Engineered osteoclasts resorb necrotic alveolar bone in anti-RANKL antibody-treated mice.
Engineered osteoclasts resorb necrotic alveolar bone in anti-RANKL antibody-treated mice.
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DOI：
10.1016/j.bone.2021.116144
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发表时间：
2021-12
期刊：
影响因子：
4.1
通讯作者：
Giachelli CM
中科院分区：
文献类型：
--
作者：
Buranaphatthana W;Yavirach A;Leaf EM;Scatena M;Zhang H;An JY;Giachelli CM
药物相关性颌骨骨坏死（MRONJ）是抗骨吸收药物（如狄诺塞单抗（人源化抗RANKL抗体））的严重副作用，但其病理生理学仍然难以捉摸。据推测，骨吸收抑制导致MRONJ中死骨积聚、新骨形成受损和伤口愈合不良的病理后遗症，但该假设尚未得到明确验证。我们先前用核因子κ B胞内结构域的条件性受体激活剂（iRANK细胞）工程化骨髓前体，其响应于不依赖于RANKL的二聚化化学诱导剂（CID）分化成破骨细胞。在本研究中，我们发现CID处理的iRANK细胞分化为破骨细胞，即使在体外存在抗RANKL抗体的情况下，也能稳健地再吸收矿化表面。然后，我们在裸鼠中开发了拔牙触发的MRONJ模型，使用抗RANKL抗体消耗破骨细胞。该模型用于确定在牙槽内重建工程化破骨细胞是否可以预防MRONJ的特定病理特征。通过绿色荧光蛋白（GFP）、抗酒石酸酸性磷酸酶（TRAP）、碳酸酐酶II、基质金属肽酶9（MMP-9）和组织蛋白酶K染色测量，局部递送的iRANK细胞在体内CID处理后成功分化为多核破骨细胞。用iRANK细胞+ CID处理的骨槽比单独接受iRANK细胞的骨槽具有显著更多的破骨细胞和更少的坏死骨。这些数据支持破骨细胞缺乏导致MRONJ中坏死骨积聚的假设。
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.
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影响因子：
--
作者：
Kim KM;Rhee Y;Kwon YD;Kwon TG;Lee JK;Kim DY
通讯作者：
Kim DY
NF-κB基因的诱导，独立于配体的受体活化剂，可控制与单核细胞前体分化的破骨细胞分化。
影响因子：
3.7
作者：
Rementer CW;Wu M;Buranaphatthana W;Yang HY;Scatena M;Giachelli CM
通讯作者：
Giachelli CM
影响因子：
16.6
作者：
Harre, Ulrike;Lang, Stefanie C.;Pfeifle, Rene;Rombouts, Yoann;Fruhbeisser, Sabine;Amara, Khaled;Bang, Holger;Lux, Anja;Koeleman, Carolien A.;Baum, Wolfgang;Dietel, Katharina;Groehn, Franziska;Malmstroem, Vivianne;Klareskog, Lars;Kroenke, Gerhard;Kocijan, Roland;Nimmerjahn, Falk;Toes, Rene E. M.;Herrmann, Martin;Scherer, Hans Ulrich;Schett, Georg
通讯作者：
Schett, Georg
影响因子：
6.2
作者：
Pan, BQ;Farrugia, AN;Zannettino, ACW
通讯作者：
Zannettino, ACW
影响因子：
6.2
作者：
Cardoso, Luis;Herman, Brad C.;Schaffler, Mitchell B.
通讯作者：
Schaffler, Mitchell B.