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The Effects of Androgens on Murine Cortical Bone Do Not Require AR or ERα Signaling in Osteoblasts and Osteoclasts
Serra Ucer1, Srividhya Iyer1, Shoshana M Bartell1
1Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, University of Arkansas for Medical Sciences and the Central Arkansas Veterans Healthcare System, Little Rock, AR, USA.
Abstract:
In men, androgens are critical for the acquisition and maintenance of bone mass in both the cortical and cancellous bone compartment. Male mice with targeted deletion of the androgen receptor (AR) in mature osteoblasts or osteocytes have lower cancellous bone mass, but no cortical bone phenotype. We have investigated the possibility that the effects of androgens on the cortical compartment result from AR signaling in osteoprogenitors or cells of the osteoclast lineage; or via estrogen receptor alpha (ERα) signaling in either or both of these two cell types upon conversion of testosterone to estradiol. To this end, we generated mice with targeted deletion of an AR or an ERα allele in the mesenchymal (AR(f/y);Prx1-Cre or ERα(f/f);Osx1-Cre) or myeloid cell lineage (AR(f/y);LysM-Cre or ERα(f/f);LysM-Cre) and their descendants. Male AR(f/y);Prx1-Cre mice exhibited decreased bone volume and trabecular number, and increased osteoclast number in the cancellous compartment. Moreover, they did not undergo the loss of cancellous bone volume and trabecular number caused by orchidectomy (ORX) in their littermate controls. In contrast, AR(f/y);LysM-Cre, ERα(f/f);Osx1-Cre, or ERα(f/f);LysM-Cre mice had no cancellous bone phenotype at baseline and lost the same amount of cancellous bone as their controls following ORX. Most unexpectedly, adult males of all four models had no discernible cortical bone phenotype at baseline, and lost the same amount of cortical bone as their littermate controls after ORX. Recapitulation of the effects of ORX by AR deletion only in the AR(f/y);Prx1-Cre mice indicates that the effects of androgens on cancellous bone result from AR signaling in osteoblasts-not on osteoclasts or via aromatization. The effects of androgens on cortical bone mass, on the other hand, do not require AR or ERα signaling in any cell type across the osteoblast or osteoclast differentiation lineage. Therefore, androgens must exert their effects indirectly by actions on some other cell type(s) or tissue(s).
Insights
Androgen receptor signaling in osteoblasts is crucial for maintaining cancellous bone mass in male mice. However, androgens affect cortical bone through indirect mechanisms, not directly via androgen or estrogen receptor signaling in bone cells.
Area of Science:
- Endocrinology
- Bone Biology
- Genetics
Background:
- Androgens are vital for bone health in men, influencing both cortical and cancellous bone.
- Previous studies linked androgen receptor (AR) deletion in mature osteoblasts/osteocytes to reduced cancellous bone mass.
- The role of AR and estrogen receptor alpha (ERα) in osteoprogenitors and osteoclasts, and the impact of testosterone aromatization to estradiol, remained unclear for cortical bone.
Purpose of the Study:
- To elucidate the specific cell lineages mediating androgen's effects on cortical and cancellous bone.
- To differentiate between direct AR signaling and indirect mechanisms, including ERα pathways, in bone maintenance.
- To determine the necessity of AR and ERα in mesenchymal and myeloid cells for bone homeostasis.
Main Methods:
- Generated genetically modified mice with targeted deletion of AR or ERα in mesenchymal (Prx1-Cre) or myeloid (LysM-Cre) lineages.
- Utilized Osterix-Cre (Osx1-Cre) to target osteoprogenitors.
- Assessed bone phenotypes at baseline and after orchidectomy (ORX) to model androgen deprivation.
Main Results:
- AR deletion in mesenchymal progenitors (AR(f/y);Prx1-Cre) mimicked orchidectomy effects on cancellous bone, reducing bone volume and trabecular number while increasing osteoclast number.
- Deletion of AR in myeloid cells or ERα in mesenchymal/myeloid cells did not affect baseline cancellous bone or ORX-induced loss.
- Unexpectedly, all four genetic models showed no baseline cortical bone phenotype and identical cortical bone loss post-ORX, indicating AR/ERα independence in these lineages for cortical bone.
Conclusions:
- Androgen's effects on cancellous bone are mediated by AR signaling specifically within osteoblasts, independent of osteoclasts or aromatization.
- Androgens do not appear to regulate cortical bone mass directly through AR or ERα signaling in osteoblast or osteoclast precursors.
- Cortical bone regulation by androgens likely involves indirect mechanisms acting on non-skeletal cell types or tissues.
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