Estrogen Regulation of the Wnt/β-catenin Pathway in Osteocytes in Response to Mechanical Loading

Abstract

Osteoporosis is a major health concern, especially for women who are peri- and post-menopausal. During this time, estrogen levels dramatically decline followed by a subsequent loss of bone density, which increases risk of bone fracture. The increased fragility of bone negatively affects the patient’s quality of life by limiting the performance of everyday activities and increasing the frequency of physician visits and medical care costs. Estrogen exerts its effects on bone at various levels. One important, yet poorly understood, aspect of its action is on the osteocyte, the most abundant cell in bone and thought to be the primary cell involved in sensing mechanical loads. The Wnt/β-catenin pathway is activated in the osteocyte upon mechanical loading. The role of estrogen (specifically estrogen loss) in regulation of this pathway in osteocytes is not fully understood. I hypothesize that estrogen is a critical factor in the responsiveness of the osteocyte to mechanical loading via regulation of the Wnt/β-catenin pathway; and in the absence of estrogen, osteocytes will have a decreased activation upon mechanical loading. The specific aims are: 1) determine the effects of ovariectomy (OVX) on the ability of the osteocyte to activate the Wnt/β-catenin pathway in response to mechanical load; 2) determine the role of estrogen on the activation of the Wnt/β-catenin pathway in vitro in response to mechanical load. The OVX group failed to activate osteocyte β-catenin signaling at 24 hours post-loading, which is normal peak activation time point of the pathway following loading. Trabecular bone had significant decreases in bone mineral density, bone volume/total volume and trabecular thickness in the OVX group, along with increases in osteoclasts and decreases in osteoblast numbers. Bone micro-architecture (lacunar size and volume) and biomechanical properties remained unchanged. In vitro studies showed osteocyte activation with fluid flow and the addition of Wnt3a, and activation was attenuated with the addition of an estrogen receptor inhibitor. These findings are consistent with a change in the intrinsic ability of the osteocyte to respond to loading in the absence of estrogen and support the hypothesis that estrogen plays a critical role in the osteocyte’s responsiveness to mechanical loading.