We will study the interactions of two sex hormones, FSH and estrogen, in regulating bone turnover. Our work shows that both FSH and estrogen receptors modulate bone differentiation and activity. Our findings, and those of others, show that crosstalk between these regulatory systems is mediated by secondary signals including TNFa. We will test the hypothesis that estrogen is anabolic, and FSH catabolic, for bone mass. In the menopause, estrogen drops to low levels and FSH climbs to high levels, leading to rapid bone loss. However, the relationship of FSH and estrogen receptor expression during bone cell differentiation is poorly understood. We will study this using human cells as the primary model. Knockout mice will also be used as sources of cells, and for long-term studies in vivo.
Aim 1 will establish how FSH and estrogen responses are regulated during differentiation of human nontransformed osteoblast and osteoclast precursor cells. This will study the hypothesis that FSH-R, mainly in an alternatively spliced form, is expressed on osteoblast MSC precursors and on osteoclasts. In contrast, estrogen, mainly via ERa, is believed to affect osteoclasts only during differentiation, while ERa is strongly expressed late in osteoblast differentiation, where it regulates bone formation.
Aim 2 will determine mechanisms of interaction of sex steroids and FSH signaling in osteoblasts and in osteoclasts. This will include quantifying the relative effects of FSH and estrogen on human osteoclast differentiation and survival. Mechanisms of cell response to FSH will be characterized. The production of TNFa, in human bone cells in response to FSH will be defined. In addition, potential counter-regulation of estrogen and FSH signaling will be studied. Effects of FSH on differentiation and survival of human osteoblasts will be evaluated, including interaction with estrogen effects. Finally, we will use a knockout mouse model to uncouple FSH-R from estrogen effects, and determine the effects on bone formation. FSH-R-/- animals will be used for studies comparing bone turnover to ovariectomized animals, with and without estrogen replacement, as functions of animal age. These studies will clarify understanding of postmenopausal bone loss, improve the ability to monitor treatment, and may improve the long-term management of hypogonadal bone disease.

Public Health Relevance

. Women at the menopause have rapid bone loss, but estrogen replacement only partially prevents this. We discovered that the pituitary hormone FSH, which regulates estrogen production, may cause bone loss directly. We will study this FSH response in bone to provide new insights into prevention of osteoporosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR055208-05
Application #
8264381
Study Section
Skeletal Biology Structure and Regeneration Study Section (SBSR)
Program Officer
Chen, Faye H
Project Start
2008-07-03
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2014-05-31
Support Year
5
Fiscal Year
2012
Total Cost
$316,768
Indirect Cost
$107,680
Name
University of Pittsburgh
Department
Pathology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Tourkova, Irina L; Witt, Michelle R; Li, La et al. (2015) Follicle stimulating hormone receptor in mesenchymal stem cells integrates effects of glycoprotein reproductive hormones. Ann N Y Acad Sci 1335:100-9
Zacherl, Janelle R; Mihalik, Stephanie J; Chace, Donald H et al. (2014) Elaidate, an 18-carbon trans-monoenoic fatty acid, inhibits *-oxidation in human peripheral blood macrophages. J Cell Biochem 115:62-70
Wang, Bin; Yang, Yanmei; Liu, Li et al. (2013) NHERF1 regulation of PTH-dependent bimodal Pi transport in osteoblasts. Bone 52:268-77
Tantikanlayaporn, Duangrat; Robinson, Lisa J; Suksamrarn, Apichart et al. (2013) A diarylheptanoid phytoestrogen from Curcuma comosa, 1,7-diphenyl-4,6-heptadien-3-ol, accelerates human osteoblast proliferation and differentiation. Phytomedicine 20:676-82
Chen, Qian; Liu, Kai; Robinson, Andria R et al. (2013) DNA damage drives accelerated bone aging via an NF-?B-dependent mechanism. J Bone Miner Res 28:1214-28
Liu, Li; Schlesinger, Paul H; Slack, Nicole M et al. (2011) High capacity Na+/H+ exchange activity in mineralizing osteoblasts. J Cell Physiol 226:1702-12
Robinson, Lisa J; Tourkova, Irina; Wang, Yujuan et al. (2010) FSH-receptor isoforms and FSH-dependent gene transcription in human monocytes and osteoclasts. Biochem Biophys Res Commun 394:12-7
Sun, Li; Zhang, Zhiyuan; Zhu, Ling-Ling et al. (2010) Further evidence for direct pro-resorptive actions of FSH. Biochem Biophys Res Commun 394:6-11
Yaroslavskiy, Beatrice B; Turkova, Irina; Wang, Yujuan et al. (2010) Functional osteoclast attachment requires inositol-1,4,5-trisphosphate receptor-associated cGMP-dependent kinase substrate. Lab Invest 90:1533-42
Robinson, Lisa J; Yaroslavskiy, Beatrice B; Griswold, Reed D et al. (2009) Estrogen inhibits RANKL-stimulated osteoclastic differentiation of human monocytes through estrogen and RANKL-regulated interaction of estrogen receptor-alpha with BCAR1 and Traf6. Exp Cell Res 315:1287-301

Showing the most recent 10 out of 12 publications