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Evaluation Among Rheumatoid Arthritis, Periodontal Disease and Bisphosphonates to Induce Osteonecrosis of the Jaws in Mice

Grant number: 12/09968-5
Support Opportunities:Scholarships in Brazil - Doctorate
Effective date (Start): September 01, 2012
Effective date (End): March 31, 2016
Field of knowledge:Health Sciences - Dentistry - Periodontology
Principal Investigator:Joni Augusto Cirelli
Grantee:Rafael Scaf de Molon
Host Institution: Faculdade de Odontologia (FOAr). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil


Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease characterized by a persistent synovitis, systemic inflammation, and autoantibodies that can lead to long-term joint damage, resulting in chronic pain, loss of function and disability. The link between periodontal disease (PD) and RA has primarily been based on pathophysiologic mechanisms shared by both disorders, specially a persistent chronic inflammation and subsequent tissue destruction. PD is an infectious disease characterized by a chronic inflammation of the periodontium and is mediated and modulated by the host immune system, in which their progression is due to an imbalance in the dynamic health and disease process between the dental biofilm and the host response to these agents. DP and RA share several pathological similarities related mainly to changes in the profile and levels of cytokines and their antagonists. Thus, the immune-inflammatory imbalance in consequence of the production of an exacerbated inflammatory/immune response from the activation of immune, inflammatory and resident cells is responsible for most of the tissue damage observed in the progression of these diseases. This feature is also present in the establishment and progression of RA. Research into new treatments for RA is exploring the development of additional biologic agents, and also the possible effectiveness of bisphosphonates in protecting against bone destruction. Bisphosphonates are powerful inhibitors of osteoclastic bone resorption and are widely used to manage diseases that are featured by bone loss such as cancer and osteoporosis. Nitrogen-containing bisphosphonates (BPs), synthetic analogues of pyrophosphate, are effective in the treatment of osteolytic lesions in multiple myeloma, bone metastases from solid tumors, and have been used for over 30 years to treat postmenopausal osteoporosis. However, a new concern is raised by the recent reports of osteonecrosis of the jaw (ONJ) in patients treated with these drugs. Oral BPs are currently the most widely used agents for the prevention and treatment of osteoporosis. ONJ is an area of exposed bone in the maxillofacial region that did not heal within 8 weeks in a patient who had been exposed to BPs. ONJ is most frequently observed after dental interventions such as tooth extraction, periodontal disease and in patients receiving corticosteroid treatment. Despite having been described in the literature since 2004, ONJ etiology and pathophysiology remain largely unknown. To the best of our knowledge no research studies correlate RA to the etiology of ONJ in patients that use bisphosphonates for the treatment of RA. Although there are many hypotheses regarding ONJ pathogenesis, none of them is completely accepted. Some factors such as pro-inflammatory cytokines, oxidative stress, infectious process, rheumatoid arthritis, periodontal disease and others play an important role in the development of ONJ, especially when BPs are used concomitantly. However, the association between RA, PD and ONJ has not been fully explained, Therefore, studies that assess the disease progression as well as the cellular and molecular characteristics of RA, PD and ONJ can be useful in elucidating the association between these diseases. Thus, the aim of this work will be evaluate in mice the interaction of RA, PD and BPs to induce ONJ.

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Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
DE MOLON, RAFAEL SCAF; HSU, CHINGYUN; BEZOUGLAIA, OLGA; DRY, SARAH M.; PIRIH, FLAVIA Q.; SOUNDIA, AKRIVOULA; CUNHA, FERNANDO QUEIROZ; CIRELLI, JONI AUGUSTO; AGHALOO, TARA L.; TETRADIS, SOTIRIOS. Rheumatoid Arthritis Exacerbates the Severity of Osteonecrosis of the Jaws (ONJ) in Mice. A Randomized, Prospective, Controlled Animal Study. Journal of Bone and Mineral Research, v. 31, n. 8, p. 1596-1607, . (12/09968-5)
DE MOLON, RAFAEL SCAF; CHEONG, SIMON; BEZOUGLAIA, OLGA; DRY, SARAH M.; PIRIH, FLAVIA; CIRELLI, JONI AUGUSTO; AGHALOO, TARA L.; TETRADIS, SOTIRIOS. Spontaneous osteonecrosis of the jaws in the maxilla of mice on antiresorptive treatment: A novel ONJ mouse model. BONE, v. 68, p. 11-19, . (12/09968-5)
DE MOLON, RAFAEL SCAF; SHIMAMOTO, HIROAKI; BEZOUGLAIA, OLGA; PIRIH, FLAVIA Q.; DRY, SARAH M.; KOSTENUIK, PAUL; BOYCE, ROGELY W.; DWYER, DENISE; AGHALOO, TARA L.; TETRADIS, SOTIRIOS. OPG-Fc but Not Zoledronic Acid Discontinuation Reverses Osteonecrosis of the Jaws (ONJ) in Mice. Journal of Bone and Mineral Research, v. 30, n. 9, p. 1627-1640, . (12/09968-5)
Academic Publications
(References retrieved automatically from State of São Paulo Research Institutions)
MOLON, Rafael Scaf de. Pathophysiology of osteonecrosis of the jaws induced by bisphosphonates and RANK-L inhibitors. 2016. Doctoral Thesis - Universidade Estadual Paulista (Unesp). Faculdade de Odontologia. Araraquara Araraquara.

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