Identification of gene pathways altered by deletion of the androgen receptor specifically in mineralizing osteoblasts and osteocytes in mice

Russell, Patricia K; Clarke, Michele V; Skinner, Jarrod P; Pang, Tammy P S; Zajac, Jeffrey D; Davey, Rachel A

doi:10.1530/jme-12-0014

Cited by 26 publications

(22 citation statements)

References 46 publications

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“…Similar findings were reported in an earlier study in which the AR was knocked out in mineralizing osteoblasts and osteocytes. (32) Nevertheless, trabecular number was significantly lower in the vertebrae already in 12-week-old ocy-ARKO, suggesting that the osteocyte AR may also be involved in the development of the cancellous bone network. As illustrated by earlier observations in global ARKO mice, AR action is indeed important for preservation as well as increase of trabecular number and this as early as at the start of puberty.…”

Section: Discussionmentioning

confidence: 90%

Androgen receptor (AR) in osteocytes is important for the maintenance of male skeletal integrity: Evidence from targeted AR disruption in mouse osteocytes

Sinnesael

Claessens

Laurent

et al. 2012

Journal of Bone and Mineral Research

102

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Androgens play a key role in the maintenance of male skeletal integrity. The regulation of this integrity by androgen receptor (AR) signaling has been mainly attributed to osteoblasts. Although osteocytes have emerged as key regulators of bone remodeling, the influence of sex steroids on these cells has been poorly studied. We aimed to investigate the role of AR signaling, specifically in osteocytes using the Cre/LoxP system in male mice (driven by dentin matrix protein 1 [ocy-ARKOs]). Osteocyte fractions of control (AR(ex2)/Y) and ocy-ARKO (ARflox(ex2)/Y; DMP1-cre) mice isolated through sequential collagenase digestion showed increasing AR expression toward the mature osteocyte fraction of control males compared with the more immature fractions, whereas this was reduced by >80% in ocy-ARKO osteocytes. The skeletal phenotype of mutant mice was further assessed by histomorphometry and quantitative micro-computed tomography at 12 and 32 weeks of age. Ocy-ARKOs had significantly lower trabecular bone volume and number in femora and tibias at 32 weeks as well as decreased trabecular number in the L 5 vertebra at 12 weeks. Biomechanical testing showed that ocy-ARKO femora were also stiffer and required a lower ultimate force to induce failure at 32 weeks. However, femoral cortical structure was not significantly different at any time point. The absence of AR in osteocyte also did not appear to affect trabecular bone formation nor its response to mechanical loading. In conclusion, selective inactivation of the AR in osteocytes of male mice accelerates age-related deterioration of skeletal integrity. These findings provide evidence for a direct role of androgens in the maintenance of trabecular bone through actions of the AR in osteocytes. ß

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Section: Discussionmentioning

confidence: 90%

Androgen receptor (AR) in osteocytes is important for the maintenance of male skeletal integrity: Evidence from targeted AR disruption in mouse osteocytes

Sinnesael

Claessens

Laurent

et al. 2012

Journal of Bone and Mineral Research

102

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“…In direct action, testosterone binds to and activates AR, enabling it to be transported into the nucleus to bind to the androgen response element. As a result, the transcription of many target genes such as the osteoblast genes AKP2 , Colla1 , and Bglap are activated to promote bone mineralization [21], [44]. Testosterone also has nongenomic effects by activating PI3K/Akt signaling pathways in osteoblasts [20], [45] and altering the activity of Elk-1, CCAAT enhancer binding protein-β, and cAMP-response element binding protein resulting in activation of the Src/Shc/ERK pathway.…”

Section: Discussionmentioning

confidence: 99%

Testosterone Delivered with a Scaffold Is as Effective as Bone Morphologic Protein-2 in Promoting the Repair of Critical-Size Segmental Defect of Femoral Bone in Mice

et al. 2013

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Loss of large bone segments due to fracture resulting from trauma or tumor removal is a common clinical problem. The goal of this study was to evaluate the use of scaffolds containing testosterone, bone morphogenetic protein-2 (BMP-2), or a combination of both for treatment of critical-size segmental bone defects in mice. A 2.5-mm wide osteotomy was created on the left femur of wildtype and androgen receptor knockout (ARKO) mice. Testosterone, BMP-2, or both were delivered locally using a scaffold that bridged the fracture. Results of X-ray imaging showed that in both wildtype and ARKO mice, BMP-2 treatment induced callus formation within 14 days after initiation of the treatment. Testosterone treatment also induced callus formation within 14 days in wildtype but not in ARKO mice. Micro-computed tomography and histological examinations revealed that testosterone treatment caused similar degrees of callus formation as BMP-2 treatment in wildtype mice, but had no such effect in ARKO mice, suggesting that the androgen receptor is required for testosterone to initiate fracture healing. These results demonstrate that testosterone is as effective as BMP-2 in promoting the healing of critical-size segmental defects and that combination therapy with testosterone and BMP-2 is superior to single therapy. Results of this study may provide a foundation to develop a cost effective and efficient therapeutic modality for treatment of bone fractures with segmental defects.

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“…Q-PCR was performed in duplicate using Applied Biosystems TaqMan gene expression assays (Supplemental Table S1) and an Applied Biosystems 7500 Real-Time PCR System as previously described. (33) Absolute expression was calculated using the DDCT method with values for the gene of interest normalized to Hmbs and expressed relative to a reference sample.…”

Section: Quantitative Real-time Pcr (Q-pcr)mentioning

confidence: 99%

Androgen Receptor Action in Osteoblasts in Male Mice Is Dependent on Their Stage of Maturation

Russell

Clarke

Cheong

et al. 2014

Journal of Bone and Mineral Research

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Androgen action via the androgen receptor (AR) is essential for normal skeletal growth and bone maintenance post-puberty in males; however, the molecular and cellular mechanisms by which androgens exert their actions in osteoblasts remains relatively unexplored in vivo. To identify autonomous AR actions in osteoblasts independent of AR signaling in other tissues, we compared the extent to which the bone phenotype of the Global-ARKO mouse was restored by replacing the AR in osteoblasts commencing at either the 1) proliferative or 2) mineralization stage of their maturation. In trabecular bone, androgens stimulated trabecular bone accrual during growth via the AR in proliferating osteoblasts and maintained trabecular bone post-puberty via the AR in mineralizing osteoblasts, with its predominant action being to inhibit bone resorption by decreasing the ratio of receptor activator of NF-kB ligand (RANKL) to osteoprotegerin (OPG) gene expression. During growth, replacement of the AR in proliferating but not mineralizing osteoblasts of Global-ARKOs was able to partially restore periosteal circumference, supporting the concept that androgen action in cortical bone to increase bone size during growth is mediated via the AR in proliferating osteoblasts. This study provides further significant insight into the mechanism of androgen action via the AR in osteoblasts, demonstrating that it is dependent on the stage of osteoblast maturation.

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Identification of gene pathways altered by deletion of the androgen receptor specifically in mineralizing osteoblasts and osteocytes in mice

Cited by 26 publications

References 46 publications

Androgen receptor (AR) in osteocytes is important for the maintenance of male skeletal integrity: Evidence from targeted AR disruption in mouse osteocytes

Androgen receptor (AR) in osteocytes is important for the maintenance of male skeletal integrity: Evidence from targeted AR disruption in mouse osteocytes

Testosterone Delivered with a Scaffold Is as Effective as Bone Morphologic Protein-2 in Promoting the Repair of Critical-Size Segmental Defect of Femoral Bone in Mice

Androgen Receptor Action in Osteoblasts in Male Mice Is Dependent on Their Stage of Maturation

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