The Role of Podocalyxin in Osteoclast Activity and Bone Metabolism

Summary

Principal Investigator: Megan M Weivoda
Abstract: DESCRIPTION (provided by applicant): Current treatments for osteoporosis, such as the bisphosphonates, target osteoclast-mediated bone resorption. While these agents effectively reduce bone loss, this is complicated by an associated decrease in bone remodeling resulting in diminished bone formation and repair. Mounting evidence suggests that the presence of osteoclasts is required for bone formation by osteoblasts. Thus, the long term goal of this project is to identify potential therapeutic targets to inhibit osteoclast activity while preservin the anabolic effects of osteoclasts on osteoblasts and bone formation. One potential target to inhibit osteoclast activity without reducing the anabolic effects of osteoclasts is podocalyxin (PODXL). PODXL has previously been identified as a mediator of cell adhesion expressed by cells of the hematopoietic lineage. Preliminary data show that deletion of PODXL specifically in the hematopoietic lineage/osteoclast precursors (Vav/PODXLdel) leads to a high bone mass phenotype in female adult mice and increased osteoblast numbers. While these mice exhibit increased osteoclast numbers, resorption by these osteoclasts is impaired. Of particular interest, this high bone mass phenotype is evident only in female mice suggesting that the loss of PODXL is exacerbated by the presence or absence of specific sex steroids. Vav/PODXLdel bone marrow derived osteoclasts exhibit reduced activation of the Rac1 GTPase. Several groups have demonstrated that Rac1 activation is reduced by estrogen and this contributes to sex specific phenotypes in animal models. The central hypothesis of my project is that PODXL is necessary for optimal Rac1 activation;deletion of PODXL exacerbates the effect of estrogen to inhibit Rac1 activation, leading to impaired osteoclast resorption and a high bone mass in estrogen-sufficient female mice. My objectives are to characterize how the bone phenotype of Vav/PODXLdel mice is impacted by sex steroids in an in vivo mouse model and to define the mechanism by which PODXL modulates Rac1 activation and osteoclastic bone resorption. Understanding the mechanism by which PODXL facilitates Rac1 activation in pre-osteoclasts and how this is impacted by circulating sex steroids may lead to novel therapeutic targets to inhibit osteoclast activity without disturbing the anabolic effects of osteoclasts on the skeleton. Additionally, studying the role of sex steroids in the Vav/PODXLdel bone phenotype may elucidate mechanisms that contribute to postmenopausal and age-related bone loss.
Funding Period: 2013-05-22 - 2014-12-19
more information: NIH RePORT

Top Publications

  1. pmc Developments in sclerostin biology: regulation of gene expression, mechanisms of action, and physiological functions
    Megan M Weivoda
    Division of Endocrinology, Metabolism, Nutrition and Diabetes, Mayo Clinic, 200 First Street NW, Rochester, MN, 55905, USA
    Curr Osteoporos Rep 12:107-14. 2014

Detail Information

Publications1

  1. pmc Developments in sclerostin biology: regulation of gene expression, mechanisms of action, and physiological functions
    Megan M Weivoda
    Division of Endocrinology, Metabolism, Nutrition and Diabetes, Mayo Clinic, 200 First Street NW, Rochester, MN, 55905, USA
    Curr Osteoporos Rep 12:107-14. 2014
    ..In this article, we discuss the latest findings in the regulation of SOST expression, sclerostin mechanisms of action, and the potential utility of targeting sclerostin in conditions of low bone mass...

Research Grants31

  1. HORMONAL CONTROL OF CALCIUM METABOLISM
    John T Potts; Fiscal Year: 2013
    ....
  2. Misty: a model for central regulation of bone remodeling
    CLIFFORD JAMES ROSEN; Fiscal Year: 2013
    ..Importantly, these studies will shed new light on the ErbB and Dock7 signaling pathways in bone and in BAT. Defining shared metabolic-skeletal networks may lead to new treatments for age-related osteoporosis. ..
  3. Mechanisms of Bone Loss from Administration of the Second-Generation Antipsychoti
    KATHERINE JEAN MOTYL; Fiscal Year: 2013
    ..My results will also add to the increasing evidence for a key role of the nervous system in regulating skeletal homeostasis. ..
  4. Actions of Endoxifen on the Skeleton
    Anne Gingery; Fiscal Year: 2013
    ....
  5. The Role Of Osteoclast PODXL, A Mediator Of Cell Adhesion, In Bone Metabolism
    Merry Jo Oursler; Fiscal Year: 2013
    ....
  6. 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. ..
  7. 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. ..
  8. Pharmacology of Risperidone Effects on Bone Remodeling and Energy Metabolism
    Karen L Houseknecht; Fiscal Year: 2013
    ....
  9. 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. ..
  10. 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. ..
  11. Prevention of age-associated musculoskeletal loss by n-3 fatty acids
    Md Mizanur Rahman; Fiscal Year: 2013
    ..abstract_text> ..
  12. 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. ..
  13. Conditional Knockout of Calcium Receptors in Bone Cells
    Dolores M Shoback; Fiscal Year: 2013
    ....
  14. Cellular Senescence and Aging
    James L Kirkland; Fiscal Year: 2013
    ..Our approach will provide timely, innovative, and clinically relevant interventional results based on addressing the fundamental question of the role of cellular senescence that has remained unanswered for many years. ..
  15. Effect of Adrenal and Gonadal Hormones on Bone Marrow and Appendicular BMD
    Catherine M Gordon; Fiscal Year: 2013
    ..Knowledge gained from this study may also have application to other diseases across the age spectrum that are associated with bone loss and involve alterations in bone marrow composition. ..
  16. FoxOs in Osteoclastic Cells
    SHOSHANA BARTELL; Fiscal Year: 2013
    ..This work should advance knowledge of how oxidative stress via FoxO activation alters bone mass, and provide a better understanding of the mechanisms controlling sex steroid deficiency- or age-related osteoporosis. ..
  17. 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. ..
  18. 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. ..