Extracellular matrix glycoprotein Reelin is associated with tumor metastasis and prognosis in various malignancies. However, its effects on multiple myeloma (MM) are not fully understood. Here, we investigated the regulatory effects of Reelin on MM and its underlying pathogenic mechanisms. Lentivirus plasmid containing short hairpin RNA targeting Reelin (LV3-Reln) was transfected into SP2/0 cells to knockdown Reelin expression. Flow cytometry assay analyzed cell cycle and apoptosis while Transwell assay evaluated invasiveness. BALB/c mice were inoculated with LV3-Reln-transfected SP2/0 cells to establish MM model. Primary myeloma cells and osteoblasts/osteoclast were isolated from tumor tissue and limb long bones respectively. ELISA examined serum biomarkers and immunohistochemistry detected immunoglobulin light chain expression. Morphological changes and osteoclast/osteoblast differentiation were observed by histological staining. mRNA and proteins expression were determined by qPCR and WB. In vitro studies showed that Reelin depletion regulated osteolysis and osteogenesis balance, cell cycle, invasiveness, and apoptosis in SP2/0 cells. In LV3-Reln mice, tumor growth and invasiveness were suppressed, meanwhile, reduced osteoclast activation and enhanced osteoblast activity were observed. Reelin knockdown alleviated extramedullary morbidity and inhibited spleen immune cell apoptosis by down-regulating CDK5, IL-10, and Cyto-C expression. Furthermore, reduced Reelin expression restrained osteoclast differentiation while promoted osteogenesis in the bone of LV3-Reln mice. This was further supported by down-regulation of osteolytic specific mRNAs and proteins (Trap, Mmp9, Ctsk, Clcn7) and up-regulation of osteogenic specific ones (COL-1, Runx2, β-Catenin). Reelin exerted important impacts on myeloma development through rebalancing osteolysis and osteogenesis, thus might be a potential therapeutic target for MM.

细胞外基质糖蛋白 Reelin 与多种恶性肿瘤的肿瘤转移和预后相关。然而，其对多发性骨髓瘤 (MM) 的影响尚不完全清楚。在这里，我们研究了 Reelin 对 MM 的调节作用及其潜在的致病机制。将含有靶向 Reelin 的短发夹 RNA (LV3-Reln) 的慢病毒质粒转染到 SP2/0 细胞中以抑制 Reelin 表达。流式细胞术分析细胞周期和细胞凋亡，而 Transwell 分析评估侵袭性。BALB/c小鼠接种LV3-Reln转染的SP2/0细胞，建立MM模型。分别从肿瘤组织和四肢长骨中分离出原代骨髓瘤细胞和成骨细胞/破骨细胞。ELISA 检查血清生物标志物，免疫组织化学检测免疫球蛋白轻链表达。通过组织学染色观察形态学变化和破骨细胞/成骨细胞分化。通过 qPCR 和 WB 确定 mRNA 和蛋白质表达。体外研究表明，Reelin 耗竭调节 SP2/0 细胞的骨溶解和成骨平衡、细胞周期、侵袭性和细胞凋亡。在 LV3-Reln 小鼠中，肿瘤生长和侵袭性受到抑制，同时观察到破骨细胞活化减少和成骨细胞活性增强。Reelin 敲低通过下调 CDK5、IL-10 和 Cyto-C 表达减轻髓外发病率并抑制脾免疫细胞凋亡。此外，降低的 Reelin 表达抑制了破骨细胞分化，同时促进了 LV3-Reln 小鼠骨骼的成骨。溶骨特异性 mRNA 和蛋白质（Trap、Mmp9、Ctsk, Clcn7) 和成骨特异性的上调 (COL-1, Runx2, β-Catenin)。Reelin 通过重新平衡骨溶解和成骨对骨髓瘤的发展产生重要影响，因此可能是 MM 的潜在治疗靶点。