Scholar 

  • Nguyen HX, Tidball JG (2003) Interactions between neutrophils and macrophages promote macrophage killing of rat muscle cells in vitro. J Physiol 547:125–132

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • O’Brien ER, Garvin MR, Stewart DK, Hinohara T, Simpson JB, Schwartz SM, Giachelli CM (1994) Osteopontin is synthesized by macrophage, smooth muscle, and endothelial cells in primary and restenotic human coronary atherosclerotic plaques. Arterioscler Thromb 14:1648–1656

    Article  PubMed  Google Scholar 

  • O’Regan A, Berman JS (2000) Osteopontin: a key cytokine in cell-mediated and granulomatous inflammation. Int J Exp Pathol 81:373–390

    Article  PubMed Central  PubMed  Google Scholar 

  • O’Regan AW, Chupp GL, Lowry JA, Goetschkes M, Mulligan N, Berman JS (1999) Osteopontin is associated with T cells in sarcoid granulomas and has T cell adhesive and cytokine-like properties in vitro. J Immunol 162:1024–1031

    PubMed  Google Scholar 

  • Paliwal P, Pishesha N, Wijaya D, Conboy IM (2012) Age dependent increase in the levels of osteopontin inhibits skeletal muscle regeneration. Aging (Albany NY) 4:553–566

    CAS  PubMed Central  Google Scholar 

  • Pardo A, Gibson K, Cisneros J, Richards TJ, Yang Y, Becerril C, Yousem S, Herrera I, Ruiz V, Selman M, Kaminski N (2005) Up-regulation and profibrotic role of osteopontin in human idiopathic pulmonary fibrosis. PLoS Med 2:e251

    Article  PubMed Central  PubMed  Google Scholar 

  • Partridge TA (1997) Models of dystrophinopathy, pathological mechanisms and assessment of therapies. In: Brown SC, Lucy JA (eds) Dystrophin: Gene Protein and Cell Biology. Cambridge University Press, Cambridge, pp 310–311

    Google Scholar 

  • Patarca R, Freeman GJ, Singh RP, Wei FY, Durfee T, Blattner F, Regnier DC, Kozak CA, Mock BA, Morse HC 3rd et al (1989) Structural and functional studies of the early T lymphocyte activation 1 (Eta-1) gene. Definition of a novel T cell-dependent response associated with genetic resistance to bacterial infection. J Exp Med 170:145–161

    Article  CAS  PubMed  Google Scholar 

  • Pegoraro E, Hoffman EP, Piva L, Gavassini BF, Cagnin S, Ermani M, Bello L, Soraru G, Pacchioni B, Bonifati MD, Lanfranchi G, Angelini C, Kesari A, Lee I, Gordish-Dressman H, Devaney JM, McDonald CM, Cooperative International Neuromuscular Research, G (2011) SPP1 genotype is a determinant of disease severity in Duchenne muscular dystrophy. Neurology 76:219–226

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Petrof BJ, Shrager JB, Stedman HH, Kelly AM, Sweeney HL (1993) Dystrophin protects the sarcolemma from stresses developed during muscle contraction. Proc Natl Acad Sci U S A 90:3710–3714

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Piva L, Gavassini BF, Bello L, Fanin M, Soraru G, Barp A, Ermani M, Angelini C, Hoffman EP, Pegoraro E (2012) TGFBR2 but not SPP1 genotype modulates osteopontin expression in Duchenne muscular dystrophy muscle. J Pathol 228:251–259

    Article  CAS  PubMed  Google Scholar 

  • Porter JD, Khanna S, Kaminski HJ, Rao JS, Merriam AP, Richmonds CR, Leahy P, Li J, Guo W, Andrade FH (2002) A chronic inflammatory response dominates the skeletal muscle molecular signature in dystrophin-deficient mdx mice. Hum Mol Genet 11:263–272

    Article  CAS  PubMed  Google Scholar 

  • Saitoh Y, Kuratsu J, Takeshima H, Yamamoto S, Ushio Y (1995) Expression of osteopontin in human glioma. Its correlation with the malignancy. Lab Invest 72:55–63

    CAS  PubMed  Google Scholar 

  • Sam F, Xie Z, Ooi H, Kerstetter DL, Colucci WS, Singh M, Singh K (2004) Mice lacking osteopontin exhibit increased left ventricular dilation and reduced fibrosis after aldosterone infusion. Am J Hypertens 17:188–193

    Article  CAS  PubMed  Google Scholar 

  • Standal T, Borset M, Sundan A (2004) Role of osteopontin in adhesion, migration, cell survival and bone remodeling. Exp Oncol 26:179–184

    CAS  PubMed  Google Scholar 

  • Stedman HH, Sweeney HL, Shrager JB, Maguire HC, Panettieri RA, Petrof B, Narusawa M, Leferovich JM, Sladky JT, Kelly AM (1991) The mdx mouse diaphragm reproduces the degenerative changes of Duchenne muscular dystrophy. Nature 352:536–539

    Article  CAS  PubMed  Google Scholar 

  • Tatsumi R, Anderson JE, Nevoret CJ, Halevy O, Allen RE (1998) HGF/SF is present in normal adult skeletal muscle and is capable of activating satellite cells. Dev Biol 194:114–128

    Article  CAS  PubMed  Google Scholar 

  • Ten Broek RW, Grefte S, Von den Hoff JW (2010) Regulatory factors and cell populations involved in skeletal muscle regeneration. J Cell Physiol 224:7–16

    PubMed  Google Scholar 

  • Tidball JG (2005) Inflammatory processes in muscle injury and repair. Am J Physiol Regul Integr Comp Physiol 288:R345–R353

    Article  CAS  PubMed  Google Scholar 

  • Tidball JG (2011) Mechanisms of muscle injury, repair, and regeneration. Compr Physiol 1:2029–2062

    PubMed  Google Scholar 

  • Turk R, Sterrenburg E, van der Wees CG, de Meijer EJ, de Menezes RX, Groh S, Campbell KP, Noguchi S, van Ommen GJ, den Dunnen JT, ‘t Hoen PA (2006) Common pathological mechanisms in mouse models for muscular dystrophies. FASEB J 20:127–129

    CAS  PubMed  Google Scholar 

  • Uaesoontrachoon K, Yoo HJ, Tudor EM, Pike RN, Mackie EJ, Pagel CN (2008) Osteopontin and skeletal muscle myoblasts: association with muscle regeneration and regulation of myoblast function in vitro. Int J Biochem Cell Biol 40:2303–2314

    Article  CAS  PubMed  Google Scholar 

  • Uaesoontrachoon K, Wasgewatte Wijesinghe DK, Mackie EJ, Pagel CN (2013) Osteopontin deficiency delays inflammatory infiltration and the onset of muscle regeneration in a mouse model of muscle injury. Dis Model Mech 6:197–205

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Vetrone SA, Montecino-Rodriguez E, Kudryashova E, Kramerova I, Hoffman EP, Liu SD, Miceli MC, Spencer MJ (2009) Osteopontin promotes fibrosis in dystrophic mouse muscle by modulating immune cell subsets and intramuscular TGF-beta. J Clin Invest 119:1583–1594

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Villalta SA, Deng B, Rinaldi C, Wehling-Henricks M, Tidball JG (2011) IFN-gamma promotes muscle damage in the mdx mouse model of Duchenne muscular dystrophy by suppressing M2 macrophage activation and inhibiting muscle cell proliferation. J Immunol 187:5419–5428

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • von der Mark K, Ocalan M (1989) Antagonistic effects of laminin and fibronectin on the expression of the myogenic phenotype. Differentiation 40:150–157

    Article  PubMed  Google Scholar 

  • Weinreb M, Shinar D, Rodan GA (1990) Different pattern of alkaline phosphatase, osteopontin, and osteocalcin expression in developing rat bone visualized by in situ hybridization. J Bone Miner Res 5:831–842

    Article  CAS  PubMed  Google Scholar 

  • Yokosaki Y, Matsuura N, Sasaki T, Murakami I, Schneider H, Higashiyama S, Saitoh Y, Yamakido M, Taooka Y, Sheppard D (1999) The integrin alpha(9)beta(1) binds to a novel recognition sequence (SVVYGLR) in the thrombin-cleaved amino-terminal fragment of osteopontin. J Biol Chem 274:36328–36334

    Article  CAS  PubMed  Google Scholar 

  • Zammit PS, Partridge TA, Yablonka-Reuveni Z (2006) The skeletal muscle satellite cell: the stem cell that came in from the cold. J Histochem Cytochem 54:1177–1191

    Article  CAS  PubMed  Google Scholar 

  • Zanotti S, Gibertini S, Di Blasi C, Cappelletti C, Bernasconi P, Mantegazza R, Morandi L, Mora M (2011) Osteopontin is highly expressed in severely dystrophic muscle and seems to play a role in muscle regeneration and fibrosis. Histopathology 59:1215–1228

    Article  PubMed  Google Scholar 

  • Zohar R, Lee W, Arora P, Cheifetz S, McCulloch C, Sodek J (1997) Single cell analysis of intracellular osteopontin in osteogenic cultures of fetal rat calvarial cells. J Cell Physiol 170:88–100

    Article  CAS  PubMed  Google Scholar 

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  1. Faculty of Veterinary Science, University of Melbourne, Parkville, Victoria, 3010, Australia

    Charles N. Pagel, Dimuthu K. Wasgewatte Wijesinghe, Neda Taghavi Esfandouni & Eleanor J. Mackie

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  1. Charles N. Pagel
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  2. Dimuthu K. Wasgewatte Wijesinghe
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  3. Neda Taghavi Esfandouni
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  4. Eleanor J. Mackie
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Pagel, C.N., Wasgewatte Wijesinghe, D.K., Taghavi Esfandouni, N. et al. Osteopontin, inflammation and myogenesis: influencing regeneration, fibrosis and size of skeletal muscle. J. Cell Commun. Signal. 8, 95–103 (2014). https://doi.org/10.1007/s12079-013-0217-3

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