Runx2 is a master osteoblast transcription factor playing pivotal roles in skeletal development and homeostasis. In humans, Runx2 haplotypes contribute to variations in bone mass. Runx1, which is expressed in osteoblasts and shares similar DNA-binding properties with Runx2, has been implicated in bone metabolism as well. Sex steroid hormones and their receptors (SHRs) also play critical roles in bone health and disease, and are targets for drugs that affect bone mass and fragility either positively or negatively. The proskeletal effects of sex steroids are mediated by anabolic effects in osteoblasts, but more importantly by attenuating bone resorption. The anti-resorptive effects of sex steroids are attributable to both increasing osteoclast apoptosis and indirect inhibition of bone turnover via poorly understood mechanisms in osteoblasts and other mesenchymal cells. We found that the activated estrogen receptor a (ERa) and the androgen receptor (AR) each inhibits Runx2, and that AR, but not ERa, inhibits Runx1. These inhibitory activities are important in light of recent data from transgenic mice whose osteoblasts over-express either Runx2 or a dominant negative form of Runx2. Both mouse models indicate that restraining the activity of Runx2 helps keep bone turnover in check and prevent osteoporosis. We therefore propose to investigate in depth the physical interactions between Runx proteins and SHRs, the mechanisms mediating the resulting inhibition of Runx2 and/or Runx1, and the physiological implications. This will be done by analyses of recombinant and transiently expressed proteins, as well as the endogenous SHR and Runx proteins in osteoblasts, including their associations with each other, with co-regulators, and with genomic Runx targets.
Specific Aim 1 is to dissect the functional and molecular interactions between ERa and Runx2.
Specific Aim 2 is to dissect the functional and molecular interactions between AR and Runx2, as well as between AR and Runx1. Based on our preliminary data, we hypothesize the existence of both similar and unique features for each of these interactions.
Specific Aim 3 is to establish in vivo the requirement for osteoblastic ERa signaling, and the timing during osteoblast differentiation, in which it confers protection on bone, and to test and characterize the anti-Runx2 anti-osteoclastogenic properties of osteoblastic SHR signaling in a co-culture setting. Incorporated into Aims 1-3 are experiments addressing novel mechanisms of action of selective estrogen receptor modulators (SERMs). Like estradiol, SERMs promote a physical interaction between ERa and Runx2. However, SERMs elicit different functional outcomes, possibly explaining the variable skeletal effects of these drugs. Our studies will provide novel insights into the regulation of skeletal metabolism by sex hormones, and will reveal commonalities and differences between the genders at the molecular level. They will decipher cryptic mechanisms of action of existing SERMs, and support the rationale development of novel ones, based on their influence on Runx proteins.

Public Health Relevance

This project will unravel fundamental mechanisms of osteoporosis that occurs as sex hormones decline. It is based on the observation that Runx proteins, which control bone metabolism, interact with receptors for both estrogens and androgens. The proposed work can ultimately lead to the development of improved drugs to treat postmenopausal osteoporosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK071122-07
Application #
8497677
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Malozowski, Saul N
Project Start
2005-04-01
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
7
Fiscal Year
2013
Total Cost
$408,533
Indirect Cost
$139,848
Name
University of Southern California
Department
Orthopedics
Type
Schools of Medicine
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
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Martin, Anthony; Xiong, Jian; Koromila, Theodora et al. (2015) Estrogens antagonize RUNX2-mediated osteoblast-driven osteoclastogenesis through regulating RANKL membrane association. Bone 75:96-104
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White, James; Shelton, Katherine H; Elgar, Frank J (2014) Prospective associations between the family environment, family cohesion, and psychiatric symptoms among adolescent girls. Child Psychiatry Hum Dev 45:544-54
Little, Gillian H; Baniwal, Sanjeev K; Adisetiyo, Helty et al. (2014) Differential effects of RUNX2 on the androgen receptor in prostate cancer: synergistic stimulation of a gene set exemplified by SNAI2 and subsequent invasiveness. Cancer Res 74:2857-68
Adisetiyo, Helty; Liang, Mengmeng; Liao, Chun-Peng et al. (2014) Dependence of castration-resistant prostate cancer (CRPC) stem cells on CRPC-associated fibroblasts. J Cell Physiol 229:1170-6
Koromila, Theodora; Baniwal, Sanjeev K; Song, Yae S et al. (2014) Glucocorticoids antagonize RUNX2 during osteoblast differentiation in cultures of ST2 pluripotent mesenchymal cells. J Cell Biochem 115:27-33
Baniwal, Sanjeev K; Chimge, Nyam-Osor; Jordan, V Craig et al. (2014) Prolactin-induced protein (PIP) regulates proliferation of luminal A type breast cancer cells in an estrogen-independent manner. PLoS One 8:e62361
White, James; Jago, Russell; Thompson, Janice L (2014) Dietary risk factors for the development of insulin resistance in adolescent girls: a 3-year prospective study. Public Health Nutr 17:361-8

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