Department of Oral Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8549, Japan.
Department of Clinical Physiology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8588, Japan.
Biochem Biophys Res Commun. 2019 Jan 29;509(1):108-113. doi: 10.1016/j.bbrc.2018.12.078. Epub 2018 Dec 19.
The precise mechanism of osteolysis induced by tumors infiltrating into the bone remains unclear. The main hypothesis is that tumor cells generate receptor activator of nuclear factor kappa-B ligand (RANKL), tumor necrosis factor-alpha (TNF-α), or other molecules that activate the expression of RANKL in osteoblasts, osteocytes, or bone marrow stromal cells. Administration of bisphosphonates or anti-RANKL antibody drugs, which suppress systemic bone resorption, prevents osteolysis induced by tumors infiltrating into the bone. However, these therapeutic agents may cause medication-related osteonecrosis of the jaw. In this study, we found a novel tumor-associated osteoclastogenesis pathway in osteoclast precursor cells. Co-culture with human oral squamous cell carcinoma cells, 3A or NEM, or culture with each of their conditioned medium induced many osteoclasts from osteoclast precursor cells, which were generated by a 24-h pretreatment of RANKL or TNF-α. Osteoprotegerin, a decoy RANKL receptor, denosumab, an anti-RANKL antibody drug, and infliximab, an anti-TNF-α antibody drug, did not prevent this tumor-associated osteoclastogenesis. Quantitative RT-PCR analysis showed that the expression of NFATc1 was decreased in this tumor-associated osteoclastogenesis, which was suggested to be independent of NFATc1. These results revealed a novel pathway for tumor-associated osteoclastogenesis, which may be a new therapeutic target for osteolysis induced by tumors infiltrating into the bone without affecting systemic bone metabolism.
肿瘤浸润性骨溶解的确切机制尚不清楚。主要假说认为，肿瘤细胞产生核因子κB 受体激活剂配体（RANKL）、肿瘤坏死因子-α（TNF-α）或其他分子，这些分子激活成骨细胞、骨细胞或骨髓基质细胞中 RANKL 的表达。双膦酸盐或抗 RANKL 抗体药物的给药可抑制全身骨吸收，从而预防肿瘤浸润性骨溶解。然而，这些治疗剂可能会导致与药物相关的下颌骨坏死。在这项研究中，我们在破骨细胞前体细胞中发现了一条新的肿瘤相关破骨细胞发生途径。与人口腔鳞状细胞癌细胞 3A 或 NEM 共培养，或用人源化口腔鳞状细胞癌细胞的条件培养基培养，可诱导大量破骨细胞前体细胞生成破骨细胞，而这些细胞是通过 RANKL 或 TNF-α 的 24 小时预处理生成的。骨保护素，一种 RANKL 的诱饵受体，地舒单抗，一种抗 RANKL 抗体药物，和英夫利昔单抗，一种抗 TNF-α 抗体药物，并不能预防这种肿瘤相关的破骨细胞发生。定量 RT-PCR 分析表明，在这种肿瘤相关的破骨细胞发生中，NFATc1 的表达减少，这提示其可能独立于 NFATc1。这些结果揭示了一条新的肿瘤相关破骨细胞发生途径，它可能是一种新的治疗肿瘤浸润性骨溶解的靶点，而不会影响全身骨代谢。
