Potential roles of metallothioneins I and II in protecting bone growth following acute methotrexate chemotherapy

Abstract

Metallothioneins (MTs) are known to participate in protection against oxidative stress. This study assessed the effects of MT-I&II gene knockout on methotrexate (MTX)-induced bone damage in growing mice. MT-I&II knockout (MT⁻/⁻) and wild type (MT⁺/⁺) male mice were injected with saline or 12.5 mg kg⁻¹ MTX for three consecutive days. MTX treatment was shown to cause more severe damage in MT⁻/⁻ mice when compared to MT⁺/⁺ mice, as demonstrated by the more obvious thinning of growth plate, reduced proliferation and increased apoptosis of chondrocytes, and reduced metaphysis heights in the knockout mice. Analysis of total liver glutathione (the most abundant intracellular antioxidant) also revealed significant lower glutathione levels in all MT⁻/⁻ mice. In conclusion, MT⁻/⁻ mice were more susceptible than MT⁺/⁺ mice to MTX-induced bone damages, which may be associated with the reduction of basal antioxidant defence, suggesting a protective role of MTs in the growing skeleton against damages caused by MTX chemotherapy.