Yamachika Eiki, Matsui Yuichi, Matsubara Masakazu, Matsumura Tatsushi, Nakata Naoki, Moritani Norifumi, Ikeda Atsushi, Tsujigiwa Hidetsugu, Ohara Naoya, Iida Seiji
Department of Oral and Maxillofacial Reconstructive Surgery, Okayama University Hospital, 2-5-1 Shikata-cho, Kitaku, Okayama 7008558, Japan.
Department of Oral and Maxillofacial Reconstructive Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-Cho, Kitaku, Okayama 7008558, Japan.
J Dent Sci. 2017 Dec;12(4):333-339. doi: 10.1016/j.jds.2017.03.007. Epub 2017 Apr 24.
BACKGROUND/PURPOSE: Few studies have investigated the possibility that bisphosphonate-related osteonecrosis of the jaw (BRONJ) might reflect an immune response; however, gamma delta T cells have been shown to significantly decline in the blood of BRONJ patients. Additionally, there have been some reports of teriparatide usage for the treatment of BRONJ. In this study, we compared the effects of zoledronate and teriparatide on lymphocyte populations and inflammatory cytokine production in mice.
Thirty female ICR mice were divided into three groups (n = 10 each): a vehicle, a zoledronate, and a teriparatide group. Drugs were administered for 8 weeks in each group. Lymphocytes in the blood and thymus were analyzed and femurs were used for histological observation and lymphocytes analysis of bone marrow. Cytokines were measured in separated serum using Milliplex multiplex immunoassay analysis.
Zoledronate decreased the T cell number in the bone marrow. Additionally, serum levels of interleukin (IL)-2, IL-7, IL-12, IL-15 and RANTES, which are cytokines that affect T cell activation, differentiation and/or proliferation, were significantly lower in zoledronate treated mice. Conversely, teriparatide treatment induced an increase in gamma delta T cells in peripheral blood.
Gamma delta T cells in the bone marrow are expected to decrease with zoledronate treatment and increase with teriparatide treatment. If BRONJ involves a loss of gamma delta T cells in the circulation or bone marrow, then the increase in gamma delta T cells that is induced by teriparatide may account for its ability to resolve BRONJ.
背景/目的：很少有研究探讨双膦酸盐相关颌骨坏死（BRONJ）可能反映免疫反应的可能性；然而，已显示γδT细胞在BRONJ患者血液中显著减少。此外，有一些关于使用特立帕肽治疗BRONJ的报道。在本研究中，我们比较了唑来膦酸盐和特立帕肽对小鼠淋巴细胞群体和炎性细胞因子产生的影响。
30只雌性ICR小鼠分为三组（每组n = 10）：溶剂对照组、唑来膦酸盐组和特立帕肽组。每组给药8周。分析血液和胸腺中的淋巴细胞，并使用股骨进行组织学观察和骨髓淋巴细胞分析。使用Milliplex多重免疫分析测定分离血清中的细胞因子。
唑来膦酸盐降低了骨髓中的T细胞数量。此外，在接受唑来膦酸盐治疗的小鼠中，影响T细胞活化、分化和/或增殖的细胞因子白细胞介素（IL）-2、IL-7、IL-12、IL-15和调节激活正常T细胞表达和分泌因子（RANTES）的血清水平显著降低。相反，特立帕肽治疗导致外周血中γδT细胞增加。
预计唑来膦酸盐治疗会使骨髓中的γδT细胞减少，而特立帕肽治疗会使其增加。如果BRONJ涉及循环或骨髓中γδT细胞的缺失，那么特立帕肽诱导的γδT细胞增加可能解释了其治愈BRONJ的能力。
