Ogata Kenichi, Katagiri Wataru, Osugi Masashi, Kawai Takamasa, Sugimura Yukiko, Hibi Hideharu, Nakamura Seiji, Ueda Minoru
Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Higashi-ku, 3-1-1 Maidashi, Fukuoka 812-8582, Japan; Department of Oral and Maxillofacial Surgery, Nagoya University Graduate School of Medicine, Aichi, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
Department of Oral and Maxillofacial Surgery, Nagoya University Graduate School of Medicine, Aichi, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
Bone. 2015 May;74:95-105. doi: 10.1016/j.bone.2015.01.011. Epub 2015 Jan 19.
Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is defined as an exposed necrotic bone in the oral cavity that does not heal after appropriate intervention for >8weeks with present or previous bisphosphonate treatment in the absence of radiotherapy. Until now, although several risk factors, including invasive dental procedures, infection, mechanical trauma to the jawbone, and concomitant use of immunosuppressive and chemotherapy drugs have been implicated in the etiology of BRONJ, its underlying mechanisms and treatments remain largely unknown. A study recently showed that intravenous administration of mesenchymal stem cells (MSCs) improved BRONJ, and it was hypothesized that paracrine effects by secretomes from MSCs are the main constituent. Here we used rat BRONJ models to examine the therapeutic effects with serum-free conditioned media from human MSCs (MSC-CM), including various secretomes. We showed that MSC-CM has protected rat MSCs and rat osteoclasts. MSC-CM enhanced the expression of osteogenic-related genes and neovascularization-related genes by real-time reverse-transcriptase polymerase chain reaction analysis in in vitro study. In in vivo study, 5-week-old Wistar/ST male rats received zoledronate (35μg/kg/week) and dexamethasone (1mg/kg/day) subcutaneously for 2weeks. Unilateral maxillary molars were then extracted. Two weeks later, rats were divided into non-treatment, serum-free Dulbecco's modified Eagle's medium, and MSC-CM groups. In the MSC-CM group, the open alveolar sockets in 63% of the rats with BRONJ healed with complete soft tissue coverage and socket bones, whereas the exposed necrotic bone with inflamed soft tissue remained in the other groups. Histological analysis showed new bone formation and the appearance of osteoclasts in the MSC-CM group. Osteoclasts were significantly reduced in the non-treatment group. Thus, we concluded that the antiapoptotic and antiinflammatory effects of MSC-CM dramatically regulated the turnover of local bone and indicated therapeutic effects on BRONJ.
双膦酸盐相关颌骨坏死（BRONJ）被定义为在未接受放疗的情况下，口腔内暴露的坏死骨在经过适当干预8周以上仍未愈合，且患者目前或既往接受过双膦酸盐治疗。到目前为止，尽管包括侵入性牙科手术、感染、颌骨机械创伤以及同时使用免疫抑制和化疗药物等多种危险因素与BRONJ的病因有关，但其潜在机制和治疗方法仍 largely未知。最近一项研究表明，静脉注射间充质干细胞（MSCs）可改善BRONJ，并且推测MSCs分泌产物的旁分泌作用是主要成分。在此，我们使用大鼠BRONJ模型，用人MSCs的无血清条件培养基（MSC-CM）（包括各种分泌产物）来研究其治疗效果。我们发现MSC-CM对大鼠MSCs和大鼠破骨细胞具有保护作用。在体外研究中，通过实时逆转录聚合酶链反应分析，MSC-CM增强了成骨相关基因和新血管生成相关基因的表达。在体内研究中，5周龄的Wistar/ST雄性大鼠皮下注射唑来膦酸（35μg/kg/周）和地塞米松（1mg/kg/天），持续2周。然后拔除单侧上颌磨牙。两周后，将大鼠分为未治疗组、无血清杜氏改良 Eagle培养基组和MSC-CM组。在MSC-CM组中，63%患有BRONJ的大鼠开放牙槽窝愈合，软组织完全覆盖且牙槽骨修复，而其他组则仍有暴露的坏死骨伴有炎症软组织。组织学分析显示，MSC-CM组有新骨形成且出现破骨细胞。未治疗组破骨细胞显著减少。因此，我们得出结论，MSC-CM的抗凋亡和抗炎作用显著调节了局部骨的更新，并显示出对BRONJ的治疗效果。
