Department of Experimental Medicine and Oncology, University of Turin, Turin, Italy.
J Oral Pathol Med. 2012 Nov;41(10):788-92. doi: 10.1111/j.1600-0714.2012.01173.x. Epub 2012 May 31.
Osteonecrosis of the jaw (ONJ) is a chronic complication of bisphosphonate therapy, mainly when intravenous, in cancer patients with bone metastases and myeloma. Its pathophysiology is not yet fully elucidated; in particular, the molecular/cellular events triggering ONJ remain unclear. This complication could result from the effect of bisphosphonates released from bone into the soft-tissues, or from osteolysis induced by soft-tissues directly exposed to bisphosphonates. This research investigated the possibility that ONJ may be evocated by changes induced in osteoblast activity by factors released by soft-tissue cells exposed to zoledronic acid.
An 'in vitro' model was used, in which human osteoblast-like MG-63 cells were grown in medium conditioned by human keratinocytes NCTC 2544, exposed or not to zoledronic acid (5 or 50 μM); 5 μM zoledronic acid was also directly administered to MG-63 cells.
In NCTC 2544 cells, zoledronic acid decreased proliferation via decreased hydroxy-3-methyl-glutaryl-CoA reductase, suggesting that a decrease in healing capability can occur in case of injury. An increased pro-inflammatory potential was also observed. Osteoblasts grown in medium conditioned in the presence of zoledronic acid showed decreased proliferation and osteogenic properties, and increased ability to induce osteoclast differentiation and inflammatory process. Zoledronic acid directly administered to MG-63 modulated only some parameters and in a lesser extent.
The research evidenced, for the first time, the direct involvement of epithelial cells in zoledronic acid-triggered molecular mechanisms leading to osteonecrosis of the jaw, by modulating both osteoblast and osteoclast properties.
颌骨坏死（ONJ）是双膦酸盐治疗的一种慢性并发症，主要发生在癌症伴骨转移和骨髓瘤患者的静脉内治疗中。其病理生理学尚未完全阐明；特别是，触发 ONJ 的分子/细胞事件仍不清楚。这种并发症可能是由于骨释放到软组织中的双膦酸盐的作用，或者是由于直接暴露于双膦酸盐的软组织引起的溶骨性作用所致。这项研究调查了由暴露于唑来膦酸的软组织细胞释放的因子引起的成骨细胞活性变化是否可能引发 ONJ 的可能性。
使用“体外”模型，其中人成骨样 MG-63 细胞在由人角质形成细胞 NCTC 2544 条件培养基中生长，暴露或不暴露于唑来膦酸（5 或 50 μM）；还将 5 μM 唑来膦酸直接给予 MG-63 细胞。
在 NCTC 2544 细胞中，唑来膦酸通过降低羟甲基戊二酰基辅酶 A 还原酶来减少增殖，这表明在受伤时可能会降低愈合能力。还观察到促炎潜力增加。在存在唑来膦酸的条件培养基中生长的成骨细胞显示增殖和成骨特性降低，并且诱导破骨细胞分化和炎症过程的能力增加。直接给予 MG-63 的唑来膦酸仅调节了一些参数，并且程度较小。
该研究首次证明了上皮细胞通过调节成骨细胞和破骨细胞的特性，直接参与唑来膦酸触发导致颌骨坏死的分子机制。
