Apoptosis of oral epithelial cells in oral lichen planus caused by upregulation of BMP-4.
BACKGROUND
Bone morphogenic protein (BMP-4) is a member of transforming growth factor (TGF-beta) family and involved in various functions including apoptosis during neural ectoderm development. The objective of this study is to determine whether BMP-4 is involved in apoptosis, one characteristic, of human oral lichen planus (OLP).


METHODS
Immunohistochemistry and in situ hybridization for BMP-4 were carried out in OLP (n = 21) and normal human oral mucosa (NOM, n = 31). Five tissue samples from NOM and OLP were underwent reverse transcriptase-polymerase chain reaction (RT-PCR). In vitro organ culture of oral mucosa was carried out with beads soaked with various concentration of BMP-4 (0.1, 1, and 10 microg/ml). The samples from in vitro organ culture were undergone haematoxylin and eosin staining, terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labelling technique (TUNEL) assay, and immunohistochemical study with p53, matrix metalloproteinases (MMP)-1, and MMP-3. Involucrin expression was determined by western blot analysis after treatment with BMP-4 or TGF-beta1 on human oral keratinocytes.


RESULTS
In immunohistochemical analysis, expression of BMP-4 was higher in OLP than NOM. BMP-4 mRNA expression was also detected in epithelial cells of both NOM and OLP together with underlying T-lymphocytes by in situ hybridization and RT-PCR. In oral mucosa organ culture, BMP-4 soaked beads induced apoptosis of epithelial cells. Acantolysis combined with apoptosis in oral epithelium was observed at 1 microg/ml of BMP-4 beads and it was due in part to the induction of p53 and MMP-1. Even MMP-3 induction was found in lower concentration of BMP-4 (0.1 and 1 microg/ml). Moreover, the expression of MMP-1 and MMP-3 was also observed in OLP. Recombinant BMP-4 or TGF-beta1 increased involucrin expression in human oral keratinocytes cell line.


CONCLUSIONS
Expression of BMP-4 of epithelial cells was higher in OLP than NOM. High concentration of BMP-4 caused an apoptosis of oral epithelial cells in oral mucosa organ culture. Therefore, over-expression of BMP-4 is one causing factor for apoptosis of oral epithelial cells through upregulation of p53, MMP1 and MMP3 in OLP.
Kim
S-G
SG
Department of Oral and Maxillofacial Surgery, College of Medicine, Hallym University, Anyang, Korea. epker@chollian.net
Chae
C-H
CH
Cho
B-O
BO
Kim
H-N
HN
Kim
H-J
HJ
Kim
I-S
IS
Choi
J-Y
JY
D000328:Adult; D017209:Apoptosis / Q000502:physiology*; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000032:analysis* / Q000494:pharmacology; D002478:Cells, Cultured; D053938:DNA Fragmentation / Q000187:drug effects; D004847:Epithelial Cells / Q000201:enzymology / Q000473:pathology; D005260:Female; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000473:pathology; D017676:Lichen Planus, Oral / Q000201:enzymology* / Q000473:pathology; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000032:analysis; D019278:Matrix Metalloproteinase 3 / Q000032:analysis; D008875:Middle Aged; D009061:Mouth Mucosa / Q000201:enzymology* / Q000473:pathology; D009924:Organ Culture Techniques; D011498:Protein Precursors / Q000032:analysis; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D053773:Transforming Growth Factor beta1; D016159:Tumor Suppressor Protein p53 / Q000032:analysis; D015854:Up-Regulation / Q000502:physiology*
C525809:BMP4 protein, human; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D011498:Protein Precursors; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D016159:Tumor Suppressor Protein p53; C032253:involucrin; D019278:Matrix Metalloproteinase 3; D020781:Matrix Metalloproteinase 1