Sex Steroids and Runx Signaling in Bone

Summary

Principal Investigator: Baruch Frenkel
Abstract: DESCRIPTION (provided by applicant): 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.
Funding Period: 2005-04-01 - 2014-06-30
more information: NIH RePORT

Top Publications

  1. ncbi Night eating: prevalence and demographic correlates
    Ruth H Striegel-Moore
    Department of Psychology, Wesleyan University, 207 High Street, Middletown, CT 06459, USA
    Obesity (Silver Spring) 14:139-47. 2006
  2. pmc Differential effects of RUNX2 on the androgen receptor in prostate cancer: synergistic stimulation of a gene set exemplified by SNAI2 and subsequent invasiveness
    Gillian H Little
    Authors Affiliations Departments of Biochemistry and Molecular Biology, Orthopedic Surgery, Preventive Medicine, and Medicine Institute for Genetic Medicine USC Norris Comprehensive Cancer Center, Keck School of Medicine of the University of Southern California, Los Angeles Departments of Molecular Pharmacology and Cancer Biology, Beckman Research Institute, City of Hope, Duarte, CaliforniaAuthors Affiliations Departments of Biochemistry and Molecular Biology, Orthopedic Surgery, Preventive Medicine, and Medicine Institute for Genetic Medicine USC Norris Comprehensive Cancer Center, Keck School of Medicine of the University of Southern California, Los Angeles Departments of Molecular Pharmacology and Cancer Biology, Beckman Research Institute, City of Hope, Duarte, California
    Cancer Res 74:2857-68. 2014
  3. ncbi Glucocorticoids antagonize RUNX2 during osteoblast differentiation in cultures of ST2 pluripotent mesenchymal cells
    Theodora Koromila
    Department of Biochemistry and Molecular Biology, Institute for Genetic Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, California
    J Cell Biochem 115:27-33. 2014
  4. pmc The role of activation functions 1 and 2 of estrogen receptor-α for the effects of estradiol and selective estrogen receptor modulators in male mice
    Anna E Börjesson
    Centre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
    J Bone Miner Res 28:1117-26. 2013
  5. ncbi The RUNX family in breast cancer: relationships with estrogen signaling
    N O Chimge
    Department of Biochemistry and Molecular Biology, Institute for Genetic Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA
    Oncogene 32:2121-30. 2013
  6. ncbi Alterations in Brca1 expression in mouse ovarian granulosa cells have short-term and long-term consequences on estrogen-responsive organs
    Hai Yun Yen
    Department of Biochemistry and Molecular Biology, USC Norris Comprehensive Cancer Center, Keck School of Medicine of University of Southern California, Los Angeles, CA, USA
    Lab Invest 92:802-11. 2012
  7. pmc Regulation of breast cancer metastasis by Runx2 and estrogen signaling: the role of SNAI2
    Nyam Osor Chimge
    Department of Biochemistry and Molecular Biology, Keck School of Medicine of the University of Southern California, 2250 Alcazar Street, Los Angeles, CA 90033, USA
    Breast Cancer Res 13:R127. 2011
  8. pmc Opposing effects of Runx2 and estradiol on breast cancer cell proliferation: in vitro identification of reciprocally regulated gene signature related to clinical letrozole responsiveness
    Nyam Osor Chimge
    Department of Biochemistry, Institute for Genetic Medicine, USC Epigenome Center, Keck School of Medicine of the University of Southern California, Los Angeles, California 90033, USA
    Clin Cancer Res 18:901-11. 2012
  9. pmc Runx2 controls a feed-forward loop between androgen and prolactin-induced protein (PIP) in stimulating T47D cell proliferation
    Sanjeev K Baniwal
    Department of Orthopaedic Surgery, Keck School of Medicine of the University of Southern California, Los Angeles, California 90033, USA
    J Cell Physiol 227:2276-82. 2012
  10. pmc Roles of transactivating functions 1 and 2 of estrogen receptor-alpha in bone
    A E Börjesson
    Centre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, S 41345 Gothenburg, Sweden
    Proc Natl Acad Sci U S A 108:6288-93. 2011

Research Grants

Detail Information

Publications17

  1. ncbi Night eating: prevalence and demographic correlates
    Ruth H Striegel-Moore
    Department of Psychology, Wesleyan University, 207 High Street, Middletown, CT 06459, USA
    Obesity (Silver Spring) 14:139-47. 2006
    ..To examine the prevalence and correlates of night eating, the core behavioral symptom of night eating syndrome among adolescents and adults, using two public access survey databases of nationally representative samples...
  2. pmc Differential effects of RUNX2 on the androgen receptor in prostate cancer: synergistic stimulation of a gene set exemplified by SNAI2 and subsequent invasiveness
    Gillian H Little
    Authors Affiliations Departments of Biochemistry and Molecular Biology, Orthopedic Surgery, Preventive Medicine, and Medicine Institute for Genetic Medicine USC Norris Comprehensive Cancer Center, Keck School of Medicine of the University of Southern California, Los Angeles Departments of Molecular Pharmacology and Cancer Biology, Beckman Research Institute, City of Hope, Duarte, CaliforniaAuthors Affiliations Departments of Biochemistry and Molecular Biology, Orthopedic Surgery, Preventive Medicine, and Medicine Institute for Genetic Medicine USC Norris Comprehensive Cancer Center, Keck School of Medicine of the University of Southern California, Los Angeles Departments of Molecular Pharmacology and Cancer Biology, Beckman Research Institute, City of Hope, Duarte, California
    Cancer Res 74:2857-68. 2014
    ..Overall, our findings suggest cooperation between AR and RUNX in the stimulation of oncogenes such as SNAI2, which might be targeted for individualized prostate cancer therapy...
  3. ncbi Glucocorticoids antagonize RUNX2 during osteoblast differentiation in cultures of ST2 pluripotent mesenchymal cells
    Theodora Koromila
    Department of Biochemistry and Molecular Biology, Institute for Genetic Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, California
    J Cell Biochem 115:27-33. 2014
    ..Investigation of the RUNX2/GR interaction may lead to the development of bone-sparing GC treatment modalities for the management of autoimmune and inflammatory diseases...
  4. pmc The role of activation functions 1 and 2 of estrogen receptor-α for the effects of estradiol and selective estrogen receptor modulators in male mice
    Anna E Börjesson
    Centre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
    J Bone Miner Res 28:1117-26. 2013
    ..All evaluated effects of Ral, Las and Bza are dependent on a functional ERαAF-1. Our findings might contribute to the development of bone-specific SERMs in males...
  5. ncbi The RUNX family in breast cancer: relationships with estrogen signaling
    N O Chimge
    Department of Biochemistry and Molecular Biology, Institute for Genetic Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA
    Oncogene 32:2121-30. 2013
    ..Finally, based on diverse expression patterns in BCa subtypes, the successful use of future RUNX-based therapies will most likely require careful patient selection...
  6. ncbi Alterations in Brca1 expression in mouse ovarian granulosa cells have short-term and long-term consequences on estrogen-responsive organs
    Hai Yun Yen
    Department of Biochemistry and Molecular Biology, USC Norris Comprehensive Cancer Center, Keck School of Medicine of University of Southern California, Los Angeles, CA, USA
    Lab Invest 92:802-11. 2012
    ....
  7. pmc Regulation of breast cancer metastasis by Runx2 and estrogen signaling: the role of SNAI2
    Nyam Osor Chimge
    Department of Biochemistry and Molecular Biology, Keck School of Medicine of the University of Southern California, 2250 Alcazar Street, Los Angeles, CA 90033, USA
    Breast Cancer Res 13:R127. 2011
    ..We asked whether the beneficial effect of estrogen signaling in late-stage BCa is attributable to the recently reported estrogen-mediated antagonism of the pro-metastatic transcription factor Runx2...
  8. pmc Opposing effects of Runx2 and estradiol on breast cancer cell proliferation: in vitro identification of reciprocally regulated gene signature related to clinical letrozole responsiveness
    Nyam Osor Chimge
    Department of Biochemistry, Institute for Genetic Medicine, USC Epigenome Center, Keck School of Medicine of the University of Southern California, Los Angeles, California 90033, USA
    Clin Cancer Res 18:901-11. 2012
    ..To assess the clinical significance of the interaction between estrogen and Runx2 signaling, previously shown in vitro...
  9. pmc Runx2 controls a feed-forward loop between androgen and prolactin-induced protein (PIP) in stimulating T47D cell proliferation
    Sanjeev K Baniwal
    Department of Orthopaedic Surgery, Keck School of Medicine of the University of Southern California, Los Angeles, California 90033, USA
    J Cell Physiol 227:2276-82. 2012
    ..Our data suggest that Runx2 controls a positive feedback loop between androgen signaling and PIP, and pharmacological inhibition of PIP may be useful to treat PIP positive tumors...
  10. pmc Roles of transactivating functions 1 and 2 of estrogen receptor-alpha in bone
    A E Börjesson
    Centre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, S 41345 Gothenburg, Sweden
    Proc Natl Acad Sci U S A 108:6288-93. 2011
    ..Selective ER modulators stimulating ERα with minimal activation of ERα AF-1 could retain beneficial actions in cortical bone, constituting 80% of the skeleton, while minimizing effects on reproductive organs...
  11. pmc Leucine-rich amelogenin peptide induces osteogenesis by activation of the Wnt pathway
    Rungnapa Warotayanont
    University of Southern California School of Dentistry, Center for Craniofacial Molecular Biology, 2250 Alcazar Street, Los Angeles, CA 90033, USA
    Biochem Biophys Res Commun 387:558-63. 2009
    ..We conclude that LRAP activates the canonical Wnt signaling pathway to induce osteogenic differentiation of mouse ES cells through the concerted regulation of Wnt agonists and antagonists...
  12. pmc Location, location, (ChIP-)location! Mapping chromatin landscapes one immunoprecipitation at a time
    Benjamin P Berman
    USC Epigenome Center, University of Southern California, Los Angeles, California 90033, USA
    J Cell Biochem 107:1-5. 2009
    ....
  13. pmc Inhibition of AR-mediated transcription by binding of Oct1 to a motif enriched in AR-occupied regions
    Unnati Jariwala
    Department of Biochemistry and Molecular Biology, USC Keck School of Medicine, Los Angeles, California 90033, USA
    Prostate 69:392-400. 2009
    ..Previously, bioinformatic analysis of 62 AR-occupied regions (ARORs) in PCa cells revealed enrichment for both AREs and a TTGGCAAATA-like motif. We undertook the present study to investigate the significance of the TTGGCAAATA-like motif...
  14. pmc Progressive recruitment of Runx2 to genomic targets despite decreasing expression during osteoblast differentiation
    Steven Pregizer
    Department of Biochemistry and Molecular Biology, University of Southern California, Los Angeles, California, USA
    J Cell Biochem 105:965-70. 2008
    ..The need for such stringent control is consistent with the severe consequences of Runx2 over-expression in vivo...
  15. ncbi Identification of transcription factor target genes by ChIP display
    Artem Barski
    Department of Biochemistry and Molecular Biology, University of Southern California Keck School of Medicine, Los Angeles, CA, USA
    Methods Mol Biol 455:177-90. 2008
    ....
  16. ncbi Androgen receptor-mediated repression of novel target genes
    Jennifer Prescott
    Department of Preventive Medicine, Norris Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
    Prostate 67:1371-83. 2007
    ....
  17. ncbi Dependence of castration-resistant prostate cancer (CRPC) stem cells on CRPC-associated fibroblasts
    Helty Adisetiyo
    Biochemistry and Molecular Biology, University of Southern California, Los Angeles, California Institute for Genetic Medicine, University of Southern California, Los Angeles, California
    J Cell Physiol 229:1170-6. 2014
    ..Factors released by CRPCAF to regulate CRPCSC may be targeted to develop novel therapeutic approaches to manage advanced prostate cancer...

Research Grants30

  1. HORMONAL CONTROL OF CALCIUM METABOLISM
    John T Potts; Fiscal Year: 2013
    ....
  2. Osteoclastic Protein-Tyrosine Phosphatase and Resorption
    Kin Hing William Lau; Fiscal Year: 2013
    ..This project may allow disclose novel targets for development of more effective anti-resorptive therapies for osteoporosis and related disease. Thus, this project is highly relevant to the VA patient care mission. ..
  3. Glucocorticoids, Bone Strength and Angiogenesis
    ROBERT STEWART WEINSTEIN; Fiscal Year: 2013
    ..The proposed studies aimed at the mechanisms of the loss of bone strength in GIO should provide new insights that are sorely needed and immediately vital to veterans health care. ..
  4. Signal Transduction Mechanism of Osteoclast Differentiation
    Nandini Ghosh-Choudhury; Fiscal Year: 2013
    ..Our results will demonstrate how BMP-2 can orchestrate a complex transcriptional network in osteoblasts to tightly regulate osteoclast activation. ..
  5. Estrogens, androgens, aging, and bone loss in males
    Stavros C Manolagas; Fiscal Year: 2013
    ..Lastly, the contribution of the ER1 deletion from osteoblastic cells to skeletal homeostasis in the male and the bone sparing efficacy of the EDC in androgen deficient wild type adult male mice will be determined. ..
  6. Pharmacology of Risperidone Effects on Bone Remodeling and Energy Metabolism
    Karen L Houseknecht; Fiscal Year: 2013
    ....
  7. DRUGS OF ABUSE - ROLE OF PROTEIN PHOSPHORYLATION
    Paul Greengard; Fiscal Year: 2013
    ..Results from the three Projects will complement each other. In addition, there will be a significant level of collaboration between the three Projects, as well as close interaction of the three Projects with the Scientific Core. ..
  8. Connection of Mineral and Energy Metabolism by the Nuclear Receptor PPAR-gamma
    Yihong Wan; Fiscal Year: 2013
    ..Therefore, this investigation will significantly impact the broader scientific, clinical, and patient community. ..
  9. Mitochondrial Dysfunction in Neurodegeneration of Aging
    Gary E Gibson; Fiscal Year: 2013
    ..Successful completion of the goals of these projects can be expected to provide new insights into neurodegenerative processes and contribute to novel approaches to ameliorating age-related neurodegenerations. ..
  10. Conditional Knockout of Calcium Receptors in Bone Cells
    Dolores M Shoback; Fiscal Year: 2013
    ....
  11. MOLECULAR AND CELLULAR MECHANISMS OF OSTEOPOROSIS
    Stavros C Manolagas; Fiscal Year: 2013
    ....
  12. Phosphorylation of PTH1R by TGF-betaRII in Bone Remodeling
    Tao Qiu; Fiscal Year: 2013
    ..This proposal may reveal a previously unrecognized function for T2RII in bone remodeling and a mechanism for PTH to regulate local growth factor at the level of membrane receptor. ..
  13. FUNCTION AND REGULATION OF OSTEONECTIN IN BONE
    Anne M Delany; Fiscal Year: 2013
    ..Information obtained from these studies could be used to identify novel targets for therapeutic intervention in the treatment of osteoporosis, and may be used to identify individuals at risk for developing osteoporosis. ..
  14. Impact of Amyloid on the Aging Brain
    Reisa A Sperling; Fiscal Year: 2013
    ..This PPG brings together an exceptional multidisciplinary team of clinical, statistical, cognitive neuroscience, imaging, and laboratory investigators dedicated to exploring the impact of amyloid on the aging brain. ..