Role of integrin VLA-6 in suppression of bone formation in myeloma

整合素VLA-6在抑制骨髓瘤骨形成中的作用

• 批准号: 9206148
• 负责人: Jing Yang
• 金额: $ 37.02万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-01 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9206148
• 关键词: Adipocytes; Alpha Cell; Antibodies; Antigens; Area; Binding; Bone Diseases; Bone Marrow; Bone Resorption; Caring; Cell Adhesion Molecules; Cell Differentiation process; Cell surface; Cells; Clinical; Clonal Expansion; Coculture Techniques; Defect; Deposition; Development; Diabetes Mellitus; Disease; Equilibrium; Foundations; Goals; In Vitro; Injectable; Integrin alpha6; Integrin alpha6beta1; Integrins; Knowledge; Lesion; Ligands; MAP Kinase Gene; MAPK14 gene; Malignant - descriptor; Mediating; Mesenchymal Stem Cells; Metastatic breast cancer; Multiple Myeloma; Mus; Newly Diagnosed; Non-Malignant; Obesity; Osteoblasts; Osteoclasts; Osteogenesis; Patients; Plasma Cells; Quality of life; Role; Signal Pathway; Signaling Molecule; Site; Testing; Therapeutic; Work; adipocyte differentiation; beta catenin; bone; clinically relevant; effective therapy; healing; improved; innovation; lipid biosynthesis; novel; novel strategies; osteoblast differentiation; palliative; public health relevance; tumor

 DESCRIPTION (provided by applicant): The goal of this project is to investigate the mechanism by which myeloma cells alter the balance of adipogenesis and osteoblastogenesis, thereby suppressing bone formation. Multiple myeloma is characterized by a clonal expansion of malignant plasma cells. Bone destruction is a hallmark of this disease, and has a severe impact on patients' quality of life and survival. Unfortunately, current treatment only offers moderate palliative effects, and bone disease associated with myeloma remains incurable. The bone changes in myeloma patients results from increased osteoclast-mediated bone resorption and decreased osteoblast-mediated bone formation. In particular, new bone formation that usually occurs at sites of previously resorbed bones is deeply suppressed; as a result areas of bone destruction rarely heal. Previous studies have shown that myeloma cells inhibit osteoblast differentiation from mesenchymal stem cells (MSCs) by myeloma cells produce dickkopf-1, which can suppress Wnt/beta-catenin signaling pathway. However, the role of dickkopf-1 in suppressed bone formation remains controversial, because myeloma cells alone do not produce sufficient dickkopf-1 to suppress osteoblast differentiation, and administration of anti-dickkopf-1 antibody in patients failed to completely restore new bone formation, indicating there must be an additional mechanism for inhibition of osteoblast differentiation seen in myeloma. We observed that myeloma patients and myeloma-bearing mice had not only decreased osteoblastic deposits but also increased adipocytic deposits in bone marrow. In vitro co-culture of MSCs with myeloma cells not only inhibited osteoblast but also enhanced adipocyte differentiation. We further identified that integrin alpha-6 in myeloma cells is a novel factor to regulate adipocyte and osteoblast differentiation. Alpha-6 can bind with alpha-1 to form the integrin very late antigen-6, a cell surface heterodimer highly expressed in myeloma cells. We observed that p38 MAPK, a signaling pathway that is shown to inhibit osteoblastogenesis, upregulated alpha-6 expression. Blocking alpha-6 by an antibody significantly reduced adipocyte but enhanced osteoblast differentiation. We therefore hypothesize that myeloma cell alpha-6 enhances adipocyte differentiation, as a result less MSC differentiation into osteoblasts and less new bone formation. We propose to determine the role and mechanism of alpha-6 in adipogenesis and osteoblastogenesis, and develop the novel strategies to enhance bone formation by targeting alpha-6 and the related signaling molecules. The knowledge gained with the successful completion of the proposed work will provide a rationale for a therapeutic to enhance bone formation, filling in the defects caused by myeloma-induced osteoclast-mediated resorption. Of equal importance, as the increased adipocytic deposit is also found in bone marrow of patients with bone-metastatic breast cancer and non-malignant diabetes mellitus and obesity, the proposed work may have direct relevance to reduced bone formation observed in these diseases, and targeting alpha-6 may prove to be a novel approach in treating these patients also.

 描述（由申请人提供）：该项目的目标是研究骨髓瘤细胞改变脂肪生成和成骨细胞生成的平衡，从而抑制骨形成的机制。多发性骨髓瘤的特征是恶性浆细胞的克隆扩增。骨质破坏是这种疾病的标志，严重影响患者的生活质量和生存。不幸的是，目前的治疗只能提供中等的姑息作用，与骨髓瘤相关的骨病仍然无法治愈。骨髓瘤患者的骨变化是由于破骨细胞介导的骨吸收增加和成骨细胞介导的骨形成减少所致。特别是，通常发生在先前吸收的骨骼部位的新骨形成受到深度抑制；因此，骨质破坏的区域很少愈合。既往研究表明，骨髓瘤细胞通过产生dickkopf-1来抑制间充质干细胞（MSCs）向成骨细胞分化，该信号通路可抑制Wnt/β-catenin信号通路。然而，dickkopf-1 在抑制骨形成中的作用仍然存在争议，因为单独的骨髓瘤细胞不能产生足够的 dickkopf-1 来抑制成骨细胞分化，并且给予抗 dickkopf-1 患者体内的抗体未能完全恢复新骨形成，这表明在骨髓瘤中一定存在抑制成骨细胞分化的额外机制。我们观察到，骨髓瘤患者和携带骨髓瘤的小鼠不仅骨髓中的成骨细胞沉积减少，而且骨髓中的脂肪细胞沉积增加。间充质干细胞与骨髓瘤细胞的体外共培养不仅抑制成骨细胞，而且增强脂肪细胞分化。我们进一步发现骨髓瘤细胞中的整合素α-6是调节脂肪细胞和成骨细胞分化的新因子。 Alpha-6 可以与 alpha-1 结合形成整合素极晚期抗原 6，这是一种在骨髓瘤细胞中高度表达的细胞表面异二聚体。我们观察到 p38 MAPK（一种抑制成骨细胞生成的信号通路）上调 alpha-6 表达。用抗体阻断 alpha-6 显着减少脂肪细胞，但增强成骨细胞分化。因此，我们假设骨髓瘤细胞 α-6 增强脂肪细胞分化，从而减少 MSC 分化为成骨细胞和减少新骨形成。我们建议确定α-6在脂肪生成和成骨细胞生成中的作用和机制，并开发通过靶向α-6和相关信号分子来增强骨形成的新策略。成功完成拟议工作所获得的知识将为增强骨形成的治疗提供理论依据，填补由骨髓瘤诱导的破骨细胞介导的吸收引起的缺陷。同样重要的是，由于骨转移性乳腺癌、非恶性糖尿病和肥胖症患者的骨髓中也发现脂肪细胞沉积增加，因此拟议的工作可能与这些疾病中观察到的骨形成减少直接相关，并且靶向α-6也可能被证明是治疗这些患者的一种新方法。