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. The central hypothesis of this proposal is that AR transactivation in the osteoblast lineage provides key regulatory signals that influence 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 second year, we have completed the initial analysis of the second line of AR-transgenic mice created using the col2.3 promoter to drive AR expression. AR overexpression in mature osteoblasts results in reduced turnover and inhibition of bone formation at the endosteal surface, resulting in thinner cortical bones with poor biomechanical properties, including a reduction in maximum load, strength and work to failure (Specific Aim 1). Ongoing analysis in both models of AR2.3- and AR3.6-transgenic animals suggests that AR transactivation in mature osteoblasts is primarily responsible for mediating the effects of androgen on matrix quality and/or mineralization (inhibitory), while immature cells mediate effects of androgen on the periosteum and body composition (anabolic). In both AR overexpression models, enhanced androgen signaling during growth produces a low turnover state and may be detrimental to skeletal quality with more damageability. After a sustained hypogonadal period, both males and females demonstrate improved bone mineral, but only males show improvements in body composition including increased lean and reduced fat mass. Thus, results to date indicate androgen is not anabolic in mineralizing bone cells, and raise concerns regarding androgen administration in young adults.
Document Details
- Document Type
- Technical Report
- Publication Date
- Dec 01, 2006
- Accession Number
- ADA463969
Entities
People
- Karl Jepsen
- Kristine M. Wiren
Organizations
- Oregon Health & Science University