Auditory ossicle abnormalities and hearing loss in the toothless (osteopetrotic) mutation in the rat and their improvement after treatment with colony-stimulating factor-1

Osteopetrosis describes a group of skeletal metabolic diseases of heterogen eous etiology and varied severity that produces a generalized accumulation df skeletal mass, the result of reduced bone resorption; Inherited in a var iety of species including humans, the most severe forms are lethal. Among c ommon features are progressive blindness and deafness of controversial etio logies for which there are no universally effective treatments. We have stu died the auditory responsiveness and auditory ossicle quantitative histomor phology and temporal bone vasculature in the toothless (tl) rat, a lethal o steopetrotic mutation with few osteoclasts, very low bone turnover, and lim ited angiogenesis in the axial skeleton. Compared with normal littermates, 3-week-old mutants showed significantly reduced auditory responsiveness, a hearing loss due to abnormalities in both form and tissue composition of th e stapes, and little capillary sprouting in the vascular bed of the tempora l bone. Treatment of mutants with colony-stimulating factor 1 (CSF-1), know n to greatly reduce sclerosis in the axial skeleton, significantly improved hearing, stapedial form and tissue composition, and angiogenesis in the te mporal bone. In normal rats, the stapes consisted of 89.3% bone, 9.1% miner alized cartilage, and 0.8% porosity. In osteopetrotic rats, the stapes cons isted of 48.3% bone, 35.9% mineralized cartilage, and 15.9% porosity, while after CSF-1 treatment, the bone content increased to 55.2%, cartilage was decreased to 21.7%, and porosity increased to 23.0%, respectively. This is the first demonstration of an auditory abnormality in an osteopetrotic anim al mutation and shows that the hearing loss in tl rats can be significantly improved following treatment with CSF-1.