Non-nuclear-initiated actions of the estrogen receptor protect cortical bone mass

Shoshana M. Bartell, Li Han, Ha Neui Kim, Sung Hoon Kim, John A. Katzenellenbogen, Benita S Katzenellenbogen, Ken L. Chambliss, Philip W. Shaul, Paula K. Roberson, Robert S. Weinstein, Robert L. Jilka, Maria Almeida, Stavros C. Manolagas

Research output: Contribution to journalArticle

Abstract

Extensive evidence has suggested that at least some of the effects of estrogens on bone are mediated via extranuclear estrogen receptor α signaling. However, definitive proof for this contention and the extent to which such effects may contribute to the overall protective effects of estrogens on bone maintenance have remained elusive. Here, we investigated the ability of a 17β;-estradiol (E2) dendrimer conjugate (EDC), incapable of stimulating nuclear-initiated actions of estrogen receptor α, to prevent the effects of ovariectomy (OVX) on the murine skeleton. We report that EDC was as potent as an equimolar dose of E2 in preventing bone loss in the cortical compartment that represents 80% of the entire skeleton, but was ineffective on cancellous bone. In contrast, E2 was effective in both compartments. Consistent with its effect on cortical bone mass, EDC partially prevented the loss of both vertebral and femoral strength. In addition, EDC, as did E2, prevented the OVX-induced increase in osteoclastogenesis, osteoblastogenesis, and oxidative stress. Nonetheless, the OVX-induced decrease in uterine weight was unaltered by EDC but was restored by E2. These results demonstrate that the protection of cortical bone mass by estrogens is mediated, at least in part, via a mechanism that is distinct from the classic mechanism of estrogen action on reproductive organs.

Original languageEnglish (US)
Pages (from-to)649-656
Number of pages8
JournalMolecular Endocrinology
Volume27
Issue number4
DOIs
StatePublished - Apr 1 2013

Fingerprint

Dendrimers
Estrogen Receptors
Estrogens
Bone and Bones
Skeleton
Ovariectomy
Thigh
Osteogenesis
Estradiol
Oxidative Stress
Maintenance
Cortical Bone
Weights and Measures

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

Cite this

Bartell, S. M., Han, L., Kim, H. N., Kim, S. H., Katzenellenbogen, J. A., Katzenellenbogen, B. S., ... Manolagas, S. C. (2013). Non-nuclear-initiated actions of the estrogen receptor protect cortical bone mass. Molecular Endocrinology, 27(4), 649-656. https://doi.org/10.1210/me.2012-1368

Non-nuclear-initiated actions of the estrogen receptor protect cortical bone mass. / Bartell, Shoshana M.; Han, Li; Kim, Ha Neui; Kim, Sung Hoon; Katzenellenbogen, John A.; Katzenellenbogen, Benita S; Chambliss, Ken L.; Shaul, Philip W.; Roberson, Paula K.; Weinstein, Robert S.; Jilka, Robert L.; Almeida, Maria; Manolagas, Stavros C.

In: Molecular Endocrinology, Vol. 27, No. 4, 01.04.2013, p. 649-656.

Research output: Contribution to journalArticle

Bartell, SM, Han, L, Kim, HN, Kim, SH, Katzenellenbogen, JA, Katzenellenbogen, BS, Chambliss, KL, Shaul, PW, Roberson, PK, Weinstein, RS, Jilka, RL, Almeida, M & Manolagas, SC 2013, 'Non-nuclear-initiated actions of the estrogen receptor protect cortical bone mass', Molecular Endocrinology, vol. 27, no. 4, pp. 649-656. https://doi.org/10.1210/me.2012-1368
Bartell, Shoshana M. ; Han, Li ; Kim, Ha Neui ; Kim, Sung Hoon ; Katzenellenbogen, John A. ; Katzenellenbogen, Benita S ; Chambliss, Ken L. ; Shaul, Philip W. ; Roberson, Paula K. ; Weinstein, Robert S. ; Jilka, Robert L. ; Almeida, Maria ; Manolagas, Stavros C. / Non-nuclear-initiated actions of the estrogen receptor protect cortical bone mass. In: Molecular Endocrinology. 2013 ; Vol. 27, No. 4. pp. 649-656.
@article{ec8fad2920124caea6d55e4988b58735,
title = "Non-nuclear-initiated actions of the estrogen receptor protect cortical bone mass",
abstract = "Extensive evidence has suggested that at least some of the effects of estrogens on bone are mediated via extranuclear estrogen receptor α signaling. However, definitive proof for this contention and the extent to which such effects may contribute to the overall protective effects of estrogens on bone maintenance have remained elusive. Here, we investigated the ability of a 17β;-estradiol (E2) dendrimer conjugate (EDC), incapable of stimulating nuclear-initiated actions of estrogen receptor α, to prevent the effects of ovariectomy (OVX) on the murine skeleton. We report that EDC was as potent as an equimolar dose of E2 in preventing bone loss in the cortical compartment that represents 80{\%} of the entire skeleton, but was ineffective on cancellous bone. In contrast, E2 was effective in both compartments. Consistent with its effect on cortical bone mass, EDC partially prevented the loss of both vertebral and femoral strength. In addition, EDC, as did E2, prevented the OVX-induced increase in osteoclastogenesis, osteoblastogenesis, and oxidative stress. Nonetheless, the OVX-induced decrease in uterine weight was unaltered by EDC but was restored by E2. These results demonstrate that the protection of cortical bone mass by estrogens is mediated, at least in part, via a mechanism that is distinct from the classic mechanism of estrogen action on reproductive organs.",
author = "Bartell, {Shoshana M.} and Li Han and Kim, {Ha Neui} and Kim, {Sung Hoon} and Katzenellenbogen, {John A.} and Katzenellenbogen, {Benita S} and Chambliss, {Ken L.} and Shaul, {Philip W.} and Roberson, {Paula K.} and Weinstein, {Robert S.} and Jilka, {Robert L.} and Maria Almeida and Manolagas, {Stavros C.}",
year = "2013",
month = "4",
day = "1",
doi = "10.1210/me.2012-1368",
language = "English (US)",
volume = "27",
pages = "649--656",
journal = "Molecular Endocrinology",
issn = "0888-8809",
publisher = "The Endocrine Society",
number = "4",

}

TY - JOUR

T1 - Non-nuclear-initiated actions of the estrogen receptor protect cortical bone mass

AU - Bartell, Shoshana M.

AU - Han, Li

AU - Kim, Ha Neui

AU - Kim, Sung Hoon

AU - Katzenellenbogen, John A.

AU - Katzenellenbogen, Benita S

AU - Chambliss, Ken L.

AU - Shaul, Philip W.

AU - Roberson, Paula K.

AU - Weinstein, Robert S.

AU - Jilka, Robert L.

AU - Almeida, Maria

AU - Manolagas, Stavros C.

PY - 2013/4/1

Y1 - 2013/4/1

N2 - Extensive evidence has suggested that at least some of the effects of estrogens on bone are mediated via extranuclear estrogen receptor α signaling. However, definitive proof for this contention and the extent to which such effects may contribute to the overall protective effects of estrogens on bone maintenance have remained elusive. Here, we investigated the ability of a 17β;-estradiol (E2) dendrimer conjugate (EDC), incapable of stimulating nuclear-initiated actions of estrogen receptor α, to prevent the effects of ovariectomy (OVX) on the murine skeleton. We report that EDC was as potent as an equimolar dose of E2 in preventing bone loss in the cortical compartment that represents 80% of the entire skeleton, but was ineffective on cancellous bone. In contrast, E2 was effective in both compartments. Consistent with its effect on cortical bone mass, EDC partially prevented the loss of both vertebral and femoral strength. In addition, EDC, as did E2, prevented the OVX-induced increase in osteoclastogenesis, osteoblastogenesis, and oxidative stress. Nonetheless, the OVX-induced decrease in uterine weight was unaltered by EDC but was restored by E2. These results demonstrate that the protection of cortical bone mass by estrogens is mediated, at least in part, via a mechanism that is distinct from the classic mechanism of estrogen action on reproductive organs.

AB - Extensive evidence has suggested that at least some of the effects of estrogens on bone are mediated via extranuclear estrogen receptor α signaling. However, definitive proof for this contention and the extent to which such effects may contribute to the overall protective effects of estrogens on bone maintenance have remained elusive. Here, we investigated the ability of a 17β;-estradiol (E2) dendrimer conjugate (EDC), incapable of stimulating nuclear-initiated actions of estrogen receptor α, to prevent the effects of ovariectomy (OVX) on the murine skeleton. We report that EDC was as potent as an equimolar dose of E2 in preventing bone loss in the cortical compartment that represents 80% of the entire skeleton, but was ineffective on cancellous bone. In contrast, E2 was effective in both compartments. Consistent with its effect on cortical bone mass, EDC partially prevented the loss of both vertebral and femoral strength. In addition, EDC, as did E2, prevented the OVX-induced increase in osteoclastogenesis, osteoblastogenesis, and oxidative stress. Nonetheless, the OVX-induced decrease in uterine weight was unaltered by EDC but was restored by E2. These results demonstrate that the protection of cortical bone mass by estrogens is mediated, at least in part, via a mechanism that is distinct from the classic mechanism of estrogen action on reproductive organs.

UR - http://www.scopus.com/inward/record.url?scp=84875535167&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84875535167&partnerID=8YFLogxK

U2 - 10.1210/me.2012-1368

DO - 10.1210/me.2012-1368

M3 - Article

VL - 27

SP - 649

EP - 656

JO - Molecular Endocrinology

JF - Molecular Endocrinology

SN - 0888-8809

IS - 4

ER -