title: Regulation of the human ADAMTS-4 promoter by transcription factors and cytokines.
abstract: 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.
authors: Musculoskeletal Research, Lilly Research Labs, Eli Lilly and Company, Indianapolis, IN 46285, USA. kannan@lilly.com
authors: Kannan
authors: K
authors: Thirunavukkarasu
authors: Yong
authors: Y
authors: Pei
authors: Terry L
authors: TL
authors: Moore
authors: He
authors: H
authors: Wang
authors: Xiao-Peng
authors: XP
authors: Yu
authors: Andrew G
authors: AG
authors: Geiser
authors: Srinivasan
authors: S
authors: Chandrasekhar