Analysis of functional disturbance of chondroctyes in oseoarthritis and establishment of new therapeutic strategies for the disease.

骨关节炎软骨细胞功能紊乱分析及该病新治疗策略的建立。

• 批准号: 15390467
• 负责人: FUKUI Naoshi
• 金额: $ 9.41万
• 依托单位: Clinical Research Center, National Hospital Organization Sagamihara Hospital
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-15390467/
• 关键词: Osteoarthritis; Laser Capture Microdissection; mRNA; real time PCR; Cartilage matrix; Chondrocyte; レーザー・マイクロダイセクション; 定量的PCR; lysyl oxidase; 細胞外基質; II型コラーゲン; IX型コラーゲン; XI型コラーゲン; cDNAマイクロアレイ; 定量的RT-PCR; レーザーマイクロダイセクション; II形コラーゲン; アグリカン

In this research project, we employed a technique of laser microdissection on osteoarthritic (OA) and normal cartilage and performed a detailed analysis on the functional alteration of chondrocyte with the disease. The findings obtained in this project are summarized below.1.In OA cartilage, chondrocytes undergo a certain phenotypic change at the surface of degenerated areas, and the profile of matrix gene expression is altered. In those areas, the expression of cartilage matrix genes such as COL2A1 and aggrecan is suppressed, and instead, the expression of pathologically induced genes, such as COL3A1 and fibronectin, is enhanced. The change or the shift in the pattern of matrix gene expression might promote matrix loss in those areas by replacing the matrix with that of a poorer quality. Assuming this to be true, it might be possible that the progression of OA could be slowed down through the normalization of cellular functions at the surface of degenerated cartilage.2.To date, no clear explanation has been give to the contradiction in the pathology of OA that the cartilage matrix is gradually lost in spite of enhanced matrix synthesis. The result of this project revealed, for the first time, that the synthetic activity by chondrocytes could be significantly impaired thorough the loss of balance in the expression of collagen genes. Even in macroscopically intact areas in OA cartilage, the expression of type IX and type XI collagen genes was relatively reduced compared with that of type II collagen. Based on the findings of human hereditary diseases and gene-manipulated mice, the reduction of these minor collagens could lead to the deterioration of cartilage matrix quality. Thus, from current results, the loss of cartilage matrix in OA could be enhanced through the disturbed matrix synthesis in OA chondrodytes.Thus, the result of this project has revealed novel, important mechanisms in the pathology of OA.

本研究采用激光显微解剖技术对骨性关节炎(OA)和正常软骨进行显微解剖，并对其软骨细胞的功能变化进行了详细的分析。本课题的研究结果总结如下：1.在骨性关节炎软骨中，软骨细胞在退化区的表面发生了一定的表型变化，基质基因的表达谱发生了改变。在这些区域，软骨基质基因如COL2A1和aggrecan的表达受到抑制，相反，病理诱导的基因如COL3A1和纤维连接蛋白的表达增强。基质基因表达模式的改变或转变可能通过用质量较差的基质取代这些区域的基质而促进这些区域的基质丢失。假设这是真的，有可能通过退变软骨表面细胞功能的正常化来减缓OA的进展。2.到目前为止，尽管软骨基质合成增强，但OA病理上的矛盾仍未得到明确的解释。该项目的结果首次揭示，软骨细胞的合成活性可能会通过胶原基因表达的失衡而显著受损。即使在大体完好的骨性关节炎软骨组织中，IX型和XI型胶原基因的表达也比II型胶原相对减少。根据人类遗传性疾病和基因操纵小鼠的研究结果，这些微小胶原蛋白的减少可能会导致软骨基质质量的恶化。因此，从目前的研究结果来看，骨性关节炎软骨基质的丢失可能通过骨性关节炎软骨基质合成的紊乱而增加，从而揭示了骨性关节炎发病机制中新的、重要的机制。

项目成果

Identification of alternatively spliced variant of Ca^<2+>-promoted Ras inactivator as possible regulator of RANKL shedding.

鉴定Ca^2-促进的Ras灭活剂的可变剪接变体作为RANKL脱落的可能调节剂。

• 发表时间: 2005
• 期刊: J Biol Chem 280
• 作者: Hikita A;Tanaka S;et al.
• 通讯作者: et al.

Identification of an alternatively spliced variant of Ca2+-promoted Ras inactivator as a possible regulator of RANKL shedding

• DOI: 10.1074/jbc.m507000200
• 发表时间: 2005-12-16
• 期刊: JOURNAL OF BIOLOGICAL CHEMISTRY
• 影响因子: 4.8
• 作者: Hikita, A;Kadono, Y;Tanaka, S
• 通讯作者: Tanaka, S

Effect of GDF-5 on ligament healing

• DOI: 10.1002/jor.20002
• 发表时间: 2006-01-01
• 期刊: JOURNAL OF ORTHOPAEDIC RESEARCH
• 影响因子: 2.8
• 作者: Tashiro, T;Hiraoka, H;Fukui, N
• 通讯作者: Fukui, N

Production of interleukin-6 and interleukin-8 by nurse-like cells from rheumatoid arthritis patients after simulation with monocytes.

用单核细胞模拟后，类风湿关节炎患者的护士样细胞产生白细胞介素 6 和白细胞介素 8。

• 发表时间: 2005
• 期刊: Mod Rheumatol 15
• 作者: Tanaka K;Fukui N;et al.
• 通讯作者: et al.

Production of interleukin-6 and interleukin-8 by nurse-like cells from rheumatoid arthritis patients after stimulation with monocytes.

类风湿性关节炎患者的护士样细胞在单核细胞刺激后产生白细胞介素 6 和白细胞介素 8。

• 发表时间: 2006
• 期刊: Mod Rheumatol. 15
• 作者: Tanaka K;Mori T;Juji T;Suzuki S;Watanabe J;Goto A;Shiobara N;Yamane S;Fukui N;Suzuki R;Ochi T
• 通讯作者: Ochi T