Collagenases and gelatinases in bone healing. The focus on mandibular fractures

Open access


Due to high amount of collagen fibres in the structure of bone, the enzymes capable of collagen digestion play a key role in bone remodelling. Matrix metalloproteinases (MMPs), prevailing extracellular endopeptideses, can digest extracellularly located proteins, e.g. collagen, proteoglycans, elastin or fibronectin. Among MMPs, collagenases (MMP-1, MMP-8 and MMP-13) and gelatinases (MMP-2 and MMP-9) can cleave collagen particles to forms that are able to undergo further steps of catabolism intracellularly. In addition, activity of the gelatinases (as an activation of proinflammatory cytokines) facilitates spreading inflammation that is necessary during the first stage of bone healing. Further studies related to the role of various MMPs in mandibular fractures should precisely explain their function in the bone healing and evaluate the influence of MMPs inhibitors on that process. This review provides the basic information about two groups among MMPs family, collagenases and gelatinases, and their role in repairing processes after mandibular fractures.

If the inline PDF is not rendering correctly, you can download the PDF file here.

  • 1. Armstrong DG. Jude EB.: The role of matrix metalloproteinases in wound healing. J Am Pediatr Med Assoc. 92 12 2002.

  • 2. Bouletreau P.J. Steinbrech D. Spector J.A. et al: Gene expression of transforming growth factor-beta 3 and tissue inhibitor of metalloproteinase type 1 during membranous bone healing in rats. J Craniofac Surg. 11 521 2000.

  • 3. Brew K. Dinakarpandian D. Nagase H.: Tissue inhibitors of metalloproteinases: evolution structure and function. Biochim Biophys Acta 1477 267 2000.

  • 4. Cha H. Kopetzki E. Huber R. et al. Structural basis of the adaptive molecular recognition by MMP9. J Mol Biol. 320 1065 2002.

  • 5. Chubinskaya S. Huch K. Mikecz K. et al.: Chondrocyte matrix metalloproteinase-8: up-regulation of neutrophil collagenase by interleukin-1 beta in human cartilage from knee and ankle joints. Lab Invest. 74 232 1996.

  • 6. Cuzner M.L. Gveric D. Strand C. et al.: The expression of tissue-type plasminogen activator matrix metalloproteases and endogenous inhibitors in the central nervous system in multiple sclerosis: comparison of stages in lesion evolution. J Neuropathol Exp Neurol. 55 1194 1996.

  • 7. Danielsen P.L. Holst A.V. Maltesen H.R. et al.: Matrix metalloproteinase-8 overexpression prevents proper tissue repair. Surgery 150 897 2011.

  • 8. Dejonckheere E. Vandenbroucke R.E. Libert C.: Matrix metalloproteinase8 has a central role in inflammatory disorders and cancer progression. Cytokine Growth Factor Rev. 22 73 2011.

  • 9. Docherty A.J. Lyons A. Smith B.J. et al.: Sequence of human tissue inhibitor of metalloproteinases and its identity to erythroidpotentiating activity. Nature 318 66 1985.

  • 10. Duerr S. Stremme S. Soeder S. et al.: MMP-2/gelatinase A is a gene product of human adult articular chondrocytes and is increased in osteoarthritic cartilage. Clin Exp Rheumatol. 22 603 2004.

  • 11. Fic P. Zakrocka I. Kurzepa J. Stepulak A.: Mat r ix metalloproteinases and atherosclerosis. Postepy Hig Med Dosw (Online) 65 16 2011.

  • 12. Galazka G. Windsor L.J. Birkedal-Hansen H. Engler JA.: APMA (4-aminophenylmercuric acetate) activation of stromelysin-1 involves protein interactions in addition to those with cysteine-75 in the propeptide. Biochemistry 35 11221 1996.

  • 13. Gross J. Lapiere C.M.: Collagenolytic activity in amphibian tissues: a tissue culture assay. Proc Natl Acad Sci USA. 48 1014 1962.

  • 14. Guedez L. Stetler-Stevenson W.G. Wolff L. et al.: In vitro suppression of programmed cell death of B cells by tissue inhibitor of metalloproteinases-1. J Clin Invest. 102 2002 1998.

  • 15. Hatibović-Kofman S. Raimundo L. Zheng L. et al.: Fracture resistance and histological findings of immature teeth treated with mineral trioxide aggregate. Dent Traumatol. 24 272 2008.

  • 16. Isnard N. Legeais J.M. Renard G. Robert L.: Effect of hyaluronan on MMP expression and activation. Cell Biol Int. 25 735 2001.

  • 17. Kalfas I.H.: Principles of bone healing. Neurosurg Focus 10 7 2001.

  • 18. Kapila S. Xie Y. Wang W.: Induction of MMP-1 (collagenase-1) by relaxin in fibrocartilaginous cells requires both the AP-1 and PEA-3 promoter sites. Orthod Craniofac Res. 12 178 2009.

  • 19. Knauper V. Cowell S. Smith B. et al.: The role of the C-terminal domain of human collagenase-3 (MMP-13) in the activation of procollagenase-3 substrate specificity and tissue inhibitor of metalloproteinase interaction. J Biol Chem. 272 7608 1997.

  • 20. Krane S.M.: Is collagenase (matrix metalloproteinase-1) necessary for bone and other connective tissue remodeling? Clin Orthop Relat Res. 313 47 1995.

  • 21. Kurzepa J. Bartosik-Psujek H. Suchozebrska-Jesionek D. et al.: Role of matrix metalloproteinases in the pathogenesis of multiple sclerosis. Neurol Neurochir Pol. 39 63 2005.

  • 22. Lee J.Y. Taub P.J. Wang L. et al.: Identification of CITED2 as a negative regulator of fracture healing. Biochem Biophys Res Commun. 387 641 2009.

  • 23. Leeman M.F. Curran S. Murray G.I.: The structure regulation and function of human matrix metalloproteinase-13. Crit Rev Biochem Mol Biol. 37 149 2002.

  • 24. Lenglet S. Mach F. Montecucco F.: Role of mat r ix metalloproteinase-8 in atherosclerosis. Mediators Inflamm. 2013 659282 2013.

  • 25. Li H. Ezra D.G. Burton M.J. Bailly M.: Doxycycline prevents matrix remodeling and contraction by trichiasis-derived conjunctival fibroblasts. Invest Ophthalmol Vis Sci. 54 4675 2013.

  • 26. Li N.G. Shi Z.H. Tang Y.P. et al.: New hope for the treatment of osteoarthritis through selective inhibition of MMP-13. Curr Med Chem. 18 977 2011.

  • 27. Loy M. Burggraf D. Martens K.H. et al.: A gelatin in situ-overlay technique localizes brain matrix metalloproteinase activity in experimental focal cerebral ischemia. J Neurosci Methods 116 125 2002.

  • 28. Madro A. Kurzepa J. Czechowska G. et al. Gelatinase activities and TIMP-2 serum level in alcohol cirrhosis and chronic pancreatitis. Curr Iss Pharm Med Sci. 26 57 2013.

  • 29. Madsen D.H. Jurgensen H.J. Ingvarsen S. et al.: Differential Actions of the Endocytic Collagen Receptor uPARAP/Endo180 and the Collagenase MMP-2 in Bone Homeostasis. PLoS One 8 e71261 2013.

  • 30. McCawley L.J. Matrisian L.M.: Matrix metalloproteinases: they’re not just for matrix anymore! Curr Opin Cell Biol. 13 534 2001.

  • 31. Mott J.D. Werb Z.: Regulation of matrix biology by matrix metalloproteinases. Curr Opin Cell Biol. 16 558 2004.

  • 32. Murphy G. Knauper V.: Relating matrix metalloproteinase structure to function: why the “hemopexin” domain? Matrix Biol. 15 511 1997.

  • 33. Nagase H. Visse R. Murphy G.: Structure and function of matrix metalloproteinases and TIMPs. Cardiovasc Res. 69 562 2006.

  • 34. Nomura S. Yoshimura K. Akiyama N. et al: HMG-CoA reductase inhibitors reduce matrix metalloproteinase-9 activity in human varicose veins. Eur Surg Res. 37 370 2005.

  • 35. Opdenakker G. Van den Steen P.E. Van Damme J.: Gelatinase B: a tuner and amplifier of immune functions. Trends Immunol. 22 571 2001.

  • 36. Palosaari H. Wahlgren J. Larmas M. et al.: The expression of MMP-8 in human odontoblasts and dental pulp cells is down-regulatedby TGF-beta1. J Dent Res. 79 77 2000.

  • 37. Pardo A. Selman M.: MMP-1: the elder of the family. Int J Biochem Cell Biol. 37 283 2005.

  • 38. Peppin G.J. Weiss S.J.: Act ivat ion of the endogenous metalloproteinase gelatinase by triggered human neutrophils. Proc Natl Acad Sci USA. 83 4322 1986.

  • 39. Polette M. Nawrocki-Raby B. Gilles C. et al. Tumour invasion and matrix metalloproteinases. Crit Rev Oncol Hematol. 49 179 2004.

  • 40. Rowsell S. Hawtin P. Minshull C.A. et al.: Crystal structure of human MMP9 in complex with a reverse hydroxamate inhibitor. J Mol Biol. 319 173 2002

  • 41. Sang Q.X. Birkedal-Hansen H. Van Wart H.E.: Proteolytic and non-proteolytic activation of human neutrophil progelatinase B. Biochim Biophys Acta 1251 99 1995.

  • 42. Sato H. Takino T. Okada Y. et al. A matrix metalloproteinase expressed on the surface of invasive tumor cells. Nature 370 61 1994.

  • 43. Schmidt R. Bultmann A. Ungerer M. et al.: Extracellular matrix metalloproteinase inducer regulates matrix metalloproteinase activity in cardiovascular cells: implications in acute myocardial infarction. Circulation 113 834 2006.

  • 44. Seltzer J.L. Lee A.Y. Akers K.T. et al.: Activation of 72-kDa type IV collagenase/gelatinase by normal fibroblasts in collagen lattices is mediated by integrin receptors but is not related to lattice contraction. Exp Cell Res. 213 365 1994.

  • 45. Serra P. Bruczko M. Zapico J.M. et al.: MMP-2 selectivity in hydroxamate-type inhibitors. Curr Med Chem. 19 1036 2012.

  • 46. Smigielski J. Kołomecki K. Ziemniak P. et al.: Degradation of collagen by metalloproteinase 2 in patients with abdominal hernias. Eur Surg Res. 42 118 2009.

  • 47. Stetler-Stevenson W.G. Bersch N. Golde D.W.: Tissue inhibitor of metalloproteinase-2 (TIMP-2) has erythroid-potentiating activity. FEBS Lett. 296 231 1992.

  • 48. Stickens D. Behonick D.J. Ortega N. et al.: Altered endochondral bone development in matrix metalloproteinase-13 deficient mice. Development 131 5883 2004.

  • 49. Uchida M. Shima M. Chikazu D. et al.: Transcriptional induction of matrix metalloproteinase-13 (collagenase-3) by 1α25- dihydroxyvitamin D3 in mouse osteoblastic MC3T3-E1 cells. J Bone Min Res. 16 221 2001.

  • 50. Van Lint P. Libert C.: Matrix metalloproteinase-8: cleavage can be decisive. Cytokine Growth Factor Rev. 17 217 2006.

  • 51. Vu T.H. Shipley J.M. Bergers G. et al.: MMP-9/gelatinase B is a key regulator of growth plate angiogenesis and apoptosis of hypertrophic chondrocytes. Cell 93 411 1998.

  • 52. Wang X. Yu Y.Y. Lieu S. et al.: MMP9 regulates the cellular response to inflammation after skeletal injury. Bone 52111 2013.

  • 53. Weiss S. Zimmermann G. Pufe T. et al.: The systemic angiogenic response during bone healing. Arch Orthop Trauma Surg. 127 989 2009.

  • 54. White L.A. Mitchell T.I. Brinckerhoff CE.: Transforming growth factor beta inhibitory element in the rabbit matrix metalloproteinase-1 (collagenase-1) gene functions as a repressor of constitutive transcription. Biochim Biophys Acta 1490 259 2000.

  • 55. Whitelock J.M. Murdoch A.D. Iozzo R.V. Underwood P.A.: The degradation of human endothelial cell-derived perlecan and release of bound basic fibroblast growth factor by stromelysin collagenase plasmin and heparanases. J Biol Chem. 271 10079 1996.

  • 56. Wilhelm S.M. Collier I.E. Marmer B.L. et al.: SV40-transformed human lung fibroblasts secrete a 92-kDa type IV collagenase which is identical to that secreted by normal human macrophages. J Biol Chem. 264 17213 1989.

  • 57. Witty J.P. Foster S.A. Stricklin G.P. et al.: Parathyroid hormoneinduced resorption in fetal rat limb bones is associated with production of the metalloproteinases collagenase and gelatinase B. J Bone Min Res. 11 72 1996.

  • 58. Yu Y. Koike T. Kitajima S. et al.: Temporal and quantitative analysis of expression of metalloproteinases (MMPs) and their endogenous inhibitors in atherosclerotic lesions. Histol Histopathol. 23 1503 2008.

Journal information
Impact Factor

CiteScore 2018: 0.32

SCImago Journal Rank (SJR) 2018: 0.154
Source Normalized Impact per Paper (SNIP) 2018: 0.285

Cited By
All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 265 98 7
PDF Downloads 119 57 4