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. We genetically engineered transgenic mice in which androgen receptor (AR) overexpression is skeletally targeted in two separate models to better understand the role of androgen signaling directly in bone. In the third year, we have completed the analysis of the second line of AR-transgenic mice, AR2.3-transgenic mice (submitted for publication). Enhanced androgen signaling directly in bone results in inhibition of bone formation by differentiated osteoblasts, with a phenotype reflecting low turnover. Comparisons between both models of AR2.3- and AR3.6-transgenic animals suggests that AR transactivation in osteocytes is primarily responsible for mediating the effects of androgen on matrix quality and/or mineralization (inhibitory), while stromal/immature cells mediate effects of androgen on the periosteum and body composition (anabolic). The consequence of androgen action in vivo is compartment-specific; anabolic effects are exhibited exclusively at periosteal surfaces, but in mature osteoblasts androgens inhibit osteogenesis with detrimental effects on matrix quality, bone fragility and whole bone strength (Specific Aim 1). Cell culture models are currently being characterized to determine the effects of androgens on osteoblast-osteoclast communication (Specific aim 2). After a sustained hypogonadal period, gender differences are observed in the response to androgen replacement: both males and females demonstrate improved bone mineral, but females are insensitive to improvements in body composition. AR overexpression in both models worsens the response. These results indicate that direct androgen is generally not anabolic in the skeleton. Differentiation in calvarial cultures from AR2.3-tg mice and gene expression analysis of androgen action in osteocytes (Specific aim 3) are ongoing.
Document Details
- Document Type
- Technical Report
- Publication Date
- Dec 01, 2007
- Accession Number
- ADA524387
Entities
People
- Karl Jepsen
- Kristine M. Wiren
Organizations
- Oregon Health & Science University