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ARS Home » Plains Area » Grand Forks, North Dakota » Grand Forks Human Nutrition Research Center » Dietary Prevention of Obesity-related Disease Research » Research » Publications at this Location » Publication #285708
Title: Blocking antibody to the beta-subunit of FSH prevents bone loss by inhibiting bone resorption and stimulating bone synthesis

Author
item ZHU, LING-LING - Mount Sinai School Of Medicine
item BLAIR, HARRY - University Of Pittsburgh Medical Center
item Cao, Jay
item YUEN, TONY - Mount Sinai School Of Medicine
item LATIF, RAUF - Mount Sinai School Of Medicine
item GUO, LIDA - University Of Pittsburgh Medical Center
item TOURKOVA, IRINA - University Of Pittsburgh Medical Center
item LI, JIANHUA - Mount Sinai School Of Medicine
item DAVIES, TERRY - Mount Sinai School Of Medicine
item SUN, LI - Mount Sinai School Of Medicine
item BIAN, ZHUAN - Wuhan University
item ROSEN, CLIFFORD - Maine Medical Center Research Institute (MMCRI)
item ZALLONE, ALBERTA - University Of Bari
item NEW, MARIA - Mount Sinai School Of Medicine
item ZAIDI, MONE - Mount Sinai School Of Medicine

Submitted to: Proceedings of the National Academy of Sciences (PNAS)
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/25/2012
Publication Date: 8/20/2012
Citation: Zhu, L., Blair, H.C., Cao, J.J., Yuen, T., Latif, R., Guo, L., Tourkova, I.L., Li, J., Davies, T.F., Sun, L., Bian, Z., Rosen, C., Zallone, A., New, M.I., Zaidi, M. 2012. Blocking antibody to the beta-subunit of FSH prevents bone loss by inhibiting bone resorption and stimulating bone synthesis. Proceedings of the National Academy of Sciences. 109(36):14574-14579.

Interpretive Summary: Hyperthyroidism is accompanied by worsening osteoporosis. Elevated thyroid hormone levels are a major contributor of the bone loss in hyperthyroidism. Serum thyroid hormone suppresses the production of thyroid stimulating hormone (TSH). TSH is low in hyperthyroid states and directly affects bone metabolism. Mice lacking the TSH receptor (TSHR) have significant bone loss. We show that TSHR-deficient mice have greater bone loss in hyperthyroid state than wild type controls. Our data suggest that TSH plays an important role in bone metabolism.

Technical Abstract: Low estrogen levels undoubtedly underlie menopausal bone thinning. However, rapid and profuse bone loss begins three years prior to 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 the late peri-menopause, 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 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.