FSH directly regulates bone mass.
Postmenopausal osteoporosis, a global public health problem, has for decades been attributed solely to declining estrogen levels. Although FSH levels rise sharply in parallel, a direct effect of FSH on the skeleton has never been explored. We show that FSH is required for hypogonadal bone loss. Neither FSHbeta nor FSH receptor (FSHR) null mice have bone loss despite severe hypogonadism. Bone mass is increased and osteoclastic resorption is decreased in haploinsufficient FSHbeta+/- mice with normal ovarian function, suggesting that the skeletal action of FSH is estrogen independent. Osteoclasts and their precursors possess G(i2alpha)-coupled FSHRs that activate MEK/Erk, NF-kappaB, and Akt to result in enhanced osteoclast formation and function. We suggest that high circulating FSH causes hypogonadal bone loss.
Sun
Li
L
Mount Sinai Bone Program, Department of Medicine and Department of Orthopedics, Mount Sinai School of Medicine, New York, NY 10029, USA.
Peng
Yuanzhen
Y
Sharrow
Allison C
AC
Iqbal
Jameel
J
Zhang
Zhiyuan
Z
Papachristou
Dionysios J
DJ
Zaidi
Samir
S
Zhu
Ling-Ling
LL
Yaroslavskiy
Beatrice B
BB
Zhou
Hang
H
Zallone
Alberta
A
Sairam
M Ram
MR
Kumar
T Rajendra
TR
Bo
Wei
W
Braun
Jonathan
J
Cardoso-Landa
Luis
L
Schaffler
Mitchell B
MB
Moonga
Baljit S
BS
Blair
Harry C
HC
Zaidi
Mone
M
D000818:Animals; D001862:Bone Resorption; D001842:Bone and Bones / Q000033:anatomy & histology / Q000502:physiology; D002454:Cell Differentiation; D002478:Cells, Cultured; D004789:Enzyme Activation; D004967:Estrogens / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D005640:Follicle Stimulating Hormone / Q000235:genetics / Q000378:metabolism*; D051960:GTP-Binding Protein alpha Subunit, Gi2 / Q000378:metabolism; D006801:Humans; D007006:Hypogonadism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism*; D010024:Osteoporosis / Q000378:metabolism; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011962:Receptors, FSH / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
D004967:Estrogens; D016328:NF-kappa B; D021122:Protein Subunits; D011962:Receptors, FSH; D005640:Follicle Stimulating Hormone; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D051960:GTP-Binding Protein alpha Subunit, Gi2