Oral Mucosa Barrier and Bisphosphonate-related Osteonecrosis of the Jaw

Summary

Principal Investigator: Ichiro Nishimura
Abstract: DESCRIPTION (provided by applicant): Bisphosphonate (BP) treatment has been shown to be effective in the management of malignant neoplasms that reside in or metastasize to bone, including multiple myeloma and breast or prostate cancer, respectively. In the recent years, there have been a number of cases reporting osteonecrosis of the jaw (ONJ) subsequent to nitrogen-containing BP treatment. The long-term objective of this project is to determine the pathological mechanism of BP associated-ONJ and to develop effective means for prevention and treatment. ONJ occurs nearly exclusively in the oral cavity, where jawbone and oral mucosa interface at a close proximity. Oral mucosa is equipped with the unique subset of adaptive and innate immunity. While oral mucosa provides one of the most effective barrier functions, over-activation of inflammatory/immune reactions has been linked to various tissue damages in the oral cavity. Therefore, we postulate that BP treatment may abnormally activate the mucosal immunity of oral barrier tissue resulting in generating a cytotoxic environment leading to osteonecrosis. The barrier tissues contain a set of lymphocytes composed of [unreadable][unreadable] T cells, NK cells, NKT cells and/or Th17 cells. Activated barrier tissue lymphocytes can regulate the epithelial integrity and orchestrate inflammatory reactions. In SA1, we propose to identify the candidate immune effector cells involved in the pathological mechanism of ONJ. Recently, PI's team developed a mouse model of ONJ, which exhibited consistent necrotic jawbones, equivalent to the human disease. In this project, the mouse ONJ model will be combined with B/T cell knockout (RAG1-/-) mice as well as B/T/NK cell knockout (RAG2/?(c)-/-) mice, in which the ONJ phenotype will be characterized. Among the barrier tissue lymphocytes, ?[unreadable] T cells present the first respondent to stress-induced signals. In this project, we separately examine the role of oral ?[unreadable] T cells in the development of ONJ lesions using ?[unreadable] T cell-knockout (TCRD-/-) mice. An important question still remains: what is the unique link between BP treatment and the activation of oral barrier immunity? Through bone resorption, BP is internalized by osteoclasts (OCs) and interferes the mevalonate pathway leading to premature inactivation of OCs. The early onset of rodent ONJ lesions demonstrated an unusual cluster of inflammatory cells juxtaposing BP-distressed OCs. This observation has led us to hypothesize that BP-distressed OCs are the cellular source of stress signals activating oral barrier immune effector cells and thus initiating ONJ pathogenesis. In SA2, we propose to establish an in vitro model involving BP-absorbed CaP disc and human monocyte-derived OCs. The effect of BP-distressed OCs on human oral lymphocytes or peripheral blood lymphocytes will be differentially evaluated by co-culture system. The outcome of this project may open a new avenue of investigations on oral mucosa barrier immune effector cells and previously unexplored stress signaling mechanisms of the pharmacologically manipulated OCs and provide the basis for therapeutic strategy of ONJ.
Funding Period: 2012-09-04 - 2017-08-31
more information: NIH RePORT

Top Publications

  1. pmc Equilibrium-dependent bisphosphonate interaction with crystalline bone mineral explains anti-resorptive pharmacokinetics and prevalence of osteonecrosis of the jaw in rats
    Akishige Hokugo
    The Weintraub Center for Reconstructive Biotechnology, Division of Advanced Prosthodontics, UCLA School of Dentistry, Los Angeles, CA 90095, USA
    Bone 53:59-68. 2013

Detail Information

Publications1

  1. pmc Equilibrium-dependent bisphosphonate interaction with crystalline bone mineral explains anti-resorptive pharmacokinetics and prevalence of osteonecrosis of the jaw in rats
    Akishige Hokugo
    The Weintraub Center for Reconstructive Biotechnology, Division of Advanced Prosthodontics, UCLA School of Dentistry, Los Angeles, CA 90095, USA
    Bone 53:59-68. 2013
    ..Our results suggest that equilibrium-dependent BP-bone interaction may, in part, determine the effectiveness and influence side effects of long-term and repeated applications of BPs...

Research Grants30

  1. HORMONAL CONTROL OF CALCIUM METABOLISM
    John T Potts; Fiscal Year: 2013
    ....
  2. T CELL MEMORY TO PATHOGENS: GENERATION AND FUNCTION
    Susan L Swain; Fiscal Year: 2013
    ..abstract_text> ..
  3. Center for Interdisciplinary Research on Nicotine Addiction (CIRNA)
    Caryn Lerman; Fiscal Year: 2013
    ..The CIRNA is proposed to replace the TTURC, since this NIH initiative is ending. ..
  4. CHEMISTRY AND BIOLOGY OF HEPARAN SULFATE
    UMESH RAMANLAL DESAI; Fiscal Year: 2013
    ..End of Abstract) ..
  5. Rocky Mountain Regional Center of Excellence or Biodefense and Emerging Infectiou
    John T Belisle; Fiscal Year: 2013
    ..abstract_text> ..
  6. BEHAVIORAL GENOMICS OF ALCOHOL NEUROADAPTATION
    John C Crabbe; Fiscal Year: 2013
    ..An Education and Outreach component trains pre- and post-doctoral students in alcohol research, disseminates research findings to the public, and engages in a range of activities with elementary-to-high school students. ..
  7. Middle Atlantic Regional Center for Excellence for Biodefense and Emerging Infect
    MYRON MAX LEVINE; Fiscal Year: 2013
    ..abstract_text> ..
  8. Signaling in Inflammation, Stress, and Tumorigenesis
    GEORGE ROBERT STARK; Fiscal Year: 2013
    ..abstract_text> ..
  9. Intracellular trafficking of Bisphosphonates in bone mesenchymal Stem Cells
    Sunday O Akintoye; Fiscal Year: 2013
    ..The goal is to formulate preventive measures for ONJ. ..
  10. Host Defense Against HIV-related Pulmonary Infections
    Judd E Shellito; Fiscal Year: 2013
    ..abstract_text> ..
  11. Molecular mechanisms of drug-induced ONJ and osteomucosal chronic wounds
    REUBEN HAN KYU KIM; Fiscal Year: 2013
    ..Current proposal would help unraveling the molecular mechanisms of rather unexplored areas of research in osteomucosal wound healing and provide knowledge for future therapeutic applications to both BRONJ and DRONJ. ..
  12. Genomics for Transplantation: Discovery and Biomarkers
    Daniel R Salomon; Fiscal Year: 2013
    ..Ultimately, we hope to create the genomic tools that will allow physicians to optimize and personalize the safety and efficacy of immunosuppression. ..
  13. Center for Narcolepsy and Related Disorders (P50)
    Emmanuel J Mignot; Fiscal Year: 2013
    ..We also want to understand why the immune system destroys hypocretin neurons in narcolepsy and to prevent/cure it. ..
  14. Salivary Biomarkers in the Diagnosis of BRONJ
    Tara L Aghaloo; Fiscal Year: 2013
    ..Aghaloo to design future clinical studies, whether for ONJ or other oral diseases. ..