Biomedical papers, 2016 (vol. 160), issue 4

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2016, 160(4):538-542 | 10.5507/bp.2016.055

MMPs and TIMPs expression in facial tissue of children with cleft lip and palate

Liene Smane-Filipovaa, Mara Pilmanea, Ilze Akotab
a Department of Morphology, Institute of Anatomy and Anthropology, Riga Stradins University, Dzirciema Street 16, Riga LV 1007, Latvia
b Institute of Stomatology, Riga Stradins University, Riga, Latvia

Background and Aims: Morphogenesis of the upper lip and palate is a complex process involving highly regulated interactions between epithelial and mesenchymal cells. Genetic evidence in humans and mice indicates the involvement of matrix metalloproteinases (MMPs) and their endogenous tissue inhibitors (TIMPs) in cleft lip palate (CLP) aetiology. This study investigated whether expression of MMP-2, MMP-8, MMP-9, TIMP-2, and TIMP-4, which are essential for the upper lip and palate fusion, is dysregulated in children with CLP.

Methods: Oral mucosa tissue samples were obtained from patients with complete unilateral (CU) CLP (n = 25) and complete bilateral (CB) CLP (n = 19) during corrective plastic surgery and in unaffected control subjects (n = 10). MMPs and TIMPs expression was assessed by immunohistochemistry, and the data were analyzed using the Kruskal - Wallis test with the Bonferroni correction.

Results: In CLP patients, MMP-2, TIMP-2 immunoreactivity in the oral mucosa was seen to have a few to abundant structures, but the overall number of MMP-2, TIMP-2-positive structures was greater than that in controls (P < 0.01). The total number of TIMP-4, MMP-9-positive cells showed a significant decrease in the CBCLP compared with that of CUCLP (P < 0.001). MMP-8 expression trends in the CLP group were similar to those of the control group.

Conclusions: The results suggest that TIMP-4 and MMP-9 are the main ECM remodeling regulatory proteins expressed in CUCLP affected tissues of the oral mucosa. The increased expression of MMP-2 and TIMP-2 in CLP tissues implicates these factors in the regulation of cell migration during ECM turnover independently of different types of clefts. Investigation of MMP and TIMP expression in tissue samples from patients with CLP appears to be a promising approach to the etiopathogenesis of CLP.

Keywords: cleft lip and palate, matrix metalloproteinases, tissue inhibitors of matrix metalloproteinases

Received: June 6, 2016; Accepted: October 24, 2016; Prepublished online: November 21, 2016; Published: December 12, 2016


References

  1. Mossey PA, Little J, Munger RG, Dixon MJ, Shaw WC. Cleft lip and palate. Lancet 2009;374(9703):1773-85. Go to original source... Go to PubMed...
  2. Jugessur A, Farlie PG, Kilpatrick N. The genetics of isolated orofacial clefts: from genotypes to subphenotypes. Oral Dis 2009;15(7):437-53. Go to original source... Go to PubMed...
  3. Murray JC. Gene/environment causes of cleft lip and/or palate. Clin Genet 2002;61(4):248-56. Go to original source... Go to PubMed...
  4. Dudas M, Li WY, Kim J, Yang A, Kaartinen V. Palatal fusion - where do the midline cells go? A review on cleft palate, a major human birth defect. Acta Histochem 2007;109(1):1-14. Go to original source... Go to PubMed...
  5. Jin JZ, Ding J. Analysis of cell migration, transdifferentiation and apoptosis during mouse secondary palate fusion. Development 2006;133(17):3341-7. Go to original source... Go to PubMed...
  6. Nawshad A. Palatal seam disintegration: to die or not to die? that is no longer the question. Dev Dyn 2008;237(10):2643-56. Go to original source... Go to PubMed...
  7. Mansell JP, Kerrigan J, McGill J, Bailey J, TeKoppele J, Sandy JR. Temporal changes in collagen composition and metabolism during rodent palatogenesis. Mech Ageing Dev 2000;119(1-2):49-62. Go to original source... Go to PubMed...
  8. François-Fiquet C, Poli-Merol ML, Nguyen P, Landais E, Gaillard D, Doco-Fenzy M. Role of angiogenesis-related genes in cleft lip/palate: review of the literature. Int J Pediatr Otorhinolaryngol 2014;78(10):1579-85. Go to original source... Go to PubMed...
  9. Shi J, Son MY, Yamada S, Szabova L, Kahan S, Chrysovergis K, Wolf L, Surmak A, Holmbeck K. Membrane-type MMPs enable extracellular matrix permissiveness and mesenchymal cell proliferation during embryogenesis. Dev Biol 2008;313(1):196-209. Go to original source... Go to PubMed...
  10. Pilmane M, Rumba I, Sundler F. & Luts A. Patterns of distribution and occurrence of neuroendocrine elements in lungs of humans with chronic lung disease. Proc Latv Acad Sci 1998;52:144-152.
  11. Meng L, Bian Z, Torensma R, Von den Hoff JW. Biological mechanisms in palatogenesis and cleft palate. J Dent Res 2009;88(1):22-33. Go to original source... Go to PubMed...
  12. Morris-Wiman J, Burch H, Basco E. Temporospatial distribution of matrix metalloproteinase and tissue inhibitors of matrix metalloproteinases during murine secondary palate morphogenesis. Anat Embryol (Berl) 2000;202(2):129-41. Go to original source... Go to PubMed...
  13. Blavier L, Lazaryev A, Groffen J, Heisterkamp N, DeClerck YA, Kaartinen V. TGF-beta3-induced palatogenesis requires matrix metalloproteinases. Mol Biol Cell 2001;12(5):1457-66. Go to original source... Go to PubMed...
  14. Nikopensius T, Kempa I, Ambrozaitytė L, Jagomägi T, Saag M, Matulevičienė A, Utkus A, Krjutškov K, Tammekivi V, Piekuse L, Akota I, Barkane B, Krumina A, Klovins J, Lace B, Kučinskas V, Metspalu A. Variation in FGF1, FOXE1, and TIMP2 genes is associated with nonsyndromic cleft lip with or without cleft palate. Birth Defects Res A Clin Mol Teratol 2011;91(4):218-25. Go to original source... Go to PubMed...
  15. Wang Z, Juttermann R, Soloway PD. TIMP-2 is required for efficient activation of proMMP-2 in vivo. J Biol Chem 2000;275(34):26411-5. Go to original source... Go to PubMed...
  16. Zhang J, Zhao YG, Cao YJ, Sang QX, Duan EK. Expression and implications of tissue inhibitor of metalloproteinases-4 in mouse embryo. Mol Hum Reprod 2003;9(3):143-9. Go to original source... Go to PubMed...
  17. Zhang B, Henney A, Eriksson P, Hamsten A, Watkins H, Ye S. Genetic variation at the matrix metalloproteinase-9 locus on chromosome 20q12.2-13.1. Hum Genet 1999;105(5):418-23. Go to original source... Go to PubMed...
  18. Letra A, da Silva RA, Menezes R, de Souza AP, de Almeida AL, Sogayar MC, Granjeiro JM. Studies with MMP9 gene promoter polymorphism and nonsyndromic cleft lip and palate. Am J Med Genet A 2007;143A(1):89-91. Go to original source... Go to PubMed...
  19. Van Lint P, Libert C. Matrix metalloproteinase-8: cleavage can be decisive. Cytokine Growth Factor Rev 2006;17(4):217-23. Go to original source... Go to PubMed...
  20. Giambernardi TA, Sakaguchi AY, Gluhak J, Pavlin D, Troyer DA, Das G, Rodeck U, Klebe RJ. Neutrophil collagenase (MMP-8) is expressed during early development in neural crest cells as well as in adult melanoma cells. Matrix Biol 2001;20(8):577-87. Go to original source... Go to PubMed...