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Targeted Overexpression of Androgen Receptor in Osteoblasts: Unexpected Complex Bone Phenotype in Growing Animals

Bone and Mineral Research Unit (K.M.W., X.-W.Z., A.R.T.), Portland Veterans Affairs Medical Center; and Departments of Medicine (K.M.W.) and Behavioral Neuroscience (K.M.W., X.-W.Z.), Oregon Health & Science University, Portland, Oregon 97239; Department of Molecular Endocrinology/Bone Biology (V.K., M.A.G.), Merck Research Laboratories, West Point, Pennsylvania 19486; and Department of Orthopaedics (K.J.J.), Mt. Sinai School of Medicine, New York, New York 10029

Address all correspondence and requests for reprints to: Kristine Wiren, Ph.D., Portland Veterans Affairs Medical Center P3-R&D39, 3710 Southwest Veterans Hospital Road, Portland, Oregon 97239. E-mail: wirenk{at}ohsu.edu.

The androgen receptor (AR), as a classic steroid receptor, generally mediates biologic responses to androgens. In bone tissue, both AR and the estrogen receptor (ER) are expressed in a variety of cell types. Because androgens can be converted into estrogen via aromatase activity, the specific role of the AR in maintenance of skeletal homoeostasis remains controversial. The goal of this study was to use skeletally targeted overexpression of AR as a means of elucidating the specific role(s) for AR transactivation in bone homeostasis. Rat AR cDNA was cloned downstream of a 3.6-kb 1(I)-collagen promoter fragment and used to create AR-transgenic mice. AR-transgenic males gain less weight and body and femur length is shorter than wild-type controls, whereas females are not different. AR-transgenic males also demonstrate thickened calvaria and increased periosteal but reduced endosteal labeling by fluorescent labeling and reduced osteocalcin levels. High-resolution micro-computed tomography shows normal mineral content in both male and female AR-transgenic mice, but male AR-transgenics reveal a reduction in cortical area and moment of inertia. Male AR-transgenics also demonstrate an altered trabecular morphology with bulging at the metaphysis. Histomorphometric analysis of trabecular bone parameters confirmed the increased bone volume comprised of more trabeculae that are closer together but not thicker. Biomechanical analysis of the skeletal phenotype demonstrate reduced stiffness, maximum load, post-yield deflection, and work-to-failure in male AR-transgenic mice. Steady-state levels of selected osteoblastic and osteoclastic genes are reduced in tibia from both male and female transgenics, with the exception of increased osteoprotegerin expression in male AR-transgenic mice. These results indicate that AR action is important in the development of a sexually dimorphic skeleton and argue for a direct role for androgen transactivation of AR in osteoblasts in modulating skeletal development and homeostasis.

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