The Role Of Osteoclast PODXL, A Mediator Of Cell Adhesion, In Bone Metabolism

Summary

Principal Investigator: Merry Jo Oursler
Abstract: DESCRIPTION (provided by applicant): Our long term goal is to delineate the molecular mechanisms by which osteoclasts contribute to bone metabolism with the expectation that this knowledge will guide more effective therapies to promote skeletal health. Ideally, new therapy targets to reduce osteoclast-mediated bone loss will block osteoclasts while also preserving bone formation. This may be challenging since evidence is mounting that osteoclasts, whether or not they are capable of resorbing bone, are needed for normal bone formation by osteoblasts. We have examined the vertebrae of mice in which the CD34 family member PODXL is deleted in hematopoietic/osteoclast lineage cells (hem lineage-PODXLdel mice). Bone density and osteoblast numbers were both elevated. Unexpectedly, the number and size of osteoclasts were also significantly higher. Thus, loss of PODXL in early osteoclast lineage cells reduces bone resorption while preserving osteoblast recruitment and bone formation. Our in vitro studies support that PODXL expression in osteoclast lineage cells reduces osteoclast differentiation. However, a relatively low level of PODXL expression is required for osteoclast actin ring formation and bone resorption. Our studies and the known functions of PODXL lead to our central hypothesis that early progenitor membrane expression levels of a PODXL membrane complex including CXCR4 and NHERF1 must be reduced to allow for precursor fusion and lower levels of this complex are required for activation of osteoclasts, enabling them to resorb bone. The following Specific Aims are designed to test this hypothesis 1. Determine the role of osteoclast lineage PODXL expression changes in skeletal acquisition and bone maintenance. We will comprehensively phenotype the hem lineage-PODXLdel mice, establish the effects of ovariectomy on bone metabolism in hem lineage-PODXLdel mice, define the impact of loss of PODXL in early osteoclast lineage cells during anabolic PTH treatment, and compare mice with PODXL deleted in late osteoclast lineage cells to the hem lineage-PODXLdel mice. 2. Interrogate the molecular mechanisms by which the PODXL, CXCR4, and NHERF-1 complex influences osteoclast lineage cells. We will identify structural domains of PODXL and NHERF1 involved in complex formation, membrane expression, differentiation, and internalization during differentiation, resolve the mechanism of down regulation of PODXL, CXCR4, and NHERF1 gene expression by M-CSF, and ascertain the influences of PODXL and binding partners on integrin interactions, actin ring formation, and osteoclast function.
Funding Period: 2010-09-30 - 2015-06-30
more information: NIH RePORT

Research Grants

Detail Information

Research Grants30

  1. HORMONAL CONTROL OF CALCIUM METABOLISM
    John T Potts; Fiscal Year: 2013
    ....
  2. Sex Steroids and Runx Signaling in Bone
    Baruch Frenkel; Fiscal Year: 2013
    ..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. ..
  3. 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. ..
  4. Osteoporosis treatment response assessed by micromechanical modeling of MRI data.
    Felix W Wehrli; Fiscal Year: 2013
    ..The successful completion of the project will provide new insight into the potential for image-based computational biomechanics for monitoring prophylactic intervention. ..
  5. 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. ..
  6. 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. ..
  7. Differential Impact of Resveratrol and Resveratrol Mimetics Upon Aging Bone
    Bruce R Troen; Fiscal Year: 2013
    ..Our work will also have significant clinical impact given the widespread and deleterious burden of osteoporosis in the elderly and can be applied to the utilization of RSV and RSV mimetics in the clinic. ..
  8. Biomechanical Stimulation &Skeletal Health in Adolescents with Anorexia Nervosa
    Amy D DiVasta; Fiscal Year: 2013
    ..Given the health care burden associated with the current epidemic of osteoporosis in the elderly, establishing effective measures to prevent bone loss during childhood and adolescence is paramount. ..
  9. The role of the atypical PKCs in osteoclast function
    JULIA THERESE WARREN; Fiscal Year: 2013
    ..We propose to study the mechanisms by which the osteoclast, the sole bone resorbing cell, functions. This will help provide the foundations for novel therapeutic development to treat osteoporosis. ..
  10. G PROTEIN SIGNALING IN OSTEOBLASTS
    ROBERT NISSENSON; Fiscal Year: 2013
    ..abstract_text> ..
  11. 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. ..
  12. Pharmacology of Risperidone Effects on Bone Remodeling and Energy Metabolism
    Karen L Houseknecht; Fiscal Year: 2013
    ....
  13. Serotonin Reuptake Inhibitors and Bone Mineralization in Adolescents
    Chadi A Calarge; Fiscal Year: 2013
    ..This is consistent with the mission of the National Institute of Mental Health. ..
  14. 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. ..
  15. 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. ..
  16. 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. ..
  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. ..