Common mechanisms of Osteoarthritis in three mouse models

三种小鼠模型骨关节炎的共同机制

• 批准号: 8074680
• 负责人: ROBERT E SEEGMILLER
• 金额: $ 4.97万
• 依托单位: BRIGHAM YOUNG UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-27 至 2010-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8074680
• 关键词: Animal Model; Animals; Antibodies; Apoptosis; Appearance; Area; Biological Markers; Cartilage; Cartilage Matrix; Cells; Chondrocytes; Chronic; Collagen; Collagen Gene; Degenerative polyarthritis; Development; Electron Microscopy; Endoplasmic Reticulum; Exhibits; Fibrillar Collagen; Future; Goals; Heterozygote; Histocytochemistry; Histologic; Human; Immunohistochemistry; Inflammation; Investigation; Joints; Knee; Knee joint; Light; Modeling; Molecular; Mouse Strains; Mus; Mutant Strains Mice; Mutation; Osteoarthrosis Deformans; Pathogenesis; Pathway interactions; Pattern; Pharmaceutical Preparations; Phase; Phenotype; Proteins; Spondyloepiphyseal Dysplasia; Staging; Stromelysin 1; Study models; Temporomandibular Joint; Testing; Therapeutic Intervention; Universities; aggrecanase; articular cartilage; biological adaptation to stress; cartilage development; chondrodysplasia; collagenase 3; disability; disease diagnosis; early onset; endoplasmic reticulum stress; gene therapy; insight; mRNA Transcript Degradation; macromolecule; molecular marker; mouse model; mutant; premature; public health relevance; research study; response; skeletal; skeletal dysplasia; success

DESCRIPTION (provided by applicant): Degeneration of synovial joint cartilage in the form of osteoarthritis (OA) is one of the leading causes of chronic disability, yet the molecular pathogenesis of OA is poorly understood. Therefore, the development and study of appropriate animal models is needed. The Disproportionate micromelia (Dmm) and spondyloepiphyseal dysplasia congenita (sedc) mouse strains are the result of mutations in the type II fibrillar collagen gene, whereas the chondrodysplasia (cho) mouse strain is the result of a mutation in the type XI fibrillar collagen gene, and all three are characterized by skeletal dysplasia. Though they result from different classes of mutations and have different skeletal phenotypes, all three mutants exhibit similar early-onset degeneration of knee-joint cartilage. Accordingly, we hypothesize that murine OA proceeds through common pathological pathways even though the degeneration may be initiated by different types of insults. To test this hypothesis and to identify the biomolecular changes that are coincident with OA and common to these three murine models, the following specific aims are proposed: 1) to characterize OA in sedc knee and temporomandibular joint (TMJ) articular cartilage histologically and ultrastructurally; 2) to identify common patterns of articular cartilage degeneration leading to OA in both knee and TMJ of the three mutants using biomarkers of cartilage degeneration and chondrocyte apoptosis; and 3) to determine whether the Dmm, sedc, and cho mutations cause ER stress that is severe enough to trigger the unfolded protein response (UPR) in developing articular cartilage, and whether that UPR activates inflammation or apoptosis pathways. Histochemistry will detect qualitative changes in cartilage matrix macromolecules, and immunohistochemistry will document the appearance of OA biomarkers (DDR-2, MMP-3, MMP-13, COL2-3/4m antibody, NITEGE and VDIPEN) and programmed cell death, all in relation to initiation of histopathological changes. Evidence of an ER stress response in the heterozygotes of these mutants would suggest that unfolded proteins are being retained in the cells and that continuous ER stress during cartilage development may contribute to the early-onset OA phenotype. This observation would thus become a new area of investigation in OA. Identification of changes that are common to all three mouse models will be the key to our success. These putative universal pathological pathways may represent new targets for therapeutic intervention and molecular markers for diagnosis of disease. PUBLIC HEALTH RELEVANCE: This study in three murine models will provide biomolecular insight into the pathogenesis of OA and pave the way for future investigations into the use of various drug and gene-based therapies.

描述（由申请人提供）：骨关节炎（OA）形式的滑膜关节软骨退行性变是慢性残疾的主要原因之一，然而OA的分子发病机制尚不清楚。因此，需要开发和研究合适的动物模型。不成比例小畸形（Dmm）和先天性脊柱骺发育不良（sedc）小鼠品系是II型纤维胶原基因突变的结果，而软骨发育不良（cho）小鼠品系是XI型纤维胶原基因突变的结果，这三种小鼠品系都以骨骼发育不良为特征。虽然它们由不同类型的突变引起，具有不同的骨骼表型，但所有三种突变都表现出类似的膝关节软骨早发性变性。因此，我们假设小鼠OA通过共同的病理途径进行，即使变性可能由不同类型的损伤引起。为了验证这一假设，并确定与OA一致的生物分子变化和这三种小鼠模型的共同之处，我们提出了以下具体目标：1)从组织学和超微结构上表征膝关节和颞下颌关节软骨的OA；2)利用软骨退变和软骨细胞凋亡的生物标志物，鉴定三种突变体导致双膝和TMJ骨性关节炎的关节软骨退变的共同模式；3)确定Dmm、sedc和cho突变是否引起内质网应激，其严重程度足以触发关节软骨发育中的未折叠蛋白反应（UPR），以及UPR是否激活炎症或凋亡途径。组织化学将检测软骨基质大分子的质变，免疫组织化学将记录OA生物标志物（DDR-2、MMP-3、MMP-13、COL2-3/4m抗体、NITEGE和VDIPEN）和程序性细胞死亡的出现，所有这些都与组织病理学改变的开始有关。在这些突变体的杂合子中，内质网应激反应的证据表明未折叠的蛋白质被保留在细胞中，并且在软骨发育过程中持续的内质网应激可能有助于早发性OA表型。因此，这一观察结果将成为OA研究的一个新领域。识别所有三种小鼠模型的共同变化将是我们成功的关键。这些假定的普遍病理途径可能是治疗干预的新靶点和疾病诊断的分子标记。公共卫生相关性：这项对三种小鼠模型的研究将为OA的发病机制提供生物分子视角，并为未来研究各种药物和基因治疗铺平道路。