Multiple myeloma is a plasma cell malignancy that thrives in the bone marrow (BM), with frequent progression to new local and distant bone sites. Our previous studies demonstrated that multiple myeloma cells at primary sites secrete soluble factors and suppress osteoblastogenesis via the inhibition of Runt-related transcription factor 2 (Runx2) in pre- and immature osteoblasts (OB) in new bone sites, prior to the arrival of metastatic tumor cells. However, it is unknown whether OB-Runx2 suppression in new bone sites feeds back to promote multiple myeloma dissemination to and progression in these areas. Hence, we developed a syngeneic mouse model of multiple myeloma in which Runx2 is specifically deleted in the immature OBs of C57BL6/KaLwRij mice (OB-Runx2-/- mice) to study the effect of OB-Runx2 deficiency on multiple myeloma progression in new bone sites. In vivo studies with this model demonstrated that OB-Runx2 deficiency attracts multiple myeloma cells and promotes multiple myeloma tumor growth in bone. Mechanistic studies further revealed that OB-Runx2 deficiency induces an immunosuppressive microenvironment in BM that is marked by an increase in the concentration and activation of myeloid-derived suppressor cells (MDSC) and the suppression and exhaustion of cytotoxic CD8+ T cells. In contrast, MDSC depletion by either gemcitabine or 5-fluorouracil treatment in OB-Runx2-/- mice prevented these effects and inhibited multiple myeloma tumor growth in BM. These novel discoveries demonstrate that OB-Runx2 deficiency in new bone sites promotes multiple myeloma dissemination and progression by increasing metastatic cytokines and MDSCs in BM and inhibiting BM immunity. Importantly, MDSC depletion can block multiple myeloma progression promoted by OB-Runx2 deficiency.Significance: This study demonstrates that Runx2 deficiency in immature osteoblasts at distant bone sites attracts myeloma cells and allows myeloma progression in new bone sites via OB-secreted metastatic cytokines and MDSC-mediated suppression of bone marrow immunity.

中文翻译：

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成骨细胞中Runx2缺乏症通过改变新骨位点的骨微环境来促进骨髓瘤的进展。

多发性骨髓瘤是浆细胞恶性肿瘤，在骨髓（BM）中壮成长，并经常进展至新的局部和远处骨部位。我们以前的研究表明，在转移灶到来之前，多个骨髓瘤细胞在原发部位和未成熟成骨细胞（OB）中通过抑制Runt相关转录因子2（Runx2）分泌可溶性因子并抑制成骨细胞生成。肿瘤细胞。但是，尚不清楚OB-Runx2在新骨部位的抑制是否会反馈促进多发性骨髓瘤向这些区域扩散并在这些区域发展。因此，我们开发了一种多发性骨髓瘤的同系小鼠模型，其中在C57BL6 / KaLwRij小鼠（OB-Runx2-/-小鼠）的未成熟OB中特异删除了Runx2，以研究OB-Runx2缺乏对新骨骼部位多发性骨髓瘤进展的影响。用此模型进行的体内研究表明，OB-Runx2缺乏症会吸引多发性骨髓瘤细胞，并促进骨骼中多发性骨髓瘤肿瘤的生长。机理研究进一步揭示，OB-Runx2缺乏会诱导BM产生免疫抑制微环境，其特征是髓样衍生抑制细胞（MDSC）的浓度和激活增加以及细胞毒性CD8 + T细胞的抑制和耗尽。相反，在OB-Runx2-/-小鼠中通过吉西他滨或5-氟尿嘧啶治疗的MDSC耗竭阻止了这些作用并抑制了BM中多发性骨髓瘤肿瘤的生长。这些新发现表明，新骨骼部位的OB-Runx2缺乏症通过增加BM中的转移性细胞因子和MDSC并抑制BM免疫力，促进了多发性骨髓瘤的传播和进展。重要的是，MDSC耗竭可以阻止由OB-Runx2缺乏促进的多发性骨髓瘤进展。意义：这项研究表明，远处骨部位未成熟成骨细胞的Runx2缺乏会吸引骨髓瘤细胞，并通过OB分泌的转移性细胞因子和MDSC允许新骨部位的骨髓瘤进展。介导的骨髓免疫抑制作用。这些新发现表明，新骨骼部位的OB-Runx2缺乏症通过增加BM中的转移性细胞因子和MDSC并抑制BM免疫力，促进了多发性骨髓瘤的传播和进展。重要的是，MDSC耗竭可以阻止由OB-Runx2缺乏促进的多发性骨髓瘤进展。意义：这项研究表明，远处骨部位未成熟成骨细胞的Runx2缺乏会吸引骨髓瘤细胞，并通过OB分泌的转移性细胞因子和MDSC允许新骨部位的骨髓瘤进展。介导的骨髓免疫抑制作用。这些新发现表明，新骨骼部位的OB-Runx2缺乏症通过增加BM中的转移性细胞因子和MDSC并抑制BM免疫力，促进了多发性骨髓瘤的传播和进展。重要的是，MDSC耗竭可以阻止由OB-Runx2缺乏促进的多发性骨髓瘤进展。意义：这项研究表明，远处骨部位未成熟成骨细胞的Runx2缺乏会吸引骨髓瘤细胞，并通过OB分泌的转移性细胞因子和MDSC允许新骨部位的骨髓瘤进展。介导的骨髓免疫抑制作用。