Common mechanisms of Osteoarthritis in three mouse models

描述（由申请人提供）：以骨关节炎（OA）形式出现的滑膜关节软骨退化是慢性残疾的主要原因之一，但对OA的分子发病机制知之甚少。因此，需要开发和研究合适的动物模型。不成比例的小肢畸形（Dmm）和先天性脊椎骨骺发育不良（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，所有三种小鼠的特征都是骨骼发育不良。虽然它们是由不同类型的突变引起的，并且具有不同的骨骼表型，但所有三种突变体都表现出相似的膝关节软骨早发性退化。因此，我们假设小鼠OA通过共同的病理途径进行，即使退化可能是由不同类型的侮辱。为了验证这一假设，并确定与OA一致的生物分子变化，并在这三种小鼠模型中共有，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（TMJ）关节软骨中的OA;（二）使用软骨变性的生物标志物鉴定导致三种突变体的膝关节和TMJ中的OA的关节软骨变性的共同模式和软骨细胞凋亡;和3）确定Dmm、sedc和cho突变是否引起严重到足以在发育中的关节软骨中触发未折叠蛋白质应答（UPR）的ER应激，以及该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定性变化，免疫组织化学将记录OA生物标志物（DDR-2、MMP-3、MMP-13、COL 2 -3/4 m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变化的开始有关。这些突变体的杂合子中的ER应激反应的证据表明，未折叠的蛋白质被保留在细胞中，并且软骨发育期间的持续ER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通路可能代表用于治疗干预的新靶点和用于疾病诊断的分子标记物。 公共卫生相关性：这项研究在三个小鼠模型将提供生物分子洞察OA的发病机制，并铺平了道路，为未来的调查使用各种药物和基因为基础的治疗。

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.