FSH Increases Bone Resorption

Abstract

Osteoporosis, a decrease in bone mass, is a common health disorder affecting postmenopausal women, and this is at least in part due to decreased estrogen. Sun et al . now show that follicle-stimulating hormone (FSH), a pituitary hormone that regulates estrogen production, has a direct effect on bone mass by stimulating the differentiation and resorptive activity of osteoclasts. Osteoclasts are the cells that degrade and resorb bone; osteoblasts are the bone-depositing cells. Mice deficient for FSHβ or the FSH receptor (FSHR) were hypogonadal and exhibited many symptoms of estrogen deficiency; however, the bone mass of these mice was normal. FSHβ heterozygote mice had a 50% reduction in circulating FSHβ and were fertile, with normal ovaries and uteri; however, these mice exhibited an increase in bone density. FSHβ +/- mice showed decreased bone resorption, decreased abundance of circulating tartrate-resistant acid phosphatase (TRAP, a marker of osteoclast activity), and decreased expression of osteoclast markers in bone marrow, all of which indicate that FSH provides a stimulatory signal to osteoclasts. FSHR mRNA and protein were detected both in mature osteoclasts and precursors and were present at the plasma membrane. In cultured cells, FSH stimulated osteoclastogenesis by stimulating differentiation, but not proliferation, and stimulated the resorptive activity of individual osteoclasts. FSH signaled through a Gα 2i producing a decrease in adenosine 3′,5′-monophosphate (cAMP) and stimulated signaling through the extracellular signal-regulated kinase (ERK) pathway, the phosphoinositide 3-kinase-Akt pathway, and the nuclear factor κB (NF-κB) pathway. These results point to a direct, estrogen-independent effect of FSH on bone density and a crucial role for this hormone in postmenopausal osteoporosis. L. Sun, Y. Peng, A. C. Sharrow, J. Iqbal, Z. Zhang, D. J. Papachristou, S. Zaidi, L.-L. Zhu, B. B. Yaroslavskiy, H. Zhou, A. Zallone, M. R. Sairam, T. R. Kumar, W. Bo, J. Braun, L. Cardoso-Landa, M. B. Schaffler, B. S. Moonga, H. C. Blair, M. Zaidi, FSH directly regulates bone mass. Cell 125 , 247-260 (2006). [Online Journal]