1. Blocking antibody to the β-subunit of FSH prevents bone loss by inhibiting bone resorption and stimulating bone synthesis
- Author
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Irina L. Tourkova, Alberta Zallone, Clifford J. Rosen, Jay Cao, Lida Guo, Tony Yuen, Li Sun, Rauf Latif, Harry C. Blair, Maria I. New, Terry F. Davies, Zhuan Bian, Ling-Ling Zhu, Mone Zaidi, and Jianhua Li
- Subjects
medicine.medical_specialty ,endocrine system ,Ovariectomy ,Osteoporosis ,Osteoclasts ,Biology ,Bone resorption ,Antibodies ,Colony-Forming Units Assay ,Follicle-stimulating hormone ,Mice ,Osteoclast ,Internal medicine ,Blocking antibody ,medicine ,Animals ,Humans ,Osteoporosis, Postmenopausal ,Mice, Knockout ,Multidisciplinary ,Bone Development ,Osteoblast ,Mesenchymal Stem Cells ,Biological Sciences ,medicine.disease ,Bone morphogenetic protein 7 ,medicine.anatomical_structure ,Endocrinology ,Follicle Stimulating Hormone, beta Subunit ,Receptors, FSH ,Female ,Follicle-stimulating hormone receptor ,hormones, hormone substitutes, and hormone antagonists - Abstract
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.
- Published
- 2012