Targeting bone homing of the MSCs to augment bone formation

靶向 MSC 的骨归巢以增强骨形成

• 批准号: 7891246
• 负责人: Wei Yao
• 金额: $ 13.63万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7891246
• 关键词: Affinity; Aging; Anabolic Agents; Animals; Antibodies; Apoptosis; Binding; Biotin; Bone Diseases; Bone Growth; Bone Marrow; Bone Regeneration; Bone Surface; Cell Count; Cell Line; Cell Proliferation; Cell-Matrix Junction; Cells; Collaborations; Cytoskeleton; Differentiation and Growth; Disease; Dose; Drug or chemical Tissue Distribution; Estrogens; Fluorescent Dyes; Fracture; Goals; Growth Factor; Health Care Costs; Home environment; Homing; Hour; Human; Hybrids; Immune; In Vitro; Incubated; Individual; Infusion procedures; Integrins; Laboratories; Lead; Libraries; Ligands; Link; Measures; Mechanics; Mesenchymal Stem Cells; Methods; Monitor; Mus; Nature; Oryctolagus cuniculus; Osteoblasts; Osteogenesis; Osteoporosis; Outcome Measure; Pharmaceutical Preparations; Research; Sampling; Skeleton; Solutions; Specificity; Stem cells; Surface; Testing; Therapeutic; Toxic effect; Tracer; Transplantation; Trauma; base; bisphosphonate; bone; bone loss; bone mass; bone strength; bone turnover; combinatorial; cost; high risk; in vivo; long bone; migration; molecular imaging; mouse model; novel; osteogenic; osteoporosis with pathological fracture; osteoprogenitor cell; primary outcome; progenitor; public health relevance; receptor; repaired; research study; response; secondary outcome; small molecule; stem cell population; stem cell therapy; substantia spongiosa

DESCRIPTION (provided by applicant): It is well known that osteoporosis is disease of increased bone fragility that results from estrogen deficiency and aging. A decrease in the number of mesenchymal stem cells (MSCs) in bone marrow with aging leads to reduced osteogenesis and thus reduces bone formation and increases bone fragility. Bone regeneration by the means of induction of osteogenesis from MSCs offers rational therapeutic implications. This approach is problematic due to the major obstacle of controlling the MSCs' commitment, growth and differentiation into functional osteoblasts on bone surface. The proposed research offers a solution to this issue. Recently our laboratory group used a combinatorial library method to identify a small molecule ligand, LLP2A, that specifically targets integrin 1421. This integrin is expressed in osteoblast progenitors and has the potential to direct the MSCs to the bone surface. We then chemically linked a bisphosphonate (a bone targeting agent) to LLP2A. This new hybrid drug, Bis-LLP2A, was found to concentrate in the bone surface. Based on these observations, we hypothesize that bone marrow progenitor cell (MSC) attachment and osteogenic differentiation would be achieved when they are "guided" to bone surface that is rich in extra cellular matrix and growth factors that are necessary for osteoblast maturation. We further hypothesize that if MSCs are guided to the bone surface, additional treatment with an anabolic agent, will augment the new bone formation and restore bone mass and bone strength. We have the following two specific aims to test our hypothesis: 1. To determine the specificity and efficacy of Bis-LLP2A for guiding MSCs to bone surface and enhancing bone formation. We will evaluate specificity and toxicity of the Bis-LLP2A to MSCs in vitro and in vivo. In addition, we will evaluate the efficacy of combination low-dose anabolic agents and Bis-LLP2A in the augmentation of bone formation in osteoporotic animals. 2.To determine the bone migration efficacy of Bis-LLP2A in homing of human MSCs in mice with severe osteoporosis. The proposal is high risk in nature but it is a critical "proof-of-concept" step before we move forward to pursue our ultimate goal, which is to screen highly specific ligand(s) for osteoprogenitors. The major obstacle for MSCs therapeutic application in bone diseases is that MSCs do not home to bone. We believe that our bisphosphonate-ligand conjugates can overcome this obstacle by guiding MSCs to the bone surface, which is the most critical step for MSC therapy in the enhancement of bone formation during bone growth, bone trauma repair and the treatment of osteoporosis. PUBLIC HEALTH RELEVANCE: Osteoporosis is disease characterized by progressive bone loss that predisposes bone to fracture. Mesenchymal stem cells (MSCs) in bone marrow are groups of cells that can differentiate into bone forming cells. However, direct infusions of MSCs failed to yield bone forming response due to the inability of MSCs migrate to the bone surface. We propose a novel method that can guide the MSCs to bone surface, which can provide novel treatment options for bone diseases such as osteoporosis and bone trauma repair.

描述（申请人提供）：众所周知，骨质疏松症是由于雌激素缺乏和衰老导致的骨质脆性增加的疾病。随着年龄的增长，骨髓中间充质干细胞（MSC）数量减少，导致骨生成减少，从而减少骨形成并增加骨脆性。通过间充质干细胞诱导成骨的方式进行骨再生提供了合理的治疗意义。由于控制 MSC 的定型、生长和分化为骨表面功能性成骨细胞的主要障碍，这种方法存在问题。拟议的研究为这个问题提供了解决方案。最近，我们的实验室小组使用组合文库方法鉴定了一种小分子配体 LLP2A，该配体专门针对整合素 1421。这种整合素在成骨细胞祖细胞中表达，具有将 MSC 引导至骨表面的潜力。然后，我们将双膦酸盐（一种骨靶向剂）与 LLP2A 进行化学连接。人们发现这种新的混合药物 Bis-LLP2A 集中在骨表面。基于这些观察，我们假设，当骨髓祖细胞（MSC）被“引导”到富含成骨细胞成熟所需的细胞外基质和生长因子的骨表面时，就会实现骨髓祖细胞（MSC）附着和成骨分化。我们进一步假设，如果间充质干细胞被引导到骨表面，用合成代谢剂进行额外治疗，将增强新骨形成并恢复骨量和骨强度。我们有以下两个具体目标来检验我们的假设： 1. 确定 Bis-LLP2A 引导 MSC 到达骨表面并增强骨形成的特异性和功效。我们将在体外和体内评估 Bis-LLP2A 对 MSC 的特异性和毒性。此外，我们将评估低剂量合成代谢药物和 Bis-LLP2A 组合在增强骨质疏松动物骨形成方面的功效。 2.测定Bis-LLP2A对重度骨质疏松小鼠体内人MSCs归巢的骨迁移功效。该提案本质上具有高风险，但在我们继续追求最终目标（即筛选骨祖细胞的高度特异性配体）之前，这是关键的“概念验证”步骤。间充质干细胞在骨疾病治疗应用的主要障碍是间充质干细胞不归巢于骨。我们相信，我们的双磷酸盐-配体缀合物可以通过引导间充质干细胞到达骨表面来克服这一障碍，这是间充质干细胞治疗在骨生长过程中增强骨形成、骨创伤修复和骨质疏松症治疗中最关键的步骤。公众健康相关性：骨质疏松症是一种以进行性骨质流失为特征的疾病，容易导致骨折。骨髓中的间充质干细胞（MSC）是一组可以分化为骨形成细胞的细胞。然而，由于间充质干细胞无法迁移到骨表面，直接输注间充质干细胞未能产生骨形成反应。我们提出了一种可以引导间充质干细胞到达骨表面的新方法，这可以为骨质疏松和骨创伤修复等骨疾病提供新的治疗选择。