Collagen Processing and its Role in Fibrosis

  • Christopher A. McCullochEmail author
  • Nuno M. Coelho
Part of the Advances in Biochemistry in Health and Disease book series (ABHD, volume 13)


In several diseases involving the heart such as pressure overload, diabetic cardiomyopathy or myocardial infarction, fibrosis is a common disorder of myocardial extracellular matrix structure and function. The clinical significance of fibrosis is that accumulation of disorganized fibrillar collagen in the cardiac interstitium can inhibit diastolic and systolic function. Fibrosis is mediated by several different cellular and extracellular processes including disruptions of fibroblast differentiation, perturbations of post-translational processing and assembly of matrix molecules, and inappropriately organized matrix degradation by proteases and intracellular digestion. The enlargement of transformed fibroblast and myofibroblast populations in the diseased cardiac interstitium plays a critical role in the disorganized matrix remodeling that occurs after pressure overload or diabetes because these cells do not process and remodel interstitial collagen in a physiological fashion. New data that have examined the regulation of pro-collagen processing by molecules such as pro-collagen C-endopeptidase enhancer and modulation of collagen assembly by the secreted protein acidic and rich in cysteine, have suggested novel therapeutic targets for ameliorating cardiac fibrosis. Further, studies of transmembrane matrix metalloproteinases, such as MT-1, indicate the remarkable breadth of function and complexity of the matrix proteolytic family since MT-1 can break down the matrix and is also important in mediating collagen degradation by phagocytosis. Our growing recognition that the myocardial matrix is highly dynamic and comprises a wide range of matricellular and non-structural proteins and proteases in addition to well-defined structural proteins, suggests new approaches for myocardial fibrosis in a spectrum of cardiac diseases.


Collagen Phagocytosis Matrix Turnover Proteases Assembly Matrix metalloproteinases 


  1. 1.
    Goldsmith EC, Bradshaw AD, Spinale FG (2013) Cellular mechanisms of tissue fibrosis. 2. Contributory pathways leading to myocardial fibrosis: moving beyond collagen expression. Am J Physiol Cell Physiol 304:C393–C402PubMedCentralPubMedCrossRefGoogle Scholar
  2. 2.
    Maya L, Villarreal FJ (2009) Diagnostic approaches for diabetic cardiomyopathy and myocardial fibrosis. J Mol Cell Cardiol 48:524–529PubMedCentralPubMedCrossRefGoogle Scholar
  3. 3.
    Srivastava PM, Calafiore P, Macisaac RJ, Patel SK, Thomas MC, Jerums G, Burrell LM (2008) Prevalence and predictors of cardiac hypertrophy and dysfunction in patients with Type 2 diabetes. Clin Sci (Lond) 114:313–320CrossRefGoogle Scholar
  4. 4.
    Heerebeek L van, Borbely A, Niessen HW, Bronzwaer JG, Velden J van der, Stienen GJ, Linke WA, Laarman GJ, Paulus WJ (2006) Myocardial structure and function differ in systolic and diastolic heart failure. Circulation 113:1966–1973PubMedCrossRefGoogle Scholar
  5. 5.
    Heerebeek L van, Hamdani N, Handoko ML, Falcao-Pires I, Musters RJ, Kupreishvili K, Ijsselmuiden AJ, Schalkwijk CG, Bronzwaer JG, Diamant M, Borbely A, Velden J van der, Stienen GJ, Laarman GJ, Niessen HW, Paulus WJ (2008) Diastolic stiffness of the failing diabetic heart: importance of fibrosis, advanced glycation end products, and myocyte resting tension. Circulation 117:43–51PubMedCrossRefGoogle Scholar
  6. 6.
    Frustaci A, Kajstura J, Chimenti C, Jakoniuk I, Leri A, Maseri A, Nadal-Ginard B, Anversa P (2000) Myocardial cell death in human diabetes. Circ Res 87:1123–1132PubMedCrossRefGoogle Scholar
  7. 7.
    Asbun J, Villarreal FJ (2006) The pathogenesis of myocardial fibrosis in the setting of diabetic cardiomyopathy. J Am Coll Cardiol 47:693–700PubMedCrossRefGoogle Scholar
  8. 8.
    Poirier P, Garneau C, Bogaty P, Nadeau A, Marois L, Brochu C, Gingras C, Fortin C, Jobin J, Dumesnil JG (2000) Impact of left ventricular diastolic dysfunction on maximal treadmill performance in normotensive subjects with well-controlled type 2 diabetes mellitus. Am J Cardiol 85:473–477PubMedCrossRefGoogle Scholar
  9. 9.
    Bhatia RS, Tu JV, Lee DS, Austin PC, Fang J, Haouzi A, Gong Y, Liu PP (2006) Outcome of heart failure with preserved ejection fraction in a population-based study. N Engl J Med 355:260–269PubMedCrossRefGoogle Scholar
  10. 10.
    Owan TE, Hodge DO, Herges RM, Jacobsen SJ, Roger VL, Redfield MM (2006) Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med 355:251–259PubMedCrossRefGoogle Scholar
  11. 11.
    Burlew BS, Weber KT (2002) Cardiac fibrosis as a cause of diastolic dysfunction. Herz 27:92–98PubMedCrossRefGoogle Scholar
  12. 12.
    Howlett JG, McKelvie RS, Arnold JM, Costigan J, Dorian P, Ducharme A, Estrella-Holder E, Ezekowitz JA, Giannetti N, Haddad H, Heckman GA, Herd AM, Isaac D, Jong P, Kouz S, Liu P, Mann E, Moe GW, Tsuyuki RT, Ross HJ, White M (2009) Canadian Cardiovascular Society Consensus Conference guidelines on heart failure, update 2009: diagnosis and management of right-sided heart failure, myocarditis, device therapy and recent important clinical trials. Can J Cardiol 25:85–105PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Brilla CG, Maisch B, Rupp H, Funck R, Zhou G, Weber KT (1995) Pharmacological modulation of cardiac fibroblast function. Herz 20:127–134PubMedGoogle Scholar
  14. 14.
    Brilla CG, Maisch B, Weber KT (1992) Myocardial collagen matrix remodelling in arterial hypertension. Eur Heart J 13(Suppl D):24–32PubMedCrossRefGoogle Scholar
  15. 15.
    Weber KT, Sun Y, Tyagi SC, Cleutjens JP (1994) Collagen network of the myocardium: function, structural remodeling and regulatory mechanisms. J Mol Cell Cardiol 26:279–292PubMedCrossRefGoogle Scholar
  16. 16.
    Perez-Tamayo R (1978) Pathology of collagen degradation. A review. Am J Pathol 92:508–566PubMedCentralPubMedGoogle Scholar
  17. 17.
    Covell JW (1990) Cardiac myocyte connective tissue interactions in health and disease, vol 13. pp. 99–112Google Scholar
  18. 18.
    Carver W, Nagpal ML, Nachtigal M, Borg TK, Terracio L (1991) Collagen expression in mechanically stimulated cardiac fibroblasts. Circ Res 69:116–122PubMedCrossRefGoogle Scholar
  19. 19.
    Yamazaki T, Komuro I, Yazaki Y (1998) Signalling pathways for cardiac hypertrophy. Cell Signal 10:693–698PubMedCrossRefGoogle Scholar
  20. 20.
    Olson EN, Srivastava D (1996) Molecular pathways controlling heart development. Science 272:671–676PubMedCrossRefGoogle Scholar
  21. 21.
    Sun Y, Weber KT (1996) Cells expressing angiotensin II receptors in fibrous tissue of rat heart. Cardiovasc Res 31:518–525PubMedCrossRefGoogle Scholar
  22. 22.
    Butt RP, Laurent GJ, Bishop JE (1995) Mechanical load and polypeptide growth factors stimulate cardiac fibroblast activity. Ann N Y Acad Sci 752:387–393PubMedCrossRefGoogle Scholar
  23. 23.
    Gonzalez A, Lopez B, Ravassa S, Beaumont J, Arias T, Hermida N, Zudaire A, Diez J (2009) Biochemical markers of myocardial remodelling in hypertensive heart disease. Cardiovasc Res 81:509–518PubMedCrossRefGoogle Scholar
  24. 24.
    Wilke A, Funck R, Rupp H, Brilla CG (1996) Effect of the renin-angiotensin-aldosterone system on the cardiac interstitium in heart failure. Basic Res Cardiol 91(Suppl 2):79–84PubMedCrossRefGoogle Scholar
  25. 25.
    Keating MT, Sanguinetti MC (1996) Molecular genetic insights into cardiovascular disease. Science 272:681–685PubMedCrossRefGoogle Scholar
  26. 26.
    Singh VP, Baker KM, Kumar R (2008) Activation of the intracellular renin-angiotensin system in cardiac fibroblasts by high glucose: role in extracellular matrix production. Am J Physiol Heart Circ Physiol 294:H1675–H1684PubMedCrossRefGoogle Scholar
  27. 27.
    Aragno M, Mastrocola R, Alloatti G, Vercellinatto I, Bardini P, Geuna S, Catalano MG, Danni O, Boccuzzi G (2008) Oxidative stress triggers cardiac fibrosis in the heart of diabetic rats. Endocrinology 149:380–388PubMedCrossRefGoogle Scholar
  28. 28.
    Tsujino T, Kawasaki D, Masuyama T (2006) Left ventricular diastolic dysfunction in diabetic patients: pathophysiology and therapeutic implications. Am J Cardiovasc Drugs 6:219–230PubMedCrossRefGoogle Scholar
  29. 29.
    Herrmann KL, McCulloch AD, Omens JH (2003) Glycated collagen cross-linking alters cardiac mechanics in volume-overload hypertrophy. Am J Physiol Heart Circ Physiol 284:H1277–H1284PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    Berg TJ, Snorgaard O, Faber J, Torjesen PA, Hildebrandt P, Mehlsen J, Hanssen KF (1999) Serum levels of advanced glycation end products are associated with left ventricular diastolic function in patients with type 1 diabetes. Diabetes Care 22:1186–1190PubMedCrossRefGoogle Scholar
  31. 31.
    Adeghate E (2004) Molecular and cellular basis of the aetiology and management of diabetic cardiomyopathy: a short review. Mol Cell Biochem 261:187–191PubMedCrossRefGoogle Scholar
  32. 32.
    Zieman S, Kass D (2004) Advanced glycation end product cross-linking: pathophysiologic role and therapeutic target in cardiovascular disease. Congest Heart Fail 10:144–149; quiz 150–141 (Greenwich, Conn)PubMedCrossRefGoogle Scholar
  33. 33.
    Casis O, Echevarria E (2004) Diabetic cardiomyopathy: electromechanical cellular alterations. Curr Vasc Pharmacol 2:237–248PubMedCrossRefGoogle Scholar
  34. 34.
    Asif M, Egan J, Vasan S, Jyothirmayi GN, Masurekar MR, Lopez S, Williams C, Torres RL, Wagle D, Ulrich P, Cerami A, Brines M, Regan TJ (2000) An advanced glycation endproduct cross-link breaker can reverse age-related increases in myocardial stiffness. Proc Natl Acad Sci U S A 97:2809–2813PubMedCentralPubMedCrossRefGoogle Scholar
  35. 35.
    Grove D, Zak R, Nair KG, Aschenbrenner V (1969) Biochemical correlates of cardiac hypertrophy. IV. Observations on the cellular organization of growth during myocardial hypertrophy in the rat. Circ Res 25:473–485PubMedCrossRefGoogle Scholar
  36. 36.
    Eghbali M (1992) Cardiac fibroblasts: function, regulation of gene expression, and phenotypic modulation. Basic Res Cardiol 87(Suppl 2):183–189PubMedGoogle Scholar
  37. 37.
    Khan R, Sheppard R (2006) Fibrosis in heart disease: understanding the role of transforming growth factor-beta in cardiomyopathy, valvular disease and arrhythmia. Immunology 118:10–24PubMedCentralPubMedCrossRefGoogle Scholar
  38. 38.
    Kuwahara F, Kai H, Tokuda K, Kai M, Takeshita A, Egashira K, Imaizumi T (2002) Transforming growth factor-beta function blocking prevents myocardial fibrosis and diastolic dysfunction in pressure-overloaded rats. Circulation 106:130–135PubMedCrossRefGoogle Scholar
  39. 39.
    Sadoshima J, Izumo S (1997) The cellular and molecular response of cardiac myocytes to mechanical stress. Annu Rev Physiol 59:551–571PubMedCrossRefGoogle Scholar
  40. 40.
    Campbell SE, Katwa LC (1997) Angiotensin II stimulated expression of transforming growth factor-beta1 in cardiac fibroblasts and myofibroblasts. J Mol Cell Cardiol 29:1947–1958PubMedCrossRefGoogle Scholar
  41. 41.
    Lee AA, Dillmann WH, McCulloch AD, Villarreal FJ (1995) Angiotensin II stimulates the autocrine production of transforming growth factor-beta 1 in adult rat cardiac fibroblasts. J Mol Cell Cardiol 27:2347–2357PubMedCrossRefGoogle Scholar
  42. 42.
    Kim NN, Villarreal FJ, Printz MP, Lee AA, Dillmann WH (1995) Trophic effects of angiotensin II on neonatal rat cardiac myocytes are mediated by cardiac fibroblasts. Am J Physiol 269:E426–E437PubMedGoogle Scholar
  43. 43.
    Burgess ML, Carver WE, Terracio L, Wilson SP, Wilson MA, Borg TK (1994) Integrin-mediated collagen gel contraction by cardiac fibroblasts. Effects of angiotensin II. Circ Res 74:291–298PubMedCrossRefGoogle Scholar
  44. 44.
    Miragoli M, Gaudesius G, Rohr S (2006) Electrotonic modulation of cardiac impulse conduction by myofibroblasts. Circ Res 98:801–810PubMedCrossRefGoogle Scholar
  45. 45.
    Miragoli M, Salvarani N, Rohr S (2007) Myofibroblasts induce ectopic activity in cardiac tissue. Circ Res 101:755–758PubMedGoogle Scholar
  46. 46.
    Zlochiver S, Munoz V, Vikstrom KL, Taffet SM, Berenfeld O, Jalife J (2008) Electrotonic myofibroblast-to-myocyte coupling increases propensity to reentrant arrhythmias in two-dimensional cardiac monolayers. Biophys J 95:4469–4480PubMedCentralPubMedCrossRefGoogle Scholar
  47. 47.
    Askar SF, Ramkisoensing AA, Schalij MJ, Bingen BO, Swildens J, Laarse A van der, Atsma DE, Vries AA de, Ypey DL, Pijnappels DA (2011) Antiproliferative treatment of myofibroblasts prevents arrhythmias in vitro by limiting myofibroblast-induced depolarization. Cardiovasc Res 90:295–304PubMedCrossRefGoogle Scholar
  48. 48.
    Porter KE, Turner NA (2009) Cardiac fibroblasts: at the heart of myocardial remodeling. Pharmacol Ther 123:255–278PubMedCrossRefGoogle Scholar
  49. 49.
    Bradshaw AD, Baicu CF, Rentz TJ, Laer AO Van, Bonnema DD, Zile MR (2010) Age-dependent alterations in fibrillar collagen content and myocardial diastolic function: role of SPARC in post-synthetic procollagen processing. Am J Physiol Heart Circ Physiol 298:H614–H622PubMedCentralPubMedCrossRefGoogle Scholar
  50. 50.
    Bradshaw AD (2009) The role of SPARC in extracellular matrix assembly. J Cell Commun Signal 3:239–246PubMedCentralPubMedCrossRefGoogle Scholar
  51. 51.
    Bradshaw AD, Baicu CF, Rentz TJ, Laer AO Van, Boggs J, Lacy JM, Zile MR (2009) Pressure overload-induced alterations in fibrillar collagen content and myocardial diastolic function: role of secreted protein acidic and rich in cysteine (SPARC) in post-synthetic procollagen processing. Circulation 119:269–280PubMedCentralPubMedCrossRefGoogle Scholar
  52. 52.
    Lenga Y, Koh A, Perera AS, McCulloch CA, Sodek J, Zohar R (2008) Osteopontin expression is required for myofibroblast differentiation. Circ Res 102:319–327PubMedCrossRefGoogle Scholar
  53. 53.
    Leslie KO, Taatjes DJ, Schwarz J, vonTurkovich M, Low RB (1991) Cardiac myofibroblasts express alpha smooth muscle actin during right ventricular pressure overload in the rabbit. Am J Pathol 139:207–216PubMedCentralPubMedGoogle Scholar
  54. 54.
    Goldsmith EC, Bradshaw AD, Zile MR, Spinale FG (2014) Myocardial fibroblast-matrix interactions and potential therapeutic targets. J Mol Cell Cardiol 70C:92–99CrossRefGoogle Scholar
  55. 55.
    Desmouliere A, Geinoz A, Gabbiani F, Gabbiani G (1993) Transforming growth factor-beta 1 induces alpha-smooth muscle actin expression in granulation tissue myofibroblasts and in quiescent and growing cultured fibroblasts. J Cell Biol 122:103–111PubMedCrossRefGoogle Scholar
  56. 56.
    Arora PD, Narani N, McCulloch CA (1999) The compliance of collagen gels regulates transforming growth factor-beta induction of alpha-smooth muscle actin in fibroblasts. Am J Pathol 154:871–882PubMedCentralPubMedCrossRefGoogle Scholar
  57. 57.
    Gabbiani G (2003) The myofibroblast in wound healing and fibrocontractive diseases. J Pathol 200:500–503PubMedCrossRefGoogle Scholar
  58. 58.
    Tomasek JJ, Gabbiani G, Hinz B, Chaponnier C, Brown RA (2002) Myofibroblasts and mechano-regulation of connective tissue remodelling. Nat Rev Mol Cell Biol 3:349–363PubMedCrossRefGoogle Scholar
  59. 59.
    Shi-Wen X, Renzoni EA, Kennedy L, Howat S, Chen Y, Pearson JD, Bou-Gharios G, Dashwood MR, Bois RM du, Black CM, Denton CP, Abraham DJ, Leask A (2007) Endogenous endothelin-1 signaling contributes to type I collagen and CCN2 overexpression in fibrotic fibroblasts. Matrix Biol 26:625–632PubMedCrossRefGoogle Scholar
  60. 60.
    Kitamura M, Shimizu M, Ino H, Okeie K, Yamaguchi M, Funjno N, Mabuchi H, Nakanishi I (2001) Collagen remodeling and cardiac dysfunction in patients with hypertrophic cardiomyopathy: the significance of type III and VI collagens. Clin Cardiol 24:325–329PubMedCrossRefGoogle Scholar
  61. 61.
    Pittet P, Lee K, Kulik AJ, Meister JJ, Hinz B (2008) Fibrogenic fibroblasts increase intercellular adhesion strength by reinforcing individual OB-cadherin bonds. J Cell Sci 121:877–886PubMedCrossRefGoogle Scholar
  62. 62.
    Hinz B, Pittet P, Smith-Clerc J, Chaponnier C, Meister JJ (2004) Myofibroblast development is characterized by specific cell-cell adherens junctions. Mol Biol Cell 15:4310–4320PubMedCentralPubMedCrossRefGoogle Scholar
  63. 63.
    Madsen DH, Leonard D, Masedunskas A, Moyer A, Jurgensen HJ, Peters DE, Amornphimoltham P, Selvaraj A, Yamada SS, Brenner DA, Burgdorf S, Engelholm LH, Behrendt N, Holmbeck K, Weigert R, Bugge TH (2013) M2-like macrophages are responsible for collagen degradation through a mannose receptor-mediated pathway. J Cell Biol 202:951–966PubMedCentralPubMedCrossRefGoogle Scholar
  64. 64.
    Everts V, Zee E van der, Creemers L, Beertsen W (1996) Phagocytosis and intracellular digestion of collagen, its role in turnover and remodelling. Histochem J 28:229–245PubMedCrossRefGoogle Scholar
  65. 65.
    Olazabal IM, Caron E, May RC, Schilling K, Knecht DA, Machesky LM (2002) Rho-kinase and myosin-II control phagocytic cup formation during CR, but not FcgammaR, phagocytosis. Curr Biol 12:1413–1418PubMedCrossRefGoogle Scholar
  66. 66.
    Rougerie P, Miskolci V, Cox D. Generation of membrane structures during phagocytosis and chemotaxis of macrophages: role and regulation of the actin cytoskeleton. Immunol Rev 256:222–239Google Scholar
  67. 67.
    Arora PD, Conti MA, Ravid S, Sacks DB, Kapus A, Adelstein RS, Bresnick AR, McCulloch CA (2008) Rap1 activation in collagen phagocytosis is dependent on nonmuscle myosin II-A. Mol Biol Cell 19:5032–5046PubMedCentralPubMedCrossRefGoogle Scholar
  68. 68.
    Arora PD, Glogauer M, Kapus A, Kwiatkowski DJ, McCulloch CA (2004) Gelsolin mediates collagen phagocytosis through a rac-dependent step. Mol Biol Cell 15:588–599PubMedCentralPubMedCrossRefGoogle Scholar
  69. 69.
    Melcher AH, Chan J (1981) Phagocytosis and digestion of collagen by gingival fibroblasts in vivo: a study of serial sections. J Ultrastruct Res 77:1–36PubMedCrossRefGoogle Scholar
  70. 70.
    Meshel AS, Wei Q, Adelstein RS, Sheetz MP (2005) Basic mechanism of three-dimensional collagen fibre transport by fibroblasts. Nat Cell Biol 7:157–164PubMedCrossRefGoogle Scholar
  71. 71.
    Hay ED (1981) Extracellular matrix. J Cell Biol 91:205s–223sPubMedCrossRefGoogle Scholar
  72. 72.
    Visse R, Nagase H (2003) Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circ Res 92:827–839PubMedCrossRefGoogle Scholar
  73. 73.
    Tam EM, Moore TR, Butler GS, Overall CM (2004) Characterization of the distinct collagen binding, helicase and cleavage mechanisms of matrix metalloproteinase 2 and 14 (gelatinase A and MT1-MMP): the differential roles of the MMP hemopexin c domains and the MMP-2 fibronectin type II modules in collagen triple helicase activities. J Biol Chem 279:43336–43344PubMedCrossRefGoogle Scholar
  74. 74.
    Egeblad M, Werb Z (2002) New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer 2:161–174PubMedCrossRefGoogle Scholar
  75. 75.
    Lee H, Overall CM, McCulloch CA, Sodek J (2006) A critical role for the membrane-type 1 matrix metalloproteinase in collagen phagocytosis. Mol Biol Cell 17:4812–4826PubMedCentralPubMedCrossRefGoogle Scholar
  76. 76.
    Arora PD, Manolson MF, Downey GP, Sodek J, McCulloch CA (2000) A novel model system for characterization of phagosomal maturation, acidification, and intracellular collagen degradation in fibroblasts. J Biol Chem 275:35432–35441PubMedCrossRefGoogle Scholar
  77. 77.
    Yuen A, Laschinger C, Talior I, Lee W, Chan M, Birek J, Young EW, Sivagurunathan K, Won E, Simmons CA, McCulloch CA Methylglyoxal-modified collagen promotes myofibroblast differentiation. Matrix Biol 29:537–548Google Scholar
  78. 78.
    Chong SA, Lee W, Arora PD, Laschinger C, Young EW, Simmons CA, Manolson M, Sodek J, McCulloch CA (2007) Methylglyoxal inhibits the binding step of collagen phagocytosis. J Biol Chem 282:8510–8520PubMedCrossRefGoogle Scholar

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© Springer International Publishing Switzerland 2015

Authors and Affiliations

  1. 1.Matrix Dynamics GroupUniversity of TorontoTorontoCanada

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