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. 2007 May 1;10(3):758–769. doi: 10.1111/j.1582-4934.2006.tb00435.x

Increase in decorin and biglycan in Duchenne Muscular Dystrophy: role of fibroblasts as cell source of these proteoglycans in the disease

Ricardo Fadic a, Valeria Mezzano b, Karin Alvarez b, Daniel Cabrera b, Jenny Holmgren c, Enrique Brandan b,*
PMCID: PMC3933157  PMID: 16989735

Abstract

Fibrosis is a common pathological feature observed in muscles of patients with Duchenne muscular dystrophy (DMD). Biglycan and decorin are small chondroitin/dermatan sulfate proteoglycans in the muscle extracellular matrix (ECM) that belong to the family of structurally related proteoglycans called small leucine-rich repeat proteins. Decorin is considered an anti-fibrotic agent, preventing the process by blocking TGF-β activity. There is no information about their expression in DMD patients. We found an increased amount of both proteoglycans in the ECM of skeletal muscle biopsies obtained from DMD patients. Both biglycan and decorin were augmented in the perimysium of muscle tissue, but only decorin increased in the endomysium as seen by immunohistochemical analyses. Fibroblasts were isolated from explants obtained from muscle of DMD patients and the incorporation of radioactive sulfate showed an increased synthesis of both decorin and biglycan in cultured fibroblasts compared to controls. The size of decorin and biglycan synthesized by DMD and control fibroblasts seems to be similar in size and anion charge. These findings show that decorin and biglycan are increased in DMD skeletal muscle and suggest that fibroblasts would be, at least, one source for these proteoglycans likely playing a role in the muscle response to dystrophic cell damage.

Keywords: Duchenne muscular dystrophy, proteoglycans, biglycan, decorin, interstitial fibrosis

References

  • 1.Bogdanovich S, Perkins KJ, Krag TO, Khurana TS. Therapeutics for Duchenne muscular dystrophy: current approaches and future directions. J Mol Med. 2004;82:102–15. doi: 10.1007/s00109-003-0484-1. [DOI] [PubMed] [Google Scholar]
  • 2.Monaco AP, Bertelson CJ, Middlesworth W, Colletti CA, Aldridge J, Fischbeck KH, Bartlett R, Pericak-Vance MA, Roses AD, Kunkel LM. Detection of deletions spanning the Duchenne muscular dystrophy locus using a tightly linked DNA segment. Nature. 1985;316:842–5. doi: 10.1038/316842a0. [DOI] [PubMed] [Google Scholar]
  • 3.van Deutekom JC, van Ommen GJ. Advances in Duchenne muscular dystrophy gene therapy. Nat Rev Genet. 2003;4:774–83. doi: 10.1038/nrg1180. [DOI] [PubMed] [Google Scholar]
  • 4.Dubowitz V. Current and future therapy in muscular dystrophy; need for a common language between basic scientists and clinicians. Acta Myol. 2004;23:V–IX. [PubMed] [Google Scholar]
  • 5.Blake DJ. Dystrobrevin dynamics in muscle-cell signalling: a possible target for therapeutic intervention in Duchenne muscular dystrophy. Neuromuscul Disord. 2002;12:S110–7. doi: 10.1016/s0960-8966(02)00091-3. [DOI] [PubMed] [Google Scholar]
  • 6.Matsumura K, Tome FM, Collin H, Leturcq F, Jeanpierre M, Kaplan JC, Fardeau M, Campbell KP. Expression of dystrophin-associated proteins in dystrophin-positive muscle fibers (revertants) in Duchenne muscular dystrophy. Neuromuscul Disord. 1994;4:115–20. doi: 10.1016/0960-8966(94)90002-7. [DOI] [PubMed] [Google Scholar]
  • 7.Bulfield G, Siller W, Wight P, Moore K. X chromosomelinked muscular dystrophy (mdx) in the mouse. Proc Natl Acad Sci USA. 1984;81:1189–92. doi: 10.1073/pnas.81.4.1189. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Rampoldi E, Meola G, Conti A, Velicogna M, Larizza L. A comparative analysis of collagen III, IV, laminin and fibronectin in Duchenne muscular dystrophy biopsies and cell cultures. Eur J Cell Biol. 1986;42:27–34. [PubMed] [Google Scholar]
  • 9.Osses N, Brandan E. ECM is required for skeletal muscle differentiation independently of muscle regulatory factor expression. Am J Physiol Cell Physiol. 2002;282:C383–94. doi: 10.1152/ajpcell.00322.2001. [DOI] [PubMed] [Google Scholar]
  • 10.Larrain J, Carey DJ, Brandan E. Syndecan-1 expression inhibits myoblast differentiation through a basic fibroblast growth factor-dependent mechanism. J Biol Chem. 1998;273:32288–96. doi: 10.1074/jbc.273.48.32288. [DOI] [PubMed] [Google Scholar]
  • 11.Fuentealba L, Carey DJ, Brandan E. Antisense inhibition of syndecan-3 expression during skeletal muscle differentiation accelerates myogenesis through a basic fibroblast growth factor-dependent mechanism. J Biol Chem. 1999;274:37876–84. doi: 10.1074/jbc.274.53.37876. [DOI] [PubMed] [Google Scholar]
  • 12.Caceres S, Cuellar C, Casar JC, Garrido J, Schaefer L, Kresse H, Brandan E. Synthesis of proteoglycans is augmented in dystrophic mdx mouse skeletal muscle. Eur J Cell Biol. 2000;79:173–81. doi: 10.1078/S0171-9335(04)70020-5. [DOI] [PubMed] [Google Scholar]
  • 13.Iozzo RV. The biology of the small leucine-rich proteoglycans. Functional network of interactive proteins. J Biol Chem. 1999;274:18843–6. doi: 10.1074/jbc.274.27.18843. [DOI] [PubMed] [Google Scholar]
  • 14.Gosselin LE, Williams JE, Deering M, Brazeau D, Koury S, Martinez DA. Localization and early time course of TGF-beta 1 mRNA expression in dystrophic muscle. Muscle Nerve. 2004;30:645–53. doi: 10.1002/mus.20150. [DOI] [PubMed] [Google Scholar]
  • 15.Bianco P, Fisher LW, Young MF, Termine JD, Robey PG. Expression and localization of the two small proteoglycans biglycan and decorin in developing human skeletal and non-skeletal tissues. J Histochem Cytochem. 1990;38:1549–63. doi: 10.1177/38.11.2212616. [DOI] [PubMed] [Google Scholar]
  • 16.Riquelme C, Larrain J, Schonherr E, Henriquez JP, Kresse H, Brandan E. Antisense inhibition of decorin expression in myoblasts decreases cell responsiveness to transforming growth factor beta and accelerates skeletal muscle differentiation. J Biol Chem. 2001;276:3589–96. doi: 10.1074/jbc.M004602200. [DOI] [PubMed] [Google Scholar]
  • 17.Bowe M, Mendis D, Fallon J. The small leucine-rich repeat proteoglycan biglycan binds to alpha-dystroglycan and is upregulated in dystrophic muscle. J Cell Biol. 2000;148:801–10. doi: 10.1083/jcb.148.4.801. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Casar JC, McKechnie BA, Fallon JR, Young MF, Brandan E. Transient up-regulation of biglycan during skeletal muscle regeneration: delayed fiber growth along with decorin increase in biglycan-deficient mice. Dev Biol. 2004;268:358–71. doi: 10.1016/j.ydbio.2003.12.025. [DOI] [PubMed] [Google Scholar]
  • 19.Suzuki K, Wang R, Kubota H, Shibuya H, Saegusa J, Sato T. Kinetics of biglycan, decorin and thrombospondin-1 in mercuric chloride-induced renal tubulointerstitial fibrosis. Exp Mol Pathol. 2005;79:68–73. doi: 10.1016/j.yexmp.2005.01.010. [DOI] [PubMed] [Google Scholar]
  • 20.Kolb M, Margetts PJ, Sime PJ, Gauldie J. Proteoglycans decorin and biglycan differentially modulate TGF-beta- mediated fibrotic responses in the lung. Am J Physiol Lung Cell Mol Physiol. 2001;280:L1327–34. doi: 10.1152/ajplung.2001.280.6.L1327. [DOI] [PubMed] [Google Scholar]
  • 21.McCroskery S, Thomas M, Platt L, Hennebry A, Nishimura T, McLeay L, Sharma M, Kambadur R. Improved muscle healing through enhanced regeneration and reduced fibrosis in myostatin-null mice. J Cell Sci. 2005;118:3531–41. doi: 10.1242/jcs.02482. [DOI] [PubMed] [Google Scholar]
  • 22.Shimizu-Hirota R, Sasamura H, Kuroda M, Kobayashi E, Hayashi M, Saruta T. Extracellular matrix glycoprotein biglycan enhances vascular smooth muscle cell proliferation and migration. Circ Res. 2004;94:1067–74. doi: 10.1161/01.RES.0000126049.79800.CA. [DOI] [PubMed] [Google Scholar]
  • 23.Haslett JN, Sanoudou D, Kho AT, Bennett RR, Greenberg SA, Kohane IS, Beggs AH, Kunkel LM. Gene expression comparison of biopsies from Duchenne muscular dystrophy (DMD) and normal skeletal muscle. Proc Natl Acad Sci USA. 2002;99:15000–5. doi: 10.1073/pnas.192571199. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Brandan E, Inestrosa NC. Isolation of the heparan sulfate proteoglycans from the extracellular matrix of rat skeletal muscle. J Neurobiol. 1987;18:271–82. doi: 10.1002/neu.480180303. [DOI] [PubMed] [Google Scholar]
  • 25.Brandan E, Fuentes ME, Andrade W. The proteoglycan decorin is synthesized and secreted by differentiated myotubes. Eur J Cell Biol. 1991;55:209–16. [PubMed] [Google Scholar]
  • 26.Fisher LW, Stubbs JT, 3rd, Young MF. Antisera and cDNA probes to human and certain animal model bone matrix noncollagenous proteins. Acta Orthop Scand Suppl. 1995;266:61–5. [PubMed] [Google Scholar]
  • 27.Melone MA, Peluso G, Galderisi U, Petillo O, Cotrufo R. Increased expression of IGF-binding protein-5 in Duchenne muscular dystrophy (DMD) fibroblasts correlates with the fibroblast-induced downregulation of DMD myoblast growth: an in vitro analysis. J Cell Physiol. 2000;185:143–53. doi: 10.1002/1097-4652(200010)185:1<143::AID-JCP14>3.0.CO;2-U. [DOI] [PubMed] [Google Scholar]
  • 28.Brandan E, Fuentes ME, Andrade W. Decorin, a chondroitin/dermatan sulfate proteoglycan is under neural control in rat skeletal muscle. J Neurosci Res. 1992;32:51–9. doi: 10.1002/jnr.490320107. [DOI] [PubMed] [Google Scholar]
  • 29.Kinsella MG, Bressler SL, Wight TN. The regulated synthesis of versican, decorin, and biglycan: extracellular matrix proteoglycans that influence cellular phenotype. Crit Rev Eukaryot Gene Expr. 2004;14:203–34. doi: 10.1615/critreveukaryotgeneexpr.v14.i3.40. [DOI] [PubMed] [Google Scholar]
  • 30.Higuchi I, Fukunaga H, Matsumura K, Inose M, Izumi K, Okubo R, Nakagawa M, Shimizu T, Osame M. Abnormal expression of heparin sulfate proteoglycan on basal lamina of muscle fibers in two Japanese patients with adhalin deficiency. Neuromuscul Disord. 1995;5:467–74. doi: 10.1016/0960-8966(95)00010-k. [DOI] [PubMed] [Google Scholar]
  • 31.Winokur ST, Barrett K, Martin JH, Forrester JR, Simon M, Tawil R, Chung SA, Masny PS, Figlewicz DA. Facioscapulohumeral muscular dystrophy (FSHD) myoblasts demonstrate increased susceptibility to oxidative stress. Neuromuscul Disord. 2003;13:322–33. doi: 10.1016/s0960-8966(02)00284-5. [DOI] [PubMed] [Google Scholar]
  • 32.Al Haj Zen A, Caligiuri G, Sainz J, Lemitre M, Demerens C, Lafont A. 2005. Decorin overexpression reduces atherosclerosis development in apolipoprotein E-deficient mice Atherosclerosis ; In Press.
  • 33.Weis SM, Zimmerman SD, Shah M, Covell JW, Omens JH, Ross J, Jr, Dalton N, Jones Y, Reed CC, Iozzo RV, McCulloch AD. A role for decorin in the remodeling of myocardial infarction. Matrix Biol. 2005;24:313–24. doi: 10.1016/j.matbio.2005.05.003. [DOI] [PubMed] [Google Scholar]
  • 34.Grisanti S, Szurman P, Warga M, Kaczmarek R, Ziemssen F, Tatar O, Bartz-Schmidt KU. Decorin modulates wound healing in experimental glaucoma filtration surgery: a pilot study. Invest Ophthalmol Vis Sci. 2005;46:191–6. doi: 10.1167/iovs.04-0902. [DOI] [PubMed] [Google Scholar]
  • 35.Schaefer L, Macakova K, Raslik I, Micegova M, Grone HJ, Schonherr E, Robenek H, Echtermeyer FG, Grassel S, Bruckner P, Schaefer RM, Iozzo RV, Kresse H. Absence of decorin adversely influences tubulointerstitial fibrosis of the obstructed kidney by enhanced apoptosis and increased inflammatory reaction. Am J Pathol. 2002;160:1181–91. doi: 10.1016/S0002-9440(10)64937-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Ishitobi M, Haginoya K, Zhao Y, Ohnuma A, Minato J, Yanagisawa T, Tanabu M, Kikuchi M, Iinuma K. Elevated plasma levels of transforming growth factor betal in patients with muscular dystrophy. Neuroreport. 2000;11:4033–5. doi: 10.1097/00001756-200012180-00026. [DOI] [PubMed] [Google Scholar]
  • 37.Bernasconi P, Di Blasi C, Mora M, Morandi L, Galbiati S, Confalonieri P, Cornelio F, Mantegazza R. Transforming growth factor-betal and fibrosis in congenital muscular dystrophies. Neuromuscul Disord. 1999;9:28–33. doi: 10.1016/s0960-8966(98)00093-5. [DOI] [PubMed] [Google Scholar]
  • 38.Droguett R, Cabello-Verrugio C, Riquelme C, Brandan E. 2006. Extracellular proteoglycans modifies TGF-beta bioavailability attenuating its signaling during skeletal muscle differentiation Matrix Biol ; In Press. [DOI] [PubMed]
  • 39.Hosaka Y, Kirisawa R, Mafune N, Takehana K. Downregulation of decorin and transforming growth factor-betal by decorin gene suppression in tendinocytes. Connect Tissue Res. 2005;46:18–26. doi: 10.1080/03008200590935510. [DOI] [PubMed] [Google Scholar]
  • 40.Li Y, Foster W, Deasy BM, Chan Y, Prisk V, Tang Y, Cummins J, Huard J. Transforming growth factor-betal induces the differentiation of myogenic cells into fibrotic cells in injured skeletal muscle: a key event in muscle fibrogenesis. Am J Pathol. 2004;164:1007–19. doi: 10.1016/s0002-9440(10)63188-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Fukushima K, Badlani N, Usas A, Riano F, Fu F, Huard J. The use of an antifibrosis agent to improve muscle recovery after laceration. Am J Sports Med. 2001;29:394–402. doi: 10.1177/03635465010290040201. [DOI] [PubMed] [Google Scholar]
  • 42.Sato K, Li Y, Foster W, Fukushima K, Badlani N, Adachi N, Usas A, Fu FH, Huard J. Improvement of muscle healing through enhancement of muscle regeneration and prevention of fibrosis. Muscle Nerve. 2003;28:365–72. doi: 10.1002/mus.10436. [DOI] [PubMed] [Google Scholar]
  • 43.Melone MA, Peluso G, Petillo O, Galderisi U, Cotrufo R. Defective growth in vitro of Duchenne Muscular Dystrophy myoblasts: the molecular and biochemical basis. J Cell Biochem. 1999;76:118–32. doi: 10.1002/(sici)1097-4644(20000101)76:1<118::aid-jcb12>3.3.co;2-6. [DOI] [PubMed] [Google Scholar]
  • 44.Gosselin LE, McCormick KM. Targeting the immune system to improve ventilatory function in muscular dystrophy. Med Sci Sports Exerc. 2004;36:44–51. doi: 10.1249/01.MSS.0000106185.22349.2C. [DOI] [PubMed] [Google Scholar]
  • 45.Hogemann B, Edel G, Schwarz K, Krech R, Kresse H. Expression of biglycan, decorin and proteoglycan-100/CSF-1 in normal and fibrotic human liver. Pathol Res Pract. 1997;193:747–51. doi: 10.1016/S0344-0338(97)80052-0. [DOI] [PubMed] [Google Scholar]
  • 46.Krull NB, Zimmermann T, Gressner AM. Spatial and temporal patterns of gene expression for the proteoglycans biglycan and decorin and for transforming growth factor-beta 1 revealed by in situ hybridization during experimentally induced liver fibrosis in the rat. Hepatology. 1993;18:581–9. [PubMed] [Google Scholar]
  • 47.Stokes MB, Holler S, Cui Y, Hudkins KL, Eitner F, Fogo A, Alpers CE. Expression of decorin, biglycan, and collagen type I in human renal fibrosing disease. Kidney Int. 2000;57:487–98. doi: 10.1046/j.1523-1755.2000.00868.x. [DOI] [PubMed] [Google Scholar]
  • 48.Tufvesson E, Westergren-Thorsson G. Biglycan and decorin induce morphological and cytoskeletal changes involving signalling by the small GTPases RhoA and Rac1 resulting in lung fibroblast migration. J Cell Sci. 2003;116:4857–64. doi: 10.1242/jcs.00808. [DOI] [PubMed] [Google Scholar]
  • 49.Junghans U, Koops A, Westmeyer A, Kappler J, Meyer HE, Muller HW. Purification of a meningeal cell-derived chondroitin sulphate proteoglycan with neurotrophic activity for brain neurons and its identification as biglycan. Eur J Neurosci. 1995;7:2341–50. doi: 10.1111/j.1460-9568.1995.tb00655.x. [DOI] [PubMed] [Google Scholar]
  • 50.Tiede K, Stoter K, Petrik C, Chen WB, Ungefroren H, Kruse ML, Stoll M, Unger T, Fischer JW. Angiotensin II AT(1)-receptor induces biglycan in neonatal cardiac fibroblasts via autocrine release of TGFbeta in vitro. Cardiovasc Res. 2003;60:538–46. doi: 10.1016/j.cardiores.2003.08.009. [DOI] [PubMed] [Google Scholar]
  • 51.Kahari VM, Larjava H, Uitto J. Differential regulation of extracellular matrix proteoglycan (PG) gene expression. Transforming growth factor-beta 1 up-regulates biglycan (PGI), and versican (large fibroblast PG) but down-regulates decorin (PGII) mRNA levels in human fibroblasts in culture. J Biol Chem. 1991;266:10608–15. [PubMed] [Google Scholar]
  • 52.Alvarez K, Fadic R, Brandan E. Augmented synthesis and differential localization of heparan sulfate proteoglycans in Duchenne muscular dystrophy. J Cell Biochem. 2002;85:703–13. doi: 10.1002/jcb.10184. [DOI] [PubMed] [Google Scholar]
  • 53.Larrain J, Alvarez J, Hassell JR, Brandan E. Expression of perlecan, a proteoglycan that binds myogenic inhibitory basic fibroblast growth factor, is down regulated during skeletal muscle differentiation. Exp Cell Res. 1997;234:405–12. doi: 10.1006/excr.1997.3648. [DOI] [PubMed] [Google Scholar]
  • 54.Brandan E, Carey DJ, Larrain J, Melo F, Campos A. Synthesis and processing of glypican during differentiation of skeletal muscle cells. Eur J Cell Biol. 1996;71:170–6. [PubMed] [Google Scholar]

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