Osteolytic bone disease is a hallmark of multiple myeloma (MM). A significant fraction (~20%) of MM patients do not develop osteolytic lesions (OLs). The molecular basis for the absence of bone disease in MM is not understood. We combined PET-CT and gene expression profiling (GEP) of purified BM CD138⁺ MM cells from 512 newly diagnosed MM patients to reveal that elevated expression of cystatin M/E (CST6) was significantly associated with the absence of OL in MM. An enzyme-linked immunosorbent assay revealed a strong correlation between CST6 levels in BM serum/plasma and CST6 mRNA expression. Both recombinant CST6 protein and BM serum from patients with high CST6 significantly inhibited the activity of the osteoclast-specific protease cathepsin K and blocked osteoclast differentiation and function. Recombinant CST6 inhibited bone destruction in ex vivo and in vivo myeloma models. Single-cell RNA-Seq showed that CST6 attenuates polarization of monocytes to osteoclast precursors. Furthermore, CST6 protein blocks osteoclast differentiation by suppressing cathepsin-mediated cleavage of NF-κB/p100 and TRAF3 following RANKL stimulation. Secretion by MM cells of CST6, an inhibitor of osteoclast differentiation and function, suppresses osteolytic bone disease in MM and probably other diseases associated with osteoclast-mediated bone loss.

中文翻译：

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CST6 通过阻断破骨细胞分化抑制多发性骨髓瘤的溶骨性骨病

溶骨性骨病是多发性骨髓瘤 (MM) 的标志。很大一部分 (~20%) 的 MM 患者不会发生溶骨性病变 (OLs)。不了解 MM 中不存在骨病的分子基础。^{我们将来自 512 名新诊断的 MM 患者的纯化 BM CD138 +} MM 细胞的 PET-CT 和基因表达谱 (GEP) 相结合，以揭示胱抑素 M/E ( CST6 ) 表达升高与 MM 中缺乏 OL 显着相关。酶联免疫吸附试验显示 BM 血清/血浆中的 CST6 水平与CST6之间存在强相关性mRNA表达。来自高 CST6 患者的重组 CST6 蛋白和 BM 血清均显着抑制破骨细胞特异性蛋白酶组织蛋白酶 K 的活性并阻断破骨细胞分化和功能。重组 CST6 在离体和体内骨髓瘤模型中抑制骨破坏。单细胞 RNA-Seq 显示 CST6 减弱了单核细胞向破骨细胞前体的极化。此外，CST6 蛋白通过在 RANKL 刺激后抑制组织蛋白酶介导的 NF-κB/p100 和 TRAF3 裂解来阻断破骨细胞分化。MM 细胞分泌的 CST6 是一种破骨细胞分化和功能的抑制剂，可抑制 MM 中的溶骨性骨病以及可能与破骨细胞介导的骨丢失相关的其他疾病。