Elucidation of mechanisms governing the activities of synovial fibroblasts

项目总结 成纤维细胞样滑膜细胞分布在关节的滑膜表面。他们在这一过程中扮演着关键角色 维持关节健康和关节炎疾病的病理学。我们的数据表明SOXC 一组转录因子在实现成纤维细胞的病理特性方面起着关键作用- 就像滑膜细胞一样。SOXC蛋白先前被证明对间充质细胞的生存至关重要 以及在胚胎中产生多种身体结构的神经前体细胞，包括 骨骼、心脏和神经系统。研究还表明，它们还能促进生物的扩散、迁移和 多种癌细胞的侵袭性。我们的初步结果表明，SoxC基因 有助于关节炎疾病中成纤维细胞样滑膜细胞的侵袭性癌细胞样行为。 该项目的主要假设是SOXC蛋白在细胞内的生物活性 成纤维细胞样滑膜细胞在炎症介导的滑膜变性中起重要作用 关节软骨和骨骼在关节炎及相关关节疾病中的作用。我们的首要目标是确定 SoxC基因是否参与了基因表达和细胞行为的调控 炎症压力下的成纤维细胞样滑膜细胞。然后我们将调查 调控成纤维细胞样中SOXC蛋白活性的上游分子机制 滑膜细胞。接下来，我们将测试阻断SOXC蛋白在成纤维细胞样滑膜细胞中的功能 减少关节炎疾病中的关节退行性变。我们预计，我们的新发现将导致更多 对成纤维样滑膜细胞在关节病理中的分子调控有深刻的认识。 这些新的发现可能会影响滑膜成纤维细胞新的、成功的策略的设计。 骨性关节炎和类风湿患者的基础关节修复和再生治疗 关节炎。

PROJECT SUMMARY Fibroblast-like synoviocytes populate the synovial surfaces of the joints. They have critical roles in the maintenance of joint health and in the pathology of arthritic diseases. Our data suggest that the SOXC group of transcription factors are key players in implementing the pathological properties of fibroblast- like synoviocytes. SOXC proteins were previously shown to be critical for the survival of mesenchymal and neural progenitor cells that give rise in the embryo to multiple body structures, including the skeleton, heart, and nervous system. They were also shown to promote the proliferation, migration and invasive properties of many types of cancer cells. Our preliminary results suggest that SoxC genes contribute to the aggressive cancer cell-like behavior of fibroblast-like synoviocytes in arthritic diseases. The overarching hypothesis of this project is that the biological activities of SOXC proteins in the fibroblast-like synoviocytes significantly contribute to the inflammation-mediated degeneration of articular cartilage and bones in arthritis and related joint diseases. Our primary goal is to determine whether the SoxC genes are involved in regulation of gene expression and cellular behavior of fibroblast-like synoviocytes that are under the stress of inflammation. We will then investigate the upstream molecular mechanisms that regulate the activities of SOXC proteins in fibroblast-like synoviocytes. Next, we will test whether blocking SOXC protein functions in fibroblast-like synoviocytes reduces joint degeneration in arthritic diseases. We anticipate that our new findings will lead to a more profound understanding of the molecular regulation of fibroblast-like synoviocytes in joint pathologies. These new findings will likely impact the design of new, successful strategies for synovial fibroblast- based joint repair and regeneration therapies for patients suffering from osteoarthritis and rheumatoid arthritis.