Division of Orthopedic Surgery, Niigata University Graduate School of Medical and Dental Sciences.
Department of Orthopedic Surgery, Uonuma Kikan Hospital.
Tohoku J Exp Med. 2019 Jun;248(2):87-97. doi: 10.1620/tjem.248.87.
Bone and soft tissue tumors are derived from mesenchymal cells, and they are hard to treat. Receptor-activator of nuclear factor-kappa B ligand (RANKL) is an essential cytokine for osteoclast differentiation and activation and is expressed on the surface of osteoblasts or stromal cells. In this study, to explore the potential of denosumab treatment for soft tissue tumors, we analyzed the expression profiles of RANKL mRNA in 425 tumor specimens of 33 histological types by real-time RT-PCR. Denosumab is a monoclonal antibody that prevents the binding of RANKL to receptor-activator of nuclear factor-kappa B (RANK). For comparison, the relative expression levels of RANK and osteoprotegerin (OPG) mRNAs were also measured. OPG functions as a soluble decoy receptor for RANKL. Higher expression levels of RANKL mRNA were detected in calcifying aponeurotic fibroma, fibrosarcoma, calcifying epithelioma, myositis ossificans, heterotopic calcification, giant cell tumor of the tendon sheath (GCTTS), and pigmented villonodular synovitis (PVNS), compared with the levels of other tumor types. Moreover, the expression levels of RANK mRNA were highest in GCTTS, followed by myositis ossificans and PVNS, whereas the expression levels of OPG mRNA were greatly varied among these histological types. We then analyzed RANKL protein expression by immunohistochemistry in 57 tumor specimens with higher expression levels of RANKL mRNA. RANKL-positive cells were detected in GCTTS, PVNS, myositis ossificans, heterotopic calcification, and calcifying aponeurotic fibroma. In conclusion, RANKL is expressed in subsets of soft tissue tumors with calcification, and denosumab is a potential therapeutic option for soft tissue tumors expressing RANKL.
骨和软组织肿瘤来源于间充质细胞，难以治疗。核因子-κB 受体激活剂配体（RANKL）是破骨细胞分化和激活所必需的细胞因子，表达于成骨细胞或基质细胞表面。在这项研究中，为了探索地舒单抗治疗软组织肿瘤的潜力，我们通过实时 RT-PCR 分析了 33 种组织学类型的 425 个肿瘤标本中 RANKL mRNA 的表达谱。地舒单抗是一种单克隆抗体，可阻止 RANKL 与核因子-κB 受体激活剂（RANK）结合。为了进行比较，还测量了 RANK 和骨保护素（OPG）mRNA 的相对表达水平。OPG 作为 RANKL 的可溶性诱饵受体发挥作用。在钙化性肌腱膜纤维瘤、纤维肉瘤、钙化性上皮瘤、骨化性肌炎、异位钙化、腱鞘巨细胞瘤（GCTTS）和色素绒毛结节性滑膜炎（PVNS）中检测到 RANKL mRNA 的表达水平高于其他肿瘤类型。此外，GCTTS 中 RANK mRNA 的表达水平最高，其次是骨化性肌炎和 PVNS，而 OPG mRNA 的表达水平在这些组织学类型中差异很大。然后，我们通过免疫组织化学分析了 57 个 RANKL mRNA 表达水平较高的肿瘤标本中的 RANKL 蛋白表达。在 GCTTS、PVNS、骨化性肌炎、异位钙化和钙化性肌腱膜纤维瘤中检测到 RANKL 阳性细胞。总之，RANKL 在具有钙化的软组织肿瘤亚群中表达，地舒单抗是表达 RANKL 的软组织肿瘤的潜在治疗选择。
