Multiple myeloma (MM) bone disease is a significant cause of morbidity but there is a paucity of data on the impact of malignant plasma cells on adjacent trabecular bone within the BM. Here, we characterize the proteome of trabecular bone tissue from BM biopsies of 56 patients with monoclonal gammopathy of undetermined significance (MGUS), smoldering (SMM), newly diagnosed (NDMM), relapsed MM (RMM), and normal controls. Proteins involved in extracellular matrix (ECM) formation and immunity pathways were decreased in SMM and active MM. Among the proteins most decreased were immunoglobulins, type IV collagen, and TIMP3, suggesting increased immunoparesis and decreased ECM remodelling within trabecular bone. Proteins most increased in SMM/MM were APP (enhances osteoclast activity), ENPP1 (enhances bone mineralization), and MZB1 (required for normal plasmablast differentiation). Pathway analyses showed that proteins involved in gamma -carboxylation, a pathway implicated in osteocalcin function, osteoblast differentiation, and normal hematopoiesis, were also overexpressed in SMM/MM. This study is the first comprehensive proteomic atlas of the BM bone proteome in dysproteinemias. We identify new key proteins and pathways for MM bone disease and potentially impaired hematopoiesis, and show for the first time that gamma -carboxylation pathways are increased in the bone tissue of SMM/MM.
多发性骨髓瘤（MM）骨病是导致发病的重要因素，但关于恶性浆细胞对骨髓内邻近骨小梁影响的数据尚显不足。本研究通过分析56例意义未明的单克隆丙种球蛋白病（MGUS）、冒烟型骨髓瘤（SMM）、新诊断骨髓瘤（NDMM）、复发骨髓瘤（RMM）患者及正常对照者的骨髓活检骨小梁组织蛋白质组，发现SMM和活动期MM患者中参与细胞外基质（ECM）形成与免疫通路的蛋白质表达下降。下降最显著的蛋白质包括免疫球蛋白、IV型胶原蛋白及TIMP3，提示骨小梁内免疫麻痹加剧且ECM重塑能力减弱。而在SMM/MM中上调最明显的蛋白质为APP（增强破骨细胞活性）、ENPP1（促进骨矿化）和MZB1（正常浆母细胞分化必需因子）。通路分析显示，参与γ-羧化通路的蛋白质（该通路与骨钙素功能、成骨细胞分化及正常造血相关）在SMM/MM中同样过表达。本研究首次构建了异常蛋白血症中骨髓骨组织蛋白质组的完整图谱，不仅确定了MM骨病及潜在造血功能障碍的新关键蛋白与通路，更首次揭示SMM/MM骨组织中γ-羧化通路活性增强。
An atlas of the bone marrow bone proteome in patients with dysproteinemias
肿瘤(癌症)患者之家