Connective tissue growth factor in drug-induced gingival overgrowth.
BACKGROUND
Drug-induced gingival overgrowth is a known side effect of certain chemotherapeutic agents used for the treatment of systemic disorders. The pathogenesis and mechanisms responsible for this condition are not fully understood. This study assesses for the presence and localization of connective tissue growth factor (CTGF) in drug-induced gingival overgrowth tissues. CTGF immunostaining was compared with sections stained with transforming growth factor (TGF)-beta1 and CD31 antibodies in order to investigate possible pathogenic mechanisms.


METHODS
Gingival overgrowth samples were obtained from patients undergoing therapy with phenytoin (n = 9), nifedipine (n = 4), cyclosporin A (n = 5), and control tissues from systemically healthy donors (n = 9). Tissue sections were subjected to peroxidase immunohistochemistry and were stained with CTGF and TGF-beta1 polyclonal primary antibodies. Possible relationships between CTGF staining and angiogenesis were also studied using an anti-CD31 antibody as a marker for endothelial cells. Staining was analyzed by computer-assisted quantitative and semiquantitative methodology at 5 defined sites in all samples based on the location of specific landmarks including epithelium and underlying connective tissues.


RESULTS
Cellular and extracellular CTGF content in phenytoin gingival overgrowth tissues was significantly (P<0.05) higher compared to the other gingival overgrowth tissues and the controls. Higher CTGF staining in phenytoin gingival overgrowth tissues was accompanied by an increased abundance of fibroblasts and connective tissue fibers. No strong association of CTGF staining with TGF-beta1 or CD31 staining was found.


CONCLUSIONS
The data from the present study show significantly higher CTGF staining in phenytoin-induced gingival overgrowth tissues compared to controls, cyclosporin A-, or nifedipine-induced gingival overgrowth. Moreover, semiquantitative analyses of histologic samples support the concept that the phenytoin overgrowth tissues are fibrotic. These associations suggest a possible role for CTGF in promoting development of fibrotic lesions in phenytoin-induced gingival overgrowth.
Uzel
M I
MI
Department of Periodontology and Oral Biology, Boston University, Goldman School of Dental Medicine, MA 02118, USA.
Kantarci
A
A
Hong
H H
HH
Uygur
C
C
Sheff
M C
MC
Firatli
E
E
Trackman
P C
PC
D000328:Adult; D000906:Antibodies; D000927:Anticonvulsants / Q000009:adverse effects; D002121:Calcium Channel Blockers / Q000009:adverse effects; D002352:Carrier Proteins / Q000032:analysis*; D004396:Coloring Agents; D003238:Connective Tissue / Q000473:pathology; D055513:Connective Tissue Growth Factor; D016572:Cyclosporine / Q000009:adverse effects; D004730:Endothelium, Vascular / Q000473:pathology; D004848:Epithelium / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000473:pathology; D005355:Fibrosis; D019214:Gingival Overgrowth / Q000139:chemically induced* / Q000473:pathology; D006133:Growth Substances / Q000032:analysis*; D006801:Humans; D007091:Image Processing, Computer-Assisted; D017874:Immediate-Early Proteins / Q000032:analysis*; D007124:Immunoenzyme Techniques; D007166:Immunosuppressive Agents / Q000009:adverse effects; D036341:Intercellular Signaling Peptides and Proteins; D007963:Leukocytes, Mononuclear / Q000473:pathology; D008297:Male; D008875:Middle Aged; D008934:Mitogens / Q000032:analysis*; D009389:Neovascularization, Pathologic / Q000473:pathology; D009543:Nifedipine / Q000009:adverse effects; D010672:Phenytoin / Q000009:adverse effects; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000032:analysis; D018709:Statistics, Nonparametric; D016212:Transforming Growth Factor beta / Q000032:analysis; D053773:Transforming Growth Factor beta1
D000906:Antibodies; D000927:Anticonvulsants; C526317:CCN2 protein, human; D002121:Calcium Channel Blockers; D002352:Carrier Proteins; D004396:Coloring Agents; D006133:Growth Substances; D017874:Immediate-Early Proteins; D007166:Immunosuppressive Agents; D036341:Intercellular Signaling Peptides and Proteins; D008934:Mitogens; D019408:Platelet Endothelial Cell Adhesion Molecule-1; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D055513:Connective Tissue Growth Factor; D010672:Phenytoin; D016572:Cyclosporine; D009543:Nifedipine