Department of Orthopaedics and Traumatology, The Chinese University of Hong Kong, Hong Kong.
Institute for Tissue Engineering and Regenerative Medicine, The Chinese University of Hong Kong, Hong Kong.
J Orthop Res. 2020 Feb;38(2):297-310. doi: 10.1002/jor.24456. Epub 2019 Sep 11.
Giant cell tumor of bone (GCTB) is a locally aggressive destructive bone lesion. The management of pulmonary metastasis and local recurrence after the surgical treatment of GCTB remains a challenge. Pathologically, stromal cells in GCTB are known as primary neoplastic cells and are recognized as incompletely differentiated preosteoblasts. Therefore, inducing GCTB stromal cells to differentiate into cells with a mature osteoblastic phenotype may stop tumor growth and recurrence. In this study, we aimed to investigate how simvastatin, a clinically approved and commonly used statin that has been known to promote the maturation of cells of the osteogenic lineage, affects GCTB stromal cells. We found that simvastatin effectively inhibited cell viability by suppressing proliferation and by inducing apoptosis in GCTB stromal cells. Moreover, simvastatin treatment upregulated the expression of genes related to osteogenic maturation, such as runt-related transcription factor 2, osteopontin, and osteocalcin, and increased the mineralization of the extracellular matrix in GCTB stromal cells. Ingenuity pathway analysis was used to discover that the vitamin D receptor pathway was involved in the simvastatin-induced osteogenic differentiation of GCTB stromal cells by upregulating the 1,25-dihydroxyvitamin D metabolism. Taken together, this in vitro study demonstrates the antitumor and differentiation-promoting effects of simvastatin on GCTB stromal cells and suggests the possibility of using simvastatin as an adjuvant therapy for GCTB. These findings support further clinical investigation of the efficacy of using simvastatin as an adjuvant therapy for GCTB to reduce recurrence and distant metastasis after surgical treatment. © 2019 Orthopedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:297-310, 2020.
骨巨细胞瘤（GCTB）是一种局部侵袭性破坏性骨病变。对于 GCTB 手术后的肺转移和局部复发的治疗仍然是一个挑战。从病理上看，GCTB 中的基质细胞被认为是原发性肿瘤细胞，被认为是不完全分化的前成骨细胞。因此，诱导 GCTB 基质细胞分化为具有成熟成骨表型的细胞可能会阻止肿瘤的生长和复发。在这项研究中，我们旨在研究临床上已被批准并常用于促进成骨谱系细胞成熟的他汀类药物辛伐他汀如何影响 GCTB 基质细胞。我们发现辛伐他汀通过抑制 GCTB 基质细胞的增殖和诱导细胞凋亡，有效地抑制了细胞活力。此外，辛伐他汀处理上调了与成骨成熟相关的基因的表达，如 runt 相关转录因子 2、骨桥蛋白和骨钙素，并增加了 GCTB 基质细胞细胞外基质的矿化。通过上调 1,25-二羟维生素 D 代谢，使用 Ingenuity 通路分析发现维生素 D 受体通路参与了辛伐他汀诱导的 GCTB 基质细胞成骨分化。总之，这项体外研究表明辛伐他汀对 GCTB 基质细胞具有抗肿瘤和促进分化的作用，并提示使用辛伐他汀作为 GCTB 的辅助治疗的可能性，以减少手术后的复发和远处转移。这些发现支持进一步研究辛伐他汀作为 GCTB 辅助治疗的疗效，以减少手术后的复发和远处转移。
