Genomes and Genes
Androgen action in bone: Overexpression of AR
Principal Investigator: KRISTINE WIREN
Abstract: Osteoporosis is a metabolic bone disease with low bone mass and compromised skeletal microarchitecture that increases bone fragility and, consequently, fracture risk. Total bone mass acquired during the active growth phases early in life is an important determinant of the risk of disease development, with bone quality being another important determinant. Osteoporosis is often coupled with a hypogonadal state in both men and women but the influence of androgen and estrogen on the skeleton remains poorly characterized. Estrogens are thought to act through an inhibition of bone resorption by the osteoclast, i.e. as anti-resorptive agents, which protect the skeleton from further loss of bone. Non-aromatizable androgens such as Salpha- dihydrotestosterohe (DHT), are anabolic agents that increase bone mass by stimulation of bone formation, and thus represent an important therapeutic class. One target of androgen action is the periosteal compartment, with activation leading to an increase in bone size believed to underlie differences in skeletal size observed between males and females, but the mechanisms remain controversial. We hypothesize that androgens influence bone formation and bone size through actions mediated by the androgen receptor (AR) in the osteoblastic lineage. We have developed an AR-transgenic animal model as a tool to better identify the important biological consequences of androgen action. AR-transgenic lines exhibit overexpressionof the AR targeted to distinct osteoblastic populations through the use of two different promoters;co!3.6 AR- transgenic mice with AR overexpression in the periosteum and throughout the osteoblast lineage vs. co!2.3 AR-transgenic mice with overexpression restricted to mineralizing mature osteoblasts. We proposethat differences between controls and selectively targeted AR-transgenic lines will provide a novel model to characterize androgen responsiveness in bone without systemic administration of hormone. In Specific Aim 1, we will define the contribution of AR signaling to the developing skeleton in mice with enhanced sensitivity to androgen in distinct osteoblast populations. In Specific Aim 2, we will characterize molecular and cellular events influenced by androgen and estrogen in osteoblast models, including periosteal and endosteal cells. These studies will identify specific molecular events/pathways influenced by androgen treatment in bone, and should lead to an improved understanding of mechanisms that influence adult bone size and quality.
Funding Period: ----------------2010 - ---------------2011-
more information: NIH RePORT
- Targeting of androgen receptor in bone reveals a lack of androgen anabolic action and inhibition of osteogenesis: a model for compartment-specific androgen action in the skeletonKristine M Wiren
Bone and Mineral Research Unit, Portland Veterans Affairs Medical Center, Portland, Oregon, USA
Bone 43:440-51. 2008..These results indicate that direct androgen action in mature osteoblasts is not anabolic, and raise concerns regarding anabolic steroid abuse in the developing skeleton or high-dose treatment in eugonadal adults...
- Androgen prevents hypogonadal bone loss via inhibition of resorption mediated by mature osteoblasts/osteocytesKristine M Wiren
Department of Veterans Affairs Medical Center, Portland, OR 97239, USA
Bone 51:835-46. 2012..Combined, these results demonstrate that in the adult mouse, androgen treatment can reduce bone resorption but has little overall anabolic activity...
- Signaling pathways implicated in androgen regulation of endocortical boneKristine M Wiren
Bone and Mineral Research Unit, Portland Veterans Affairs Medical Center, USA
Bone 46:710-23. 2010..Such detrimental effects of androgen on osteoblast function may underlie the generally disappointing results of androgen therapy...
- Body composition changes and inhibition of fat development in vivo implicates androgen in regulation of stem cell lineage allocationAnthony A Semirale
Research Service, Veterans Affairs Medical Center, Portland, Oregon 97239, USA
J Cell Biochem 112:1773-86. 2011....
- Bone vs. fat: embryonic origin of progenitors determines response to androgen in adipocytes and osteoblastsKristine M Wiren
Bone and Mineral Research Unit, Portland Veterans Affairs Medical Center, Portland, OR 97239, USA
Bone 49:662-72. 2011..Further, these data these data suggest that the periosteum surrounding long bone is derived from neural crest...
- Stem cell activation in adults can reverse detrimental changes in body composition to reduce fat and increase lean mass in both sexesKristine M Wiren
Research Service, Veterans Affairs Medical Center, Portland, OR 97239, USA
J Cell Biochem 112:3638-47. 2011....