Department of Oral Health Sciences, School of Dentistry, University of Washington, Seattle, WA, USA; Department of Oral Biology and Oral Diagnostic Sciences, Faculty of Dentistry, Chiang Mai University, Chiang Mai, Thailand.
Department of Oral Health Sciences, School of Dentistry, University of Washington, Seattle, WA, USA.
Bone. 2021 Dec;153:116144. doi: 10.1016/j.bone.2021.116144. Epub 2021 Aug 8.
Medication-related osteonecrosis of the jaw (MRONJ) is a serious side effect of antiresorptive medications such as denosumab (humanized anti-RANKL antibody), yet its pathophysiology remains elusive. It has been posited that inhibition of osteoclastic bone resorption leads to the pathological sequelae of dead bone accumulation, impaired new bone formation, and poor wound healing in MRONJ, but this hypothesis has not been definitively tested. We previously engineered myeloid precursors with a conditional receptor activator of nuclear factor kappa-Β intracellular domain (iRANK cells), which differentiate into osteoclasts in response to a chemical inducer of dimerization (CID) independently of RANKL. In this study, we showed that CID-treated iRANK cells differentiated into osteoclasts and robustly resorbed mineralized surfaces even in the presence of anti-RANKL antibody in vitro. We then developed a tooth extraction-triggered MRONJ model in nude mice using anti-RANKL antibody to deplete osteoclasts. This model was used to determine whether reconstitution of engineered osteoclasts within sockets could prevent specific pathological features of MRONJ. Locally delivered iRANK cells successfully differentiated into multinucleated osteoclasts in response to CID treatment in vivo as measured by green fluorescent protein (GFP), tartrate-resistant acid phosphatase (TRAP), carbonic anhydrase II, matrix metallopeptidase 9 (MMP-9), and cathepsin K staining. Sockets treated with iRANK cells + CID had significantly more osteoclasts and less necrotic bone than those receiving iRANK cells alone. These data support the hypothesis that osteoclast deficiency leads to accumulation of necrotic bone in MRONJ.
药物相关性下颌骨坏死（MRONJ）是抗吸收药物（如地舒单抗[人源化抗 RANKL 抗体]）的一种严重副作用，但其病理生理学仍不清楚。有人提出，破骨细胞骨吸收的抑制导致 MRONJ 中死骨堆积、新骨形成受损和伤口愈合不良的病理后果，但这一假说尚未得到明确验证。我们之前曾构建过具有条件核因子 kappa-B 受体激活剂胞内结构域（iRANK 细胞）的髓样前体细胞，这些细胞在化学二聚化诱导剂（CID）的作用下可分化为破骨细胞，而无需 RANKL。在这项研究中，我们表明 CID 处理的 iRANK 细胞分化为破骨细胞，并在体外即使存在抗 RANKL 抗体也能强烈吸收矿化表面。然后，我们使用抗 RANKL 抗体在裸鼠中开发了一种拔牙触发的 MRONJ 模型，以耗尽破骨细胞。该模型用于确定在牙槽窝内重建工程化破骨细胞是否可以预防 MRONJ 的特定病理特征。局部递送的 iRANK 细胞在体内对 CID 处理的反应中成功分化为多核破骨细胞，这可通过绿色荧光蛋白（GFP）、抗酒石酸酸性磷酸酶（TRAP）、碳酸酐酶 II、基质金属蛋白酶 9（MMP-9）和组织蛋白酶 K 染色来测量。与仅接受 iRANK 细胞的窝相比，接受 iRANK 细胞+CID 处理的窝中破骨细胞明显更多，而坏死骨更少。这些数据支持了这样一种假说，即破骨细胞缺乏会导致 MRONJ 中坏死骨的积累。
