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 fourth year, we have published the analysis of the second line of AR-transgenic mice, AR2.3-transgenic mice. 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). Gene expression profiling has identified important signaling pathways by which androgens influence osteoblast-osteoclast communication (Specific aim 2). Ex vivo differentiation analysis of proliferation and differentiation in calvarial cultures from AR3.6-tg and AR2.3-tg mice demonstrates inhibition of proliferation that is not affected by the AR-tg (likely because expression levels are low in proliferating cultures), and robust inhibition of osteoblast matrix maturation and mineralization that is most severe in cultures with AR overexpression throughout the osteoblast lineage (Specific aim 3).
Document Details
- Document Type
- Technical Report
- Publication Date
- Dec 01, 2009
- Accession Number
- ADA518379
Entities
People
- Kristine M. Wiren
Organizations
- University of Portland