DDR2 and hepatic fibrosis

October 31, 2001

Deposition of interstial collagen in abnormal locations, the hallmark of fibrosis, can occur in many organs in response to physical trauma or other kinds of insults. Olaso and coworkers report here that type I collagen accumulation in the liver is not just a marker for this fibrotic response, but actually helps to perpetuate damage to hepatic tissue following injury. They show that the collagen receptor DDR2, rather than any of the better studied ECM receptors of the integrin family, is at the heart of this response. Transcription of DDR2, a receptor tyrosine kinase that signals in response to triple helical collagen in the surroundings, is induced early during the activation of hepatic stellate cells. These mesenchymal cells are responsible for collagen I biosynthesis following injury, and Olaso et al. show that stellate cell DDR2 is phosphorylated in response to collagen stimulation, leading the cells to divide and to express the degradative enzyme MMP2. The cells that express this enzyme adopt an invasive phenotype in culture, which probably explains their ability to subendothelial space and remodel the ECM, replacing the normal basement membrane constituents with fibrotic material. The newly deposited collagen would then further activates stellate cell proliferation and invasion in an autocrine manner. However, this destructive cycle can apparently be broken by blocking DDR2 function, collagen deposition, or MMP2 activity. Interestingly, providing large amounts of normal basement membrane as a substratum also reverts the activated phenotype of stellate cells and can suppress their expression of DDR2.
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