Blocking antibody to the β-subunit of FSH prevents bone loss by inhibiting bone resorption and stimulating bone synthesis.
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 β-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.
Mount Sinai Bone Program, Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA.
Ling-Ling
LL
Zhu
Harry
H
Blair
Jay
J
Cao
Tony
T
Yuen
Rauf
R
Latif
Lida
L
Guo
Irina L
IL
Tourkova
Jianhua
J
Li
Terry F
TF
Davies
Li
L
Sun
Zhuan
Z
Bian
Clifford
C
Rosen
Alberta
A
Zallone
Maria I
MI
New
Mone
M
Zaidi
D000818:Animals; D000906:Antibodies / Q000378:metabolism* / Q000494:pharmacology; D001846:Bone Development / Q000187:drug effects / Q000502:physiology*; D003114:Colony-Forming Units Assay; D005260:Female; D037201:Follicle Stimulating Hormone, beta Subunit / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects*; D015663:Osteoporosis, Postmenopausal / Q000517:prevention & control*; D010052:Ovariectomy; D011962:Receptors, FSH / Q000235:genetics
D000906:Antibodies; D037201:Follicle Stimulating Hormone, beta Subunit; D011962:Receptors, FSH