Contribution of Osteocytes to the Musculoskeletal Effects of Multiple Myeloma

骨细胞在多发性骨髓瘤肌肉骨骼效应中的作用 MPI：鲁德曼和贝利多 7.摘要 骨中溶骨性癌症(OCIB)常见于癌症患者，是导致骨量减少的主要原因之一。 生存和生活质量。OCIB在多发性骨髓瘤(MM)中引起的病理性骨折增加了他们的风险 与没有骨折的患者相比，死亡率为20%。此外，OCIB还诱导了严重的全身肌肉 功能障碍进一步对表现状态、生活质量和生存产生负面影响。虽然很多都是 已知肿瘤细胞、破骨细胞、成骨细胞、基质细胞和免疫细胞对 骨破坏过程中骨细胞(OTS)的作用，骨细胞是骨骼中数量最多的细胞类型 以及骨重建的主要调节因素，目前尚不清楚。导致这一应用的研究表明，尽管 OTS赋存于矿化基质深处，是OCIB效应的主要贡献者。MM细胞和OTS 体内的物理相互作用，这些相互作用激活双向Notch信号驱动MM细胞 促进OTS的增殖和OT的凋亡，增强OTS的破骨细胞分化潜能。MM-OT互动增加 RANKL、肿瘤坏死因子α、细胞周期蛋白D1和Notch1-4受体在MM细胞中的表达，并上调RANKL和 骨形成抑制剂，硬化素，在OTS中。我们的研究还表明，已知的MIP-1和HMGB1 也可能涉及RANKL的刺激物，因为MM来源的MIP-1直接作用于增加胃酸-1。 OTS诱导HMGB1。此外，RANKL、MIP-1和HMGB1也可诱导骨吸收 MM的肌肉功能障碍这一建议将检验MM-OT相互作用是主要的假说 OCIB的贡献者通过增加肿瘤生长和骨吸收，减少骨 形成，并导致肌肉功能障碍。这一假设将通过追求特定的目标来提出。 结合了体外、体外和体内的方法，使用骨细胞系、真实的骨细胞、人类 和小鼠MM细胞系，来自患者的原代MM细胞，来自转基因小鼠的骨骼，以及 MM.Aim 1小鼠模型将确定双向MM/OT Notch信号对OCIB的影响 干扰Notch激活的遗传和药理工具。目标2将确定以下方面的贡献 MM和OT来源的RANKL到OCIB以及HMGB1和MIP1在RANKL调节中的作用。而《目标3》将 确定MM/OT相互作用诱导的硬化素在肿瘤负担、骨病和肌肉中的作用 OCIB引起的功能障碍。

Contribution of Osteocytes to the Musculoskeletal Effects of Multiple Myeloma MPI: Roodman and Bellido 7. Abstract Osteolytic cancer in bone (OCIB) occurs frequently in cancer patients and is a major contributor to decreased survival and quality of life. Pathologic fractures caused by OCIB in multiple myeloma (MM) increases their risk of death >20% compared to patients without fractures. In addition, OCIB induced severe systemic muscle dysfunction further negatively impacting the performance status, quality of life, and survival. Although much is known about the contribution of tumor cells, osteoclasts, osteoblasts, stroma cells, and immune cells to the bone destructive process in OCIB, the role of osteocytes (Ots), the most numerous cell type in the skeleton and major regulators of bone remodeling, is unknown. Studies leading to this application showed that, although Ots reside deep in mineralized matrix, they are major contributors to the effects of OCIB. MM cells and Ots physically interact in vivo, and these interactions activate bidirectional Notch signaling driving MM cell proliferation and Ot apoptosis, and enhance the osteoclastogenic potential of Ots. MM-Ot interactions increase RANKL, TNFα, cyclinD1 and Notch1-4 receptor expression in MM cells, and upregulate RANKL and the inhibitor of bone formation, sclerostin, in Ots. Our studies also suggest that MIP-1 and HMGB1, known stimulators of RANKL, may also be involved because MM-derived MIP-1 acts directly to increase acid- induced HMGB1 by Ots. Further, RANKL, MIP-1 and HMGB1-driven bone resorption could also induce muscle dysfunction in MM. This proposal will test the hypothesis that MM-Ot interactions are major contributors to OCIB through increasing tumor growth and bone resorption, decreasing bone formation, and inducing muscle dysfunction. This hypothesis will be advanced by pursuing specific aims that combine in vitro, ex vivo and in vivo approaches, using osteocytic cell lines, authentic osteocytes, human and murine MM cells lines, primary MM cells derived from patients, bones from genetically modified mice, and a mouse model of MM. Aim 1 will determine the impact of bidirectional MM/Ot Notch signaling on OCIB using genetic and pharmacological tools that interfere with Notch activation. Aim 2 will determine the contribution of MM- and Ot-derived RANKL to OCIB and the role of HMGB1 and MIP-1 in RANKL regulation. And Aim 3 will determine the role of sclerostin induced by MM/Ot interactions in tumor burden, bone disease, and muscle dysfunction induced by OCIB.