Molecular Laboratory for Gene Therapy & Tooth Regeneration, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Capital Medical University School of Stomatology, Beijing, China.
Stem Cells Dev. 2013 Jul 15;22(14):2047-56. doi: 10.1089/scd.2012.0615. Epub 2013 Apr 6.
Bisphosphonates (BPs), which are used to treat a variety of clinical disorders, have the side effect of jawbone necrosis. Currently, there is no reliable treatment for BP-related osteonecrosis of the jaw (BRONJ) due to a lack of understanding of its pathogenesis. To investigate the pathogenesis of BRONJ and observe the treatment effect of bone marrow mesenchymal stem cell (BMMSC) transplantation, we established a preclinical animal model of BRONJ in miniature pigs (minipigs). After treatment with zoledronic acid, the clinical and radiographic manifestations of BRONJ could be observed in minipigs after first premolar extraction. The biological and immunological properties of BMMSCs were impaired in the BP-treated minipigs. Moreover, the ratio of Foxp3-positive regulatory T-cells (Tregs) in peripheral blood decreased, and interleukin (IL)-17 increased in the serum of BP-treated minipigs. After allogeneic BMMSC transplantation via intravenous infusion, mucosal healing and bone reconstruction were observed; IL-17 levels were reduced; and Tregs were elevated. In summary, we established a clinically relevant BRONJ model in minipigs and tested a promising allogeneic BMMSC-based therapy, which may have potential clinical applications for treating BRONJ.
双膦酸盐（BPs）被用于治疗多种临床疾病，但具有导致颌骨坏死的副作用。目前，由于对其发病机制缺乏了解，针对 BP 相关性颌骨坏死（BRONJ）尚无可靠的治疗方法。为了研究 BRONJ 的发病机制并观察骨髓间充质干细胞（BMMSC）移植的治疗效果，我们在小型猪（mini 猪）中建立了 BRONJ 的临床前动物模型。在唑来膦酸治疗后，在第一前磨牙拔除后，可以观察到 mini 猪出现 BRONJ 的临床和影像学表现。BP 处理的 mini 猪的 BMMSC 的生物学和免疫特性受损。此外，BP 处理的 mini 猪外周血中 Foxp3 阳性调节性 T 细胞（Tregs）的比例降低，血清中白细胞介素（IL）-17 增加。通过静脉输注进行同种异体 BMMSC 移植后，观察到黏膜愈合和骨重建；IL-17 水平降低；Tregs 升高。总之，我们在 mini 猪中建立了一种具有临床相关性的 BRONJ 模型，并测试了一种有前途的同种异体 BMMSC 为基础的治疗方法，这可能为治疗 BRONJ 提供潜在的临床应用。
