Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 109, Issue 36, Pages 14574-14579Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1212806109
Keywords
osteoporosis; sex steroids; skeletal anabolic; gonadotropin
Categories
Funding
- National Institutes of Health [DK80459, AG23176, AG40132, AR053976, AR055208]
- Department of Veterans Affairs (VA Merit Award)
- Maria I. New Children's Hormone Research Foundation
- Italian Space Agency
- National Science Foundation of China, Ministry of China
- US Department of Agriculture, Agricultural Research Service, Current Research Information System Program Grant [5450-51000-046-00D]
- Chinese University of Hong Kong
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Low estrogen levels undoubtedly underlie menopausal bone thinning. However, rapid and profuse bone loss begins 3 y before the last menstrual period, when serum estrogen is relatively normal. We have shown that the pituitary hormone FSH, the levels of which are high during late perimenopause, directly stimulates bone resorption by osteoclasts. Here, we generated and characterized a polyclonal antibody to a 13-amino-acid-long peptide sequence within the receptor-binding domain of the FSH beta-subunit. We show that the FSH antibody binds FSH specifically and blocks its action on osteoclast formation in vitro. When injected into ovariectomized mice, the FSH antibody attenuates bone loss significantly not only by inhibiting bone resorption, but also by stimulating bone formation, a yet uncharacterized action of FSH that we report herein. Mesenchymal cells isolated from mice treated with the FSH antibody show greater osteoblast precursor colony counts, similarly to mesenchymal cells isolated from FSH receptor (FSHR)(-/-)mice. This suggests that FSH negatively regulates osteoblast number. We confirm that this action is mediated by signaling-efficient FSHRs present on mesenchymal stem cells. Overall, the data prompt the future development of an FSH-blocking agent as a means of uncoupling bone formation and bone resorption to a therapeutic advantage in humans.
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