Adamik Juraj, Roodman G David, Galson Deborah L
Department of Medicine Division of Hematology/Oncology, UPMC Hillman Cancer Center, The McGowan Institute for Regenerative Medicine University of Pittsburgh Pittsburgh PA USA.
Department of Medicine Division of Hematology-Oncology Indiana University Indianapolis IN USA.
JBMR Plus. 2019 Mar 15;3(3):e10183. doi: 10.1002/jbm4.10183. eCollection 2019 Mar.
Multiple myeloma (MM) bone disease is characterized by the development of osteolytic lesions, which cause severe complications affecting the morbidity, mortality, and treatment of myeloma patients. Myeloma tumors seeded within the bone microenvironment promote hyperactivation of osteoclasts and suppression of osteoblast differentiation. Because of this prolonged suppression of bone marrow stromal cells' (BMSCs) differentiation into functioning osteoblasts, bone lesions in patients persist even in the absence of active disease. Current antiresorptive therapy provides insufficient bone anabolic effects to reliably repair MM lesions. It has become widely accepted that myeloma-exposed BMSCs have an altered phenotype with pro-inflammatory, immune-modulatory, anti-osteogenic, and pro-adipogenic properties. In this review, we focus on the role of epigenetic-based modalities in the establishment and maintenance of myeloma-induced suppression of osteogenic commitment of BMSCs. We will focus on recent studies demonstrating the involvement of chromatin-modifying enzymes in transcriptional repression of osteogenic genes in MM-BMSCs. We will further address the epigenetic plasticity in the differentiation commitment of osteoprogenitor cells and assess the involvement of chromatin modifiers in MSC-lineage switching from osteogenic to adipogenic in the context of the inflammatory myeloma microenvironment. Lastly, we will discuss the potential of employing small molecule epigenetic inhibitors currently used in the MM research as therapeutics and bone anabolic agents in the prevention or repair of osteolytic lesions in MM. © 2019 The Authors. published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
多发性骨髓瘤（MM）骨病的特征是溶骨性病变的发展，这会导致严重并发症，影响骨髓瘤患者的发病率、死亡率及治疗。植入骨微环境中的骨髓瘤肿瘤会促进破骨细胞的过度活化并抑制成骨细胞分化。由于骨髓基质细胞（BMSC）向功能性成骨细胞的分化受到长期抑制，即使在没有活动性疾病的情况下，患者的骨病变依然存在。目前的抗吸收疗法提供的骨合成代谢作用不足，无法可靠地修复MM病变。骨髓瘤暴露的BMSC具有改变的表型，具有促炎、免疫调节、抗成骨和促脂肪生成特性，这一点已被广泛接受。在本综述中，我们聚焦基于表观遗传学的方式在建立和维持骨髓瘤诱导的BMSC成骨定向抑制中的作用。我们将关注最近的研究，这些研究证明了染色质修饰酶参与MM - BMSC中成骨基因的转录抑制。我们还将进一步探讨骨祖细胞分化定向中的表观遗传可塑性，并评估在炎性骨髓瘤微环境中染色质修饰剂在MSC谱系从成骨向成脂转换中的作用。最后，我们将讨论在MM研究中目前用作治疗剂和骨合成代谢剂的小分子表观遗传抑制剂在预防或修复MM溶骨性病变中的潜力。© 2019作者。由Wiley Periodicals, Inc.代表美国骨与矿物质研究学会出版。
