Thirunavukkarasu Kannan, Pei Yong, Moore Terry L, Wang He, Yu Xiao-Peng, Geiser Andrew G, Chandrasekhar Srinivasan
Musculoskeletal Research, Lilly Research Labs, Eli Lilly and Company, Indianapolis, IN 46285, USA.
Biochem Biophys Res Commun. 2006 Jun 23;345(1):197-204. doi: 10.1016/j.bbrc.2006.04.023. Epub 2006 May 4.
ADAMTS-4 (aggrecanase-1) is a metalloprotease that plays a role in aggrecan degradation in the cartilage extracellular matrix. In order to understand the regulation of ADAMTS-4 gene expression we have cloned and characterized a functional 4.5kb human ADAMTS-4 promoter. Sequence analysis of the promoter revealed the presence of putative binding sites for nuclear factor of activated T cells (NFAT) and Runx family of transcription factors that are known to regulate chondrocyte maturation and differentiation. Using promoter-reporter assays and mRNA analysis we have analyzed the role of chondrocyte-expressed transcription factors NFATp and Runx2 and have shown that ADAMTS-4 is a potential downstream target of these two factors. Our results suggest that inhibition of the expression/function of NFATp and/or Runx2 may enable us to modulate aggrecan degradation in normal physiology and/or in degenerative joint diseases. The ADAMTS-4 promoter would serve as a valuable mechanistic tool to better understand the regulation of ADAMTS-4 expression by signaling pathways that modulate cartilage matrix breakdown.
ADAMTS-4（软骨聚集蛋白聚糖酶-1）是一种金属蛋白酶，在软骨细胞外基质中聚集蛋白聚糖的降解过程中发挥作用。为了了解ADAMTS-4基因表达的调控机制，我们克隆并鉴定了一个功能性的4.5kb人类ADAMTS-4启动子。对该启动子的序列分析显示，存在已知可调节软骨细胞成熟和分化的活化T细胞核因子（NFAT）和Runx转录因子家族的假定结合位点。通过启动子-报告基因分析和mRNA分析，我们研究了软骨细胞表达的转录因子NFATp和Runx2的作用，并表明ADAMTS-4是这两个因子的潜在下游靶点。我们的结果表明，抑制NFATp和/或Runx2的表达/功能可能使我们能够在正常生理状态和/或退行性关节疾病中调节聚集蛋白聚糖的降解。ADAMTS-4启动子将成为一个有价值的机制工具，以更好地理解通过调节软骨基质分解的信号通路对ADAMTS-4表达的调控。
