Progressive increase in bone mass and development of odontomas in aging osteopetrotic c-src-deficient mice

The critical role of c-src in osteoclast-mediated bone resorption has been emphasized by gene deletion experiments in mice. However, the long-term eff ects of the lack of c-src and impaired osteoclast function on the skeleton remain unknown, To further study the physiological role of c-src and to cir cumvent the early death of src(-/-) mice, due to starvation in the absence of erupted teeth, we maintained mice on a liquid diet. At the age of 2 mont hs the src(-/-) mice presented signs of airway obstruction and all mice die d progressively between 2.5 and 6 months of age. Radiography demonstrated s evere osteopetrosis of the whole skeleton. Histomorphometrical analysis of the src(-/-) mice confirmed a significant increase in bone mass with age, r esulting in complete loss of bone marrow spaces in some bones and explainin g the consistent hepatosplenomegaly, due to extraskeletal hematopoesis. His topathological examination of the skull revealed the presence of odontomas in the region of the unerupted incisors, with a penetrance of 100% in the a ging src(-/-) mice. Although odontomas are benign lesions, their progressiv e growth leads to the obliteration of the nasal airways, progressive suffoc ation, and death in src(-/-) mice. These results suggest that: (i) in the a bsence of bone resorption, bone formation continues and leads to progressiv e accentuation of the osteopetrotic phenotype in src(-/-) mice; (ii) osteoc lastic function is required for regular eruption of the incisors and defici ent bone resorption is associated with the development of odontomas; and (i ii) src(-/-) mice die by suffocation due to airway obliteration as a result of progressive odontoma growth. (C) 2000 by Elsevier Science Inc. All righ ts reserved.