Otosclerosis: Disturbed Balance Between Cell Survival and Apoptosis

Hypothesis: Otosclerosis is an inflammatory bone remodeling disorder of the human otic capsule, which might be characterized by a disturbed balance between cell survival and apoptosis due to an increased expression of inflammatory cytokines, mainly tumor necrosis factor-alpha (TNF-alpha). Background: Histologic features of otosclerosis have been well described; however, different histopathologic and clinical stages have not been attributed precisely to the molecular biology of the pathologically increased metabolism of bone-forming and bone-resorbing cells. Methods: Forty ankylotic stapes footplates (n = 40, males = 17, females = 23) removed by stapedectomy were histologically analyzed by conventional hematoxylin-eosin staining, and hCIAP1/2 (inhibitors of apoptosis) and granzyme-beta (apoptosis inducer) specific immunofluorescent assays were performed. Four normal stapes footplates obtained from cadavers with negative otologic history were used as negative controls. Results: Active otosclerosis (n = 19) was featured by robust expression of apoptosis inhibitor proteins hCIAP1/2 and negligible expression of granzyme-beta. Inactive cases of otosclerosis (n = 8) were characterized by inverse reaction: granzyme-beta was highly expressed; however, hCIAP1/2 specific immunoreactions were absent. Nonotosclerotic and normal stapes specimens showed no considerable little granzyme-beta expression and moderate hCIAP1/2-specific immunoreactions. Expression pattern of apoptosis-associated proteins showed strong correlation with the histologic diagnosis and activity of otosclerosis (Yates-corrected chi(2) test, p < 0.001). Conclusion: Detection of the inversely expressed apoptosis inhibitor and inducer proteins in active and inactive stages of otosclerosis demonstrates pathologic regulation of cell survival and apoptosis. These results may suggest active otosclerosis inactivation by TNF-alpha induced apoptosis. Anti-TNF-alpha biologics may serve as an option in the medical treatment of active otosclerosis.