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：Roodman和Bellido 7.摘要 骨溶骨癌（OCIB）经常发生在癌症患者中，是降低骨密度的主要原因。 生存和生活质量。多发性骨髓瘤（MM）中OCIB引起的病理性骨折增加了其风险 与无骨折患者相比，死亡率>20%。此外，OCIB诱导严重的全身肌肉 功能障碍进一步负面地影响表现状态、生活质量和存活。虽然很多 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形成的贡献。 骨破坏过程中OCIB，骨细胞（Ots）的作用，最众多的细胞类型的骨骼 和骨重建的主要调节因子，是未知的。导致这一应用的研究表明，尽管 Ots存在于矿化基质深处，它们是OCIB效应的主要贡献者。MM细胞和Ots 在体内物理相互作用，这些相互作用激活双向Notch信号传导，驱动MM细胞 增殖和Ot凋亡，并增强Ots的破骨细胞生成能力。MM-Ot相互作用增加 RANKL、TNFα、cyclinD 1和Notch 1 -4受体在MM细胞中的表达，并上调RANKL和TNF α的表达。 骨形成抑制剂，硬化素，在Ots。我们的研究还表明，已知的MIP-1 β和HMGB 1 RANKL的刺激因子，也可能参与，因为MM衍生的MIP-1直接作用于增加酸- Ots诱导HMGB 1表达。此外，RANKL、MIP-1 β和HMGB 1驱动的骨吸收也可诱导骨吸收， 这项建议将测试的假设，MM-Ot的相互作用是主要的 通过增加肿瘤生长和骨吸收、减少骨质而导致OCIB 形成，并诱导肌肉功能障碍。这一假设将通过追求特定的目标来推进 其结合联合收割机体外、离体和体内方法，使用骨细胞系、真实骨细胞、人 和鼠MM细胞系，来源于患者的原代MM细胞，来自遗传修饰小鼠的骨，和 MM的小鼠模型Aim 1将使用以下方法确定双向MM/Ot Notch信号传导对OCIB的影响： 遗传和药理学工具干扰Notch激活。目标2将决定 MM和OT衍生的RANKL与OCIB的关系以及HMGB 1和MIP-1在RANKL调节中的作用。Aim 3将 确定MM/Ot相互作用诱导的硬化蛋白在肿瘤负荷、骨疾病和肌肉中的作用 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.