Estrogen receptor dependent gene expression by osteoblasts – Direct, indirect, circumspect, and speculative effects

Hormone activated estrogen receptors (ERs) have long been appreciated as potent mediators of gene expression in female reproductive tissues. These highly targeted responses likely evolved from more elemental roles in lower organisms, in agreement with their widespread effects in the cardiovascular, immunological, central nervous, and skeletal tissue systems. Still, despite intense investigation, the multiple and often perplexing roles of ERs retain significant attention. In the skeleton, this in part derives from apparently opposing effects by ER agonists on bone growth versus bone remodeling, and in younger versus older individuals. The complexity associated with ER activation can also derive from their interactions with other hormone and growth factor systems, and their direct and indirect effects on gene expression. We propose that part of this complexity results from essential interactions between ERs and other transcription factors, each with their own biochemical and molecular intricacies. Solving some of the many questions that persist may help to achieve better, or better directed, use of agents that can drive ER activation in focused and possibly tissue restricted ways.

► Estrogen receptors (ERs) have complex effects on gene expression beyond DNA binding.
► These include interactions with other hormone and growth factor systems in bone.
► They involve physical associations by ERs with other transcription factors.
► Osteoblasts can metabolize and synthesize ER ligands and precursors.
► Bone cells thus have a self contained system to control ER sensitive gene expression.