Transforming growth factor beta and wound healing in human cholesteatoma.
OBJECTIVE
Cholesteatoma is a nonmalignant, destructive lesion of the temporal bone that gradually expands and causes complications by the erosion of the adjacent bony structures. The consequences can be as severe as facial paralysis and intracranial complications. Until now, surgery has been the only treatment of choice. The pathogenesis of cholesteatoma remains controversial. Current concepts postulate that cholesteatoma may be a wound-healing process, although formal proof is lacking as of yet. Several reports provide evidence for the involvement of transforming growth factor (TGF)beta in both normal and abnormal wound healing.


METHODS
The expression of TGFbeta, the activated form of its intracellular effector, phosphorylated-Sma-Mad (pSmad)2, its natural inhibitor, Smad7, and target gene extra domain A-positive fibronectin (EDA-FN) were examined.


METHODS
Quantitative immunohistochemical analysis was performed using an image analysis system.


RESULTS
In 12 cholesteatoma and control samples, protein expressions showed consistent relationships among TGFbeta, nuclear pSmad2, and Smad7. We found concordant expressions of TGFbeta and nuclear pSmad2 in cholesteatoma epithelium and its control. Epithelial Smad7 expression was significantly reduced in cholesteatoma when compared with control epithelium (P = .04). In cholesteatoma extracellular matrix (ECM), a significantly increased TGFbeta, and nuclear pSmad2 was demonstrated (P < .01). Smad7 expression in the ECM was comparable in cholesteatoma and its control. EDA-FN deposition in cholesteatoma ECM was excessive, whereas EDA-FN expression was absent in controls.


CONCLUSIONS
Our results confirm reports of in vitro experiments and support the concept that cholesteatoma behaves as a chronic wound healing process.
Huisman
Margriet A
MA
Department of Ear, Nose and Throat, Leiden University Medical Center, Leiden, The Netherlands. m.a.huisman@lumc.nl
de Heer
Emile
E
Ten Dijke
Peter
P
Grote
Jan J
JJ
D002467:Cell Nucleus / Q000648:ultrastructure; D018424:Cholesteatoma, Middle Ear / Q000473:pathology* / Q000503:physiopathology; D003238:Connective Tissue / Q000473:pathology; D003593:Cytoplasm / Q000648:ultrastructure; D004848:Epithelium / Q000473:pathology; D005109:Extracellular Matrix / Q000473:pathology; D005353:Fibronectins / Q000032:analysis / Q000502:physiology; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D020033:Protein Isoforms / Q000032:analysis / Q000502:physiology; D012867:Skin / Q000473:pathology; D051899:Smad2 Protein / Q000032:analysis / Q000502:physiology; D051906:Smad7 Protein / Q000032:analysis / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000032:analysis / Q000502:physiology*; D014945:Wound Healing / Q000502:physiology
D005353:Fibronectins; D020033:Protein Isoforms; C497782:SMAD2 protein, human; C497806:SMAD7 protein, human; D051899:Smad2 Protein; D051906:Smad7 Protein; D016212:Transforming Growth Factor beta