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Evidence that 2-methoxyestradiol suppresses proliferation and accelerates apoptosis in normal rat growth plate
Jean D Sibonga1, Ulrike Sommer, Russell T Turner
1Department of Orthopedics, Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA, Sibonga.Jean@mayo.edu
Purpose:
2-Methoxyestradiol (2ME(2)), a metabolite of 17beta-estradiol, is currently undergoing extensive clinical testing as an antitumor agent. This drug antagonizes both angiogenesis and induces apoptosis in some tumor cell lines. Growth plate alterations as well as an inhibition of longitudinal bone growth have been reported in young rats treated with a pharmacological dose of 2ME(2). However, 2ME(2)'s mechanism of action at the growth plate is unknown. To uncover the mechanism, we examined the dose-response effects of 2ME(2) on growth plate chondrocytes.
Methods:
2ME(2) (4-, 20-, and 75 mg.kg.day) was administered orally to recently ovariectomized 10-week-old rats. The number of cells undergoing DNA synthesis was evaluated with (3)H-thymidine radioautography, apoptosis-induced DNA fragmentation was detected with TUNEL assay, and longitudinal growth rates were determined with fluorochrome labeling.
Results:
2ME(2) reduced bone elongation ( P< or =0.05), suppressed chondrocyte proliferation ( P< or =0.05), and induced chondrocyte apoptosis ( P< or =0.05). Furthermore, 1-week treatment with 2ME(2) did not affect the size of hypertrophic chondrocytes.
Conclusion:
Thus, pharmacological doses of 2ME(2) utilized for tumor suppression can inhibit normal bone elongation in growing rats by reducing the number of proliferating chondrocytes in the growth plate and accelerating apoptosis in differentiated chondrocytes. This demonstration identifies another organ in which toxicity should potentially be monitored in ongoing and future clinical trials of 2ME(2).
Insights
Pharmacological doses of 2-methoxyestradiol (2ME(2)), used as an antitumor agent, inhibit bone elongation in rats by reducing chondrocyte proliferation and increasing apoptosis. This highlights potential toxicity in growing bone during clinical trials.
Area of Science:
- Endocrinology
- Oncology
- Skeletal Biology
Background:
- 2-Methoxyestradiol (2ME(2)), a 17beta-estradiol metabolite, is investigated as an antitumor agent.
- 2ME(2) exhibits anti-angiogenic and pro-apoptotic properties in tumor cell lines.
- Previous studies reported growth plate alterations and inhibited longitudinal bone growth in young rats treated with 2ME(2).
Purpose of the Study:
- To elucidate the mechanism of 2-methoxyestradiol's action on the growth plate.
- To examine the dose-response effects of 2ME(2) on growth plate chondrocytes.
Main Methods:
- Ovariectomized rats were administered varying oral doses of 2ME(2).
- Chondrocyte proliferation was assessed using (3)H-thymidine radioautography.
- Apoptosis was detected via TUNEL assay, and longitudinal growth was measured using fluorochrome labeling.
Main Results:
- 2ME(2) significantly reduced bone elongation, chondrocyte proliferation, and induced chondrocyte apoptosis.
- No significant effect on hypertrophic chondrocyte size was observed after 1-week of 2ME(2) treatment.
Conclusions:
- Pharmacological doses of 2ME(2) inhibit normal bone elongation by impacting chondrocyte proliferation and apoptosis.
- These findings suggest that bone toxicity should be monitored in patients undergoing 2ME(2) treatment for cancer.