Bidirectional Notch Signaling and Osteocyte-Derived Factors in the Bone Marrow Microenvironment Promote Tumor Cell Proliferation and Bone Destruction in Multiple Myeloma.
Bidirectional Notch Signaling and Osteocyte-Derived Factors in the Bone Marrow Microenvironment Promote Tumor Cell Proliferation and Bone Destruction in Multiple Myeloma.
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DOI：
10.1158/0008-5472.can-15-1703
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发表时间：
2016-03-01
期刊：
影响因子：
11.2
通讯作者：
Bellido T
中科院分区：
文献类型：
--
作者：
Delgado-Calle J;Anderson J;Cregor MD;Hiasa M;Chirgwin JM;Carlesso N;Yoneda T;Mohammad KS;Plotkin LI;Roodman GD;Bellido T
在多发性骨髓瘤（MM）中，由于骨吸收增加和骨形成抑制，骨髓中单克隆浆细胞数量增加会诱导很少愈合的局部溶骨性病变。许多研究报道了MM微环境中不同细胞类型对MM生长和骨病的贡献，但基质包埋的骨细胞在MM中的作用尚不清楚，其占骨细胞的95%以上，是破骨细胞和成骨细胞活性的主要调节因子。我们报告，在MM承载骨的骨细胞在体内与MM细胞发生物理相互作用，经历半胱天冬酶3依赖性凋亡，并表达更高的RANKL和Sclerostin水平比对照小鼠的骨细胞。机制研究表明，骨细胞凋亡是通过与MM细胞直接接触激活骨细胞中的Notch信号而启动的，并被MM细胞分泌的TNFα进一步放大。这种Notch/TNFα诱导的骨细胞凋亡增加了骨细胞Rankl表达、骨细胞Rankl/Opg比率和骨细胞吸引破骨细胞前体的能力，从而诱导局部骨吸收。此外，与MM细胞接触的骨细胞表达高水平的Sost/Sclerostin，其降低成骨细胞中的Wnt信号传导并抑制成骨细胞分化。重要的是，骨细胞和MM细胞之间的直接接触可激活Notch信号传导并增加MM细胞中的Notch受体表达，特别是Notch 3和4，并刺激MM细胞生长。这些研究揭示了MM细胞和骨细胞之间的双向Notch信号传导的先前未知作用，其增强MM生长和骨疾病，并表明靶向骨细胞-MM细胞相互作用作为新型MM治疗的潜力。
In multiple myeloma (MM) increased numbers of monoclonal plasma cells in the bone marrow induce localized osteolytic lesions that rarely heal, due to increased bone resorption and suppressed bone formation. Numerous studies reported the contributions that different cell types in the MM microenvironment make to MM growth and bone disease, but the role of matrix-embedded osteocytes in MM, which comprise >95% of bone cells and are major regulators of osteoclast and osteoblast activity, is unclear. We report that osteocytes in MM-bearing bones physically interact with MM cells in vivo, undergo caspase3-dependent apoptosis, and express higher RANKL and Sclerostin levels than osteocytes from control mice. Mechanistic studies revealed that osteocyte apoptosis is initiated by activation of Notch signaling in osteocytes through direct contact with MM cells, and is further amplified by MM cell-secreted TNFα. This Notch/TNFα induced osteocyte apoptosis increases osteocytic Rankl expression, the osteocytic Rankl/Opg ratio and the ability of osteocytes to attract osteoclast precursors to induce local bone resorption. Further, osteocytes in contact with MM cells express high levels of Sost/Sclerostin that decrease Wnt signaling in osteoblasts and inhibit osteoblast differentiation. Importantly, direct contact between osteocytes and MM cells reciprocally activates Notch signaling and increases Notch receptor expression in MM cells, in particular Notch3 and 4, and stimulates MM cell growth. These studies reveal a previously unknown role for bidirectional Notch signaling between MM cells and osteocytes that enhances MM growth and bone disease, and suggest the potential of targeting osteocyte-MM cell interactions as a novel MM treatment.