Metallothionein-null mice are more susceptible than wild-type mice to chronic CdCl2-induced bone injury

Cadmium (Cd) is an environmental pollutant and is toxic to a number of orga ns. Chronic exposure to Cd causes loss of bone mass and increased incidence of bone fractures, as seen in Itai-itai patients and laboratory animals. M etallothionein (MT), a low-molecular weight, cysteine-rich, metal-binding p rotein, 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 agai nst Cd-induced bone injury. Wild-type and MT-I/II knockout (MT-null) mice w ere given repeated sc injections of CdCl2 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 i n bone was much lower than that found in the liver and kidney (11 vs 400 an d 120 mu g/g, respectively) of the same mice. There was no difference in bo ne Cd content between wild-type and MT-null mice. Repeated Cd injections pr oduced 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 ph otography showed decreasing bone density along the entire bone length with increasing dose and time of Cd exposure. The decrease in bone density was m ore marked in MT-null mice than in wild-type mice at the same dose and time points. Histopathology showed dilatation of haversian canals with increase d osteoid seams, rounded osteocytes with expanded pericellular space, and e xpansion 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-i nduced bone mass loss and bone injury, and thus indicates that MT plays a p rotective role in Cd-induced toxicity in bone, as it does in other tissues.