It is believed that phytoestrogens have selective estrogen receptor modulatory activity and, hence, the compounds have been classified by some as SERMs. In this highly hypothesis-driven application, the principal investigator postulates that phytoestrogens affect osteoclastogenesis by interacting with estrogen receptors on supporting osteoblasts, thus reducing their expression of osteoclastogenic cytokines, such as CSF-1 (that activates the fms receptor) or RANK-ligand (that activates the NF-kB pathway. He also hypothesizes that phytoestrogens, such as genistein, in addition to their action on the estrogen receptor, also inhibit tyrosine kinase through a non-estrogen receptor mechanism. Thus, in Specific Aim 1, the applicant proposes to assess the effects of phytoestrogens, genistein and daidzein, on (a) osteoblastic production of CSF-1 and RANK-ligand, (b) osteoclastic receptors and downstream signals for CSF-1 and RANK-L, and (c) the processes of osteoclastogenesis and osteoclastic bone resorption.
In Specific Aim 2, the principal investigator intends to study the activity of phytoestrogens on osteoclast development and function when estrogen receptors are either eliminated through antisense approaches, or through the use of a specific antagonist, IC182780. In the same aim, the research team will also compare the binding of the two phytoestrogens, genistein and daidzein, in competition assays for the presence or absence of estrogen receptors.
In Specific Aim 3, the applicant proposes to characterize the non-estrogen receptor -mediated osteoclastic effects of phytoestrogen, specifically on osteoclast acid secretion in intact cells, and in isolated osteoclast membranes. Thus, through a systematic and logically set series of experiments, the principal investigator proposes to clarify a role for phytoestrogens in bone cell regulation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
1R01AR047700-01
Application #
6326629
Study Section
Orthopedics and Musculoskeletal Study Section (ORTH)
Program Officer
Sharrock, William J
Project Start
2000-08-17
Project End
2005-06-30
Budget Start
2000-08-17
Budget End
2001-06-30
Support Year
1
Fiscal Year
2000
Total Cost
$192,866
Indirect Cost
Name
University of Pittsburgh
Department
Pathology
Type
Schools of Medicine
DUNS #
053785812
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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
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
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Iqbal, Jameel; Sun, Li; Kumar, T Rajendra et al. (2006) Follicle-stimulating hormone stimulates TNF production from immune cells to enhance osteoblast and osteoclast formation. Proc Natl Acad Sci U S A 103:14925-30

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