Pathogenesis of Osteoarthritis

骨关节炎的发病机制

• 批准号: 7592484
• 负责人: Joy Blair
• 金额: $ 52.78万
• 依托单位: NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7592484
• 关键词: Adhesions; Adult; Affect; Age; Aging; Alleles; American; Animal Model; Arthritis; Biological Markers; Bone Density; Bone Injury; Bone and Cartilage Funding; Bone callus; Bone remodeling; Cartilage; Cell Communication; Cell Shape; Cell-Matrix Junction; Cells; Cessation of life; Chondrocytes; Collagen Type I; Degenerative polyarthritis; Development; Disease; Disease Progression; Early Diagnosis; Environment; Evaluation; Event; Exercise; Extracellular Matrix; Failure; Fibronectins; Functional disorder; Future; Gene Mutation; Genetic; Glycoproteins; Goals; Growth; Image; Imaging Techniques; Injury; Inorganic Sulfates; Invasive; Joints; Kidney; Knee; Knee Osteoarthritis; Knock-in Mouse; Knock-out; Knockout Mice; Lead; Lesion; Longitudinal Studies; Lymphocyte; Magnetic Resonance Imaging; Measurement; Mechanics; Metabolism; Minerals; Modality; Modeling; Mus; Mutation; Natural regeneration; Nervous system structure; Normal tissue morphology; Osteoblasts; Osteocalcin; Osteogenesis; Osteogenesis Imperfecta; Oxygen measurement, partial pressure, arterial; Pathogenesis; Pathway interactions; Placenta; Play; Population; Prevalence; Prevention strategy; Process; Production; Proteins; Rate; Role; Serum; Severity of illness; Signal Transduction; Site; Specimen; Staging; Staining method; Stains; Standards of Weights and Measures; Stimulus; Stress; Surface; Symptoms; Tissue Banks; Tissues; Today; United States National Institutes of Health; Unspecified or Sulfate Ion Sulfates; Ursidae Family; Uterus; Weight-Bearing state; age related; articular cartilage; bone; bone cell; cartilage cell; cell type; design; embryo tissue; extracellular; insight; macrophage; mouse model; nonhuman primate; osteopontin; primitive cell; promoter; response; shear stress

Osteoarthritis is a disease of aging and is directly related to the stresses of weight bearing, mechanical overuse or injury to the joint. Both joint space cartilage and the subchondral bone are implicated in the disease process. The role of the bone in initiating and/or propagating this process is not clearly understood. More than thirty years ago, it was proposed that changes in bone might be the predisposing event leading to the development of osteoarthritis. Today, although it is recognized that bony changes are a prominent feature of OA, we remain uncertain of causal relationship to this disease. In osteoarthritis, it is believed that the bone immediately below the articular cartilage (the subchondral bone) is prone to stress injury, which leads to microcracks in the bone. These microcracks may lead to the death of bone cells, and the initiation of the bone remodeling process. This bone remodeling results in the formation of bony over-growth in the form of mineralized callus at the bone injury site. These calluses increase the bone volume and stiffness, when compared to normal tissue. We have undertaken three projects to gain insight into the pathogenesis of osteoarthritis. In the first project, we utilized an animal model of osteogenesis imperfecta. Osteogenesis imperfecta (OI) comprises a variety of genetic lesions that result in brittle bones. In many cases, the disease is due mutations of the gene encoding type I collagen. We have employed a knock-in murine model for OI that carries a typical OI mutation in type I collagen under the control of the endogenous promoter. This mouse is termed the Brittle (Brtl) mouse, which bears a gly349cys substitution in one col1a1 alleles. We assessed the development of osteoarthritis in these mice and determined that there is increased rate of development of osteoarthritis in these mice. We used a combination of standard histological assessments as well as more sophisticated imaging techniques. The results indicate that abnormalities in subchondral bone appear to promote the development of osteoarthritis. In the second project, we investigated the role of Osteopontin (OPN) in the pathogenesis of osteoarthritis. OPN a specialized protein (phosphorylated and sulphated glycoprotein). It can be found in a variety of tissues; e.g., bone forming cells, primitive cells from the uterus, placenta, kidney, and nervous system. It has also been found in activated macrophage and lymphocytes. OPN plays an important role in bone formation. It is believed that OPN in bone send signals to the cells in response to mechanical stimuli. In the embryonic tissue, OPN is detected in the bone-forming and cartilage cells. It is usually absent in normal healthy adult cartilage. However, in osteoarthritis, OPN is present in the cartilage and its presence increases with the severity of the disease. It can also be found in the bone forming cells (osteoblasts) of the subchondral bone. OPN production by the bone remodeling cells plays an important role in new bone formation. OPN's role may be to facilitate cell attachment to the mineral component of the bone.It also interacts with other bone forming components like type I collagen, osteocalcin, and fibronectin. Mechanical forces stimulate OPN production by acting on the cell to produce shear stress at its adhesion site. This stress transmits a signal to the cell, resulting in OPN production. The final result is a change in the shape of the cell and how it responds to (or interacts with) its environment. We used OPN knockout mouse model to examine the role of cartilage and bone forming cells in modulating the development of exercise-induced OA. We hypothesized that the OPN-deficient (OPN -/-) mouse may be an ideal model to study chondrocyte viability in articular cartilage, and the role of the subchondral bone alterations in knee osteoarthritis. This study is still underway. Cartilage is a very specialized tissue containing only one cell type, the chondrocyte. Chondrocyte metabolism and function are influenced by the composition of the extracellular environment (Oxygen tension, pH, ionic concentration), the extracellular matrix composition, the matrix-cell interactions and the physical signals (stress and stain) transmitted across the articular surfaces of the joint. The failure of cartilage to regenerate itself is believed to be one of the fundamental pathways in the pathophysiology of degenerative osteoarthritis. The goals of this project are to determine the utility of non-invasive imaging techniques for early detection and longitudinal progression of age-related degenerative joint disease in a non-human primate model for spontaneous osteoarthritis; and to examine the reparative potential of chondrocytes taken from aging non-human primates at various stages of joint degeneration. Non-human primate knees have been collected from the NIH tissue bank and the specimens have been imaged by micro-CT and micro-MRI. These results indicate that micro-MRI and micro-CT can be used to detect early degenerative changes in nonhuman primate knee articular cartilage and subchondral bone respectively. These imaging modalities are also valuable in the long-term studies of the rate of disease progression, to quantify joint destruction, osteophyte formation and changes in bone mineral density in the non-human primate model for spontaneous OA. During the past year, we have concentrated our efforts towards determining the volume of knee articular cartilage in the aging nonhuman primate knee, and to correlate these findings with the respective subchondral bone mineral density. Our future goal is to complete the evaluation of the above studies, and to correlate our findings with quantitative measurements of serum biomarkers. These studies are also underway.

骨关节炎是一种衰老疾病，与负重轴承，机械过度使用或关节受伤的应力直接相关。关节空调和软骨下骨都与疾病过程有关。 骨骼在启动和/或传播这一过程中的作用尚不清楚。三十多年前，有人提出骨骼的变化可能是导致骨关节炎发展的诱发事件。如今，尽管人们认识到骨变化是OA的重要特征，但我们仍然不确定与这种疾病的因果关系。 在骨关节炎中，人们认为关节软骨下方（软骨下骨）的骨头容易受到应力损伤，这会导致骨骼中的微裂纹。这些微裂纹可能导致骨细胞死亡，并开始骨骼重塑过程。这种骨骼重塑导致在骨损伤部位以矿化愈伤组织的形式形成骨过度生长。与正常组织相比，这些老茧会增加骨头的体积和刚度。 我们已经进行了三个项目，以深入了解骨关节炎的发病机理。 在第一个项目中，我们利用了成骨的动物模型。 成骨不完美（OI）包括多种导致骨骼脆弱的遗传病变。 在许多情况下，这种疾病是应有的基因编码I型胶原蛋白的突变。 我们采用了OI的敲入鼠模型，该模型在内源性启动子的控制下携带I型胶原蛋白的典型OI突变。该小鼠被称为脆性（BRTL）小鼠，该小鼠在一个Col1a1等位基因中带有Gly349Cys的替代。 我们评估了这些小鼠中骨关节炎的发展，并确定这些小鼠的骨关节炎发育率增加。 我们结合了标准的组织学评估以及更复杂的成像技术。结果表明，软骨下骨异常似乎促进了骨关节炎的发展。 在第二个项目中，我们研究了骨桥蛋白（OPN）在骨关节炎发病机理中的作用。 OPN专门的蛋白质（磷酸化和硫酸糖蛋白）。它可以在多种组织中找到。例如，骨形成细胞，子宫，胎盘，肾脏和神经系统的原始细胞。在活化的巨噬细胞和淋巴细胞中也发现了它。 OPN在骨形成中起重要作用。据信，骨骼中的OPN响应机械刺激而向细胞发送信号。在胚胎组织中，在骨形成和软骨细胞中检测到OPN。通常在正常健康的成人软骨中不存在。但是，在骨关节炎中，软骨存在OPN，其存在随着疾病的严重程度而增加。它也可以在软骨下骨的骨形成细胞（成骨细胞）中找到。 骨骼重塑细胞的OPN产生在新骨形成中起重要作用。 OPN的作用可能是促进细胞附着骨的矿物质成分。它还与其他骨形成成分（如I型胶原蛋白，骨钙素和纤连蛋白）相互作用。机械力通过在细胞上作用以在其粘附部位产生剪切应力来刺激OPN产生。这种应力将信号传输到细胞，从而导致OPN产生。最终结果是细胞形状的变化及其对其环境的反应（或与之相互作用）。 我们使用OPN敲除小鼠模型来检查软骨和骨形成细胞在调节运动引起的OA发展中的作用。 我们假设OPN缺陷型（OPN - / - ）小鼠可能是研究关节软骨中软骨细胞生存力的理想模型，以及膝盖骨关节炎的软骨下骨改变的作用。 这项研究仍在进行中。 软骨是一种非常专业的组织，仅包含一种细胞类型，即软骨细胞。软骨细胞的代谢和功能受细胞外环境（氧张力，pH，离子浓度）的组成影响，细胞外基质组成，基质细胞相互作用以及物理信号（应力和污渍）跨关节的关节表面传播。 软骨无法再生本身的失败被认为是退化性骨关节炎病理生理学中的基本途径之一。 该项目的目标是确定非侵入性成像技术在非人类灵长类动物模型中对年龄相关的退行性关节疾病的早期检测和纵向进展的实用性；并检查在关节变性的各个阶段，从衰老的非人类灵长类动物中获得的软骨细胞的修复潜力。已经从NIH组织库收集了非人类灵长类的膝盖，并且标本是由Micro-CT和Micro-MRI成像的。这些结果表明，微MRI和微CT可用于检测非人类灵长类动物膝关节软骨和软骨下骨的早期退化性变化。这些成像方式在对疾病进展速率的长期研究中也很有价值，以量化无人类灵长类动物模型的自发OA的关节破坏，骨属植物的形成和骨矿物质密度的变化。在过去的一年中，我们集中精力确定衰老的非人类灵长类动物膝关节膝关节软骨的体积，并将这些发现与各自的软骨下骨矿物质密度相关联。我们的未来目标是完成对上述研究的评估，并将我们的发现与血清生物标志物的定量测量相关联。 这些研究也在进行中。