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）：本项目的目的是研究骨髓瘤细胞改变脂肪生成和成骨细胞生成平衡，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性扩增。骨质破坏是这种疾病的一个标志，严重影响患者的生活质量和生存率。不幸的是，目前的治疗只能提供中等的姑息治疗效果，与骨髓瘤相关的骨疾病仍然无法治愈。骨髓瘤患者的骨骼变化是由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引起的。特别是，通常发生在先前吸收骨的部位的新骨形成被深深抑制;因此，骨破坏的区域很少愈合。已有研究表明，骨髓瘤细胞通过产生dickkopf-1抑制间充质干细胞（MSCs）向成骨细胞分化，dickkopf-1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，并且施用抗dickkopf-1抗体， 在骨髓瘤患者中，抗体未能完全恢复新骨形成，表明骨髓瘤中观察到的成骨细胞分化抑制一定存在另外的机制。我们观察到骨髓瘤患者和骨髓瘤小鼠骨髓中不仅成骨细胞沉积减少，而且脂肪细胞沉积增加。骨髓瘤细胞与骨髓间充质干细胞体外共培养不仅抑制了成骨细胞的分化，而且促进了脂肪细胞的分化。我们进一步确定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。α-6可以与α-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源二聚体。我们观察到，p38 MAPK，一种抑制成骨细胞生成的信号通路，上调α-6表达。阻断α-6抗体显着减少脂肪细胞，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，结果MSC分化成成骨细胞较少，新骨形成较少。本研究旨在明确α-6在脂肪和成骨细胞形成中的作用和机制，并通过靶向α-6及其相关信号分子来开发促进骨形成的新策略。成功完成所提出的工作所获得的知识将为增强骨形成的治疗提供理论基础，填补骨髓瘤诱导的破骨细胞介导的再吸收引起的缺陷。同样重要的是，由于在骨转移性乳腺癌和非恶性糖尿病和肥胖症患者的骨髓中也发现了增加的脂肪细胞存款，因此所提出的工作可能与在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新方法。