The Role of Creb5 in Maintaining Synovial Joint Homeostasis

Creb5 在维持滑膜关节稳态中的作用

• 批准号: 10517751
• 负责人: Andrew Bruce Lassar
• 金额: $ 70.39万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-28 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10517751
• 关键词: 3' Untranslated Regions; Address; Adult; Aging; Animals; Arthritis; Attenuated; Cattle; Cells; Chondrocytes; Competence; DNA Binding Domain; Degenerative polyarthritis; Development; Ectopic Expression; Embryo; Engineering; Enhancers; Environment; Epidermal Growth Factor Receptor; Epiphysial cartilage; Event; Exons; Failure; Fibroblasts; Friction; Genes; Genetic Recombination; Genetic Transcription; Goals; Hallmark Cell; Health; Homeostasis; Human; In Vitro; Injury; Joints; Knee; Knee joint; LoxP-flanked allele; Maintenance; Mechanics; Mediating; Meniscus structure of joint; Mus; Natural regeneration; Operative Surgical Procedures; Patients; Play; Proteins; Proteoglycan; Rattus; Rheumatoid Arthritis; Role; Sheep; Signal Pathway; Signal Transduction; Surface; Synovial Cell; Synovial Fluid; Synovial joint; Tissues; Transforming Growth Factor Beta 2; Transforming Growth Factor beta; Work; aged; articular cartilage; cartilage degradation; in vivo; insight; joint injury; lubricin; mouse model; novel; programs; protein expression; response; stem cell population; tissue regeneration; transcription factor

Project Summary/Abstract. The broad, long-term goal of this project is to develop a comprehensive understanding of the regulatory network that regulates the differentiation and maintenance of articular cartilage, which plays a central role in maintaining the low-friction environment of the joint space. Indeed, a hallmark of cells comprising the articular cartilage is their expression of proteoglycans, such as the protein lubricin, encoded by the Prg4 gene, that lubricates the joint and protects against the development of arthritis. Prg4 is specifically expressed in the superficial-most layer of the articular cartilage. Findings by both the Lassar lab and others have established that Prg4-expressing cells in the superficial zone of articular cartilage (in embryonic and early post-natal mice) serve as a stem cell population for all deeper regions of the articular cartilage in the adult. Furthermore, in both humans and mice lacking Prg4 (which encodes lubricin), the surface of the articular cartilage becomes damaged and precocious joint failure occurs. Notably, decreased levels of lubricin have been observed following surgically induced osteoarthritis in sheep, and in synovial fluid from patients with either osteoarthritis or rheumatoid arthritis. Furthermore, a decrease in lubricin expression during aging, correlates with increasing sensitivity of aged knees to cartilage degradation. Thus, a key objective of the Lassar lab has been to identify tissue-specific transcription factors that regulate the expression of both Prg4 and other genes that are specifically expressed in the superficial zone of the articular cartilage. Recent findings in the Lassar lab indicate that the transcription factor Creb5 is uniquely expressed in superficial zone articular chondrocytes (as opposed to both deeper zone articular chondrocytes and growth plate chondrocytes) and is a crucial regulator of Prg4 expression. Most notably, ectopic expression of Creb5 in deep zone bovine articular chondrocytes (which do not expression Prg4) enabled TGF-b2 and EGFR signals to induce Prg4 expression in these cells, to a level equal to that expressed by superficial zone articular chondrocytes. These findings suggest that Creb5 establishes a competent state in chondrocytes to express Prg4 in response to these signaling pathways. In addition, the Lassar lab has found that mice engineered to lack functional Creb5 fail to form many synovial joints. Taken together, these findings indicate that Creb5 plays a critical role in both the formation of synovial joints and is a both a novel and crucial regulator of Prg4/lubricin expression in articular chondrocytes. This project will determine the role of Creb5 in maintaining the health of all tissues in the mature synovial joint; will determine whether expression of Creb5 in either articular chondrocytes or synovial fibroblasts is attenuated during aging or during osteoarthritis; and finally will determine whether sustained expression of exogenous Creb5 in the synovial joint can boost lubricin expression and block degradation of this tissue either during aging or in a murine model for post-traumatic osteoarthritis.

项目概要/摘要。 本项目的广泛、长期目标是全面了解监管网络 调节关节软骨的分化和维持，关节软骨在维持关节软骨中起着核心作用。 关节空间的低摩擦环境。事实上，构成关节软骨的细胞的标志是 它们表达蛋白聚糖，例如由Prg 4基因编码的润滑蛋白，其润滑细胞， 关节和防止关节炎的发展。Prg 4特异性表达于表皮-最 关节软骨层。Lassar实验室和其他人的研究结果已经确定，表达Prg 4的细胞可能是一种细胞因子。 关节软骨表面区域的细胞（在胚胎和出生后早期的小鼠中）作为干细胞 成人关节软骨的所有较深区域。此外，在人类和小鼠中， 缺乏Prg 4（编码润滑素），关节软骨的表面会受损和早熟 发生关节失效。值得注意的是，在手术诱导后观察到润滑素水平降低， 绵羊骨关节炎以及骨关节炎或类风湿性关节炎患者的滑液中。 此外，老化过程中润滑素表达的减少与老年膝关节敏感性的增加相关。 导致软骨退化因此，Lassar实验室的一个关键目标是确定组织特异性转录 调节Prg 4和其他基因表达的因子，这些基因特异性地表达在表皮细胞中， 关节软骨区。Lassar实验室的最新发现表明，转录因子Creb 5是一种 在浅区关节软骨细胞中唯一表达（与深区关节软骨细胞和深区关节软骨细胞相反， 软骨细胞和生长板软骨细胞），并且是Prg 4表达的关键调节剂。最明显的是， Creb 5在深层牛关节软骨细胞（不表达Prg 4）中的表达使TGF-β 2 EGFR信号诱导Prg 4在这些细胞中表达，达到与表浅区表达的水平相等的水平 关节软骨细胞。这些发现表明，Creb 5在软骨细胞中建立了一种能力状态， 表达Prg 4以响应这些信号通路。此外，拉萨尔实验室发现， 缺乏功能性Creb 5不能形成许多滑膜关节。综上所述，这些发现表明Creb 5 在滑膜关节的形成中起着关键作用，并且是一种新的和关键的调节剂， 关节软骨细胞中Prg 4/润滑素的表达。该项目将确定Creb 5在维护 成熟滑膜关节中所有组织的健康状况;将决定Creb 5在 关节软骨细胞或滑膜成纤维细胞在老化或骨关节炎期间衰减;并且最终将 确定外源性Creb 5在滑膜关节中的持续表达是否可以促进润滑素表达 并在老化过程中或在创伤后骨关节炎的小鼠模型中阻断该组织的降解。