Steroid action in bone development (#128)
The sex steroids play a crucial role in many aspects of bone development, such as bone mass accrual, skeletal modelling and growth plate regulation, including epiphyseal fusion. However, the mechanisms underlying their effects are yet to be fully defined. The recognition of males with oestrogen receptor mutations or aromatase deficiency highlighted the importance of oestrogen in both genders. Subsequent studies have demonstrated differential roles of the two main oestrogen receptor subtypes, ER alpha and beta, in rodent receptor knockout models, but translating these findings to human models has proved problematic. We found that selectively blocking ER alpha signalling in an in vitro model of growth plate chondrogenesis inhibited both proliferation and differentiation, while blocking ER beta had the opposite effect(1), These data support the rodent findings, where unopposed ER beta activity causes slower growth and epiphyseal fusion. The findings of osteoporosis in the male with ER alpha mutation coupled with rodent studies suggests that bone mass may also be influenced variably by the two ER subtypes.
Interfering with the action of oestrogen on the growth plate can delay epiphyseal fusion and potentially increase final height. However, the physiological actions of oestrogen at this crucial stage of development in both genders means this strategy may cause harm. Aromatase inhibitors have been trialled to increase final height in males, with some modest improvements in height outcomes. However, we demonstrated that rodent models exposed to aromatase inhibitors showed reduction in bone strength, alteration in skeletal geometry, lowering of IGF-I levels and focal prostatic hyperplasia(2) . Human subjects treated with aromatase inhibitors have shown increased rates of vertebral deformities(3). Therefore, there is a need for the development of a selective strategy that inhibits oestrogen action at the growth plate without causing unwanted non-skeletal effects. Greater understanding of ER subtypes will greatly assist in this process..
- 1. Simm, P.J., Russo, V.C., and Werther, G.A. 2011. The effect of selective oestrogen receptor antagonists in an in vitro model of growth plate chondrogenesis. Endocrine 40:27-34.
- 2. Bajpai, A., Simm, P.J., McPherson, S.J., Russo, V.C., Azar, W.J., Wark, J.D., Risbridger, G.P., and Werther, G.A. 2010. Peripubertal aromatase inhibition in male rats has adverse long-term effects on bone strength and growth and induces prostatic hyperplasia. J Endocrinol 207:27-34.
- 3. Hero, M., Toiviainen-Salo, S., Wickman, S., Makitie, O., and Dunkel, L. 2010. Vertebral morphology in aromatase inhibitor-treated males with idiopathic short stature or constitutional delay of puberty. J Bone Miner Res 25:1536-1543.