# Androgens, estrogens, and bone loss in males

> **NIH VA I01** · CENTRAL ARKANSAS VETERANS HLTHCARE SYS · 2021 · —

## Abstract

Both androgens and estrogens contribute to the maintenance of bone mass during adult life in men, but the cell
targets and molecular mechanisms of these effects remain poorly understood. During the preceding funding
period, we found that the effects of androgens on cancellous bone result from AR signaling in cells of the
mesenchymal lineage leading to a decrease in osteoclasts; and orchidectomy (ORX) increases soluble RANKL
levels as well as the number of B-lymphocytes in the murine bone marrow. RANKL derived from osteocytes is
critical for cancellous bone remodeling and B-lymphocyte-derived RANKL contributes to the loss of cancellous
bone mass in ovariectomized (OVX) mice. In cortical bone, however, the effects of androgens do not require AR
signaling in any cell type of the mesenchymal lineage, nor do they require ERα signaling downstream of
committed osteoblast progenitors targeted by Osx1-Cre, or AR or ERα signaling in the osteoclast lineage.
Estrogens, nonetheless, attenuate endocortical resorption in females by ERα signaling in uncommitted
mesenchymal progenitors targeted by Prx1-Cre. In addition, the mRNA and secreted protein levels of SDF1 – a
chemotactic cytokine of the CXC family that is abundantly expressed in Prx1-Cre targeted cells and promotes
osteoclast generation – are higher in GFP-tagged ERα null cells as well as bone marrow cell cultures from female
ERαf/f;Prx1-Cre mice as compared to identical cultures from littermate controls; and so is osteoclastogenesis in
co-cultures of ERα null BM stromal or calvaria cells with macrophages. Furthermore, both OVX and ORX
increase SDF1 in the bone marrow plasma, administration of E2 to ORX mice prevents this increase, and E2,
but not DHT, prevents cortical bone loss in ORX mice. Finally, we found that the OVX- or ORX-induced cortical
bone loss is prevented by restraining H2O2 generation in osteoclast mitochondria; and the loss of cortical bone
mass in OVX mice is prevented by a 17β-E2 dendrimer conjugate (EDC), incapable of stimulating nuclear-
initiated actions of ERα. Based on these advances, we will test the interrelated hypotheses that: in males, the
protective effects of androgens on cancellous bone result from AR signaling in osteocytes, B-lymphocytes, or
both. These actions result in the attenuation of RANKL and thereby attenuation of the number of cancellous
osteoclasts. The protective effects of androgens against endocortical resorption result, at least in part, from ERα-
mediated actions (upon aromatization of androgens to estrogens) on Prx1-Cre targeted uncommitted
mesenchymal progenitors. These actions repress SDF1 production, thereby attenuating osteoclast formation
and homing at the endosteal surfaces. The suppressive effect of estrogens on SDF1 production ultimately leads
to the restraining of H2O2 accumulation in osteoclasts and results from non-nuclear-initiated signaling of the
ERα. To advance these hypotheses we will try to elucidate the mechanism of the protective effect...

## Key facts

- **NIH application ID:** 10254219
- **Project number:** 5I01BX001405-09
- **Recipient organization:** CENTRAL ARKANSAS VETERANS HLTHCARE SYS
- **Principal Investigator:** STAVROS C. MANOLAGAS
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2012-01-01 → 2021-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10254219

## Citation

> US National Institutes of Health, RePORTER application 10254219, Androgens, estrogens, and bone loss in males (5I01BX001405-09). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10254219. Licensed CC0.

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