Metallothionein-null mice are more susceptible than wild-type mice to chronic CdCl(2)-induced bone injury

Cadmium (Cd) is an environmental pollutant and is toxic to a number of organs. Chronic exposure to Cd causes loss of bone mass and increased incidence of bone fractures, as seen in Itai-itai patients and laboratory animals. Metallothionein (MT), a low-molecular weight, cysteine-rich, metal-binding protein, has been shown to play an important role in the detoxication of Cd. Thus, this study was designed to test the hypothesis that MT protects against Cd-induced bone injury. Wild-type and MT-I/II knockout (MT-null) mice were given repeated sc injections of CdCl(2) over a wide range of doses for 10 weeks, and Cd-induced bone injury was examined. Cd produced dose- and time-dependent increases in bone Cd content. However, the concentration of Cd in bone was much lower than that found in the liver and kidney (11 vs 400 and 120 microg/g, respectively) of the same mice. There was no difference in bone Cd content between wild-type and MT-null mice. Repeated Cd injections produced a dose-dependent loss of bone mass (up to 25%), as shown by analysis of the femur, tibia, and lumbar vertebrae. The loss of bone mass was more marked in MT-null mice than in wild-type mice, as shown by dry bone weight, defatted bone weight, bone ash weight, and total calcium content. X-ray photography showed decreasing bone density along the entire bone length with increasing dose and time of Cd exposure. The decrease in bone density was more marked in MT-null mice than in wild-type mice at the same dose and time points. Histopathology showed dilatation of haversian canals with increased osteoid seams, rounded osteocytes with expanded pericellular space, and expansion of hyperplastic bone marrow into metaphyseal cortical bone. Again, these lesions were more marked in MT-null mice. In conclusion, this study demonstrates that deficiency in MT renders animals more susceptible to Cd-induced bone mass loss and bone injury, and thus indicates that MT plays a protective role in Cd-induced toxicity in bone, as it does in other tissues.