Enhanced Androgen Signaling with Androgen Receptor Overexpression in the Osteoblast Lineage Controls Skeletal Turnover, Matrix Quality, and Bone Architecture
Abstract
Androgens have been shown to be important mediators of bone growth and remodeling independent of estrogen. A better understanding of the consequences of androgen action in bone is particularly important given increased anabolic steroid abuse. In addition, since bone architecture and bone material properties play important roles in stress fracture, analysis of this model represents a unique opportunity to characterize the consequences of androgen action in both genders on bone microarchitectural quality and the integrity of the skeleton in vivo. We genetically engineered transgenic mice in which androgen receptor (AR) overexpression is skeletally targeted to better understand the role of androgen signaling in bone. The central hypothesis of this proposal is that AR transactivation in the osteoblast lineage provides key regulatory signals that regulate the progression of osteoblast differentiation and osteogenesis, control the resorption of calcified bone, and modulate lineage determination in the marrow, to influence skeletal architecture and matrix quality. In the first year, we have successfully created the second line of AR-transgenic mice using the col2.3 promoter to drive AR expression. Ongoing analysis of studies (proposed in Specific Aim 1) suggest that AR transactivation (in young adults of col2.3 with col3.6 ARtransgenic animals) in mature osteoblasts is primarily responsible for mediating the effects of androgen on matrix quality and/or mineralization, while immature cells mediate effects of androgen on the periosteum and potentially body composition. Further, enhanced androgen signaling during growth appears to produce a low turnover state and may be detrimental to skeletal quality with more damageability. Preliminary analysis of studies (proposed in Specific Aim 3) has shown androgenmediated enhancement of apoptosis of cells in the osteoblast lineage in vivo and in vitro.
Document Details
- Document Type
- Technical Report
- Publication Date
- Dec 01, 2005
- Accession Number
- ADA448583
Entities
People
- Karl Jepsen
- Kristine M. Wiren
Organizations
- Oregon Health & Science University