Ho Matthew, Dasari Surendra, Visram Alissa, Drake Matthew, Charlesworth Cristine, Johnson Kenneth, Pujari Ganesh, Jevremovic Dragan, Kourelis Taxiarchis
Mayo Clinic.
Mayo Clinic Rochester, MN, USA.
Res Sq. 2023 Jan 23:rs.3.rs-2468383. doi: 10.21203/rs.3.rs-2468383/v1.
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）骨病是发病的一个重要原因，但关于恶性浆细胞对骨髓内相邻小梁骨的影响的数据却很匮乏。在此，我们对56例意义未明的单克隆丙种球蛋白病（MGUS）、冒烟型（SMM）、新诊断（NDMM）、复发型MM（RMM）患者以及正常对照者的骨髓活检小梁骨组织的蛋白质组进行了特征分析。参与细胞外基质（ECM）形成和免疫途径的蛋白质在SMM和活动性MM中减少。减少最为明显的蛋白质包括免疫球蛋白、IV型胶原和TIMP3，这表明小梁骨内免疫球蛋白缺乏增加且ECM重塑减少。SMM/MM中增加最为明显的蛋白质是APP（增强破骨细胞活性）、ENPP1（增强骨矿化）和MZB1（正常成浆细胞分化所必需）。通路分析表明，参与γ-羧化作用（一种与骨钙素功能、成骨细胞分化和正常造血相关的通路）的蛋白质在SMM/MM中也过表达。本研究是第一份关于蛋白异常血症中骨髓骨蛋白质组的全面蛋白质组图谱。我们确定了MM骨病和潜在造血功能受损的新关键蛋白质和通路，并首次表明γ-羧化途径在SMM/MM的骨组织中增加。
