ADAM metallopeptidase with thrombospondin type 1 motif 2 inactivation reduces the extent and stability of carbon tetrachloride-induced hepatic fibrosis in mice.
ADAMTS2 belongs to the "ADAM metallopeptidase with thrombospondin type 1 motif" (ADAMTS) family. Its primary function is to process collagen type I, II, III, and V precursors into mature molecules by excising the aminopropeptide. This process allows the correct assembly of collagen molecules into fibrils and fibers, which confers to connective tissues their architectural structure and mechanical resistance. To evaluate the impact of ADAMTS2 on the pathological accumulation of extracellular matrix proteins, mainly type I and III collagens, we evaluated carbon tetrachloride-induced liver fibrosis in ADAMTS2-deficient (TS2(-/-)) and wild-type (WT) mice. A single carbon tetrachloride injection caused a similar acute liver injury in deficient and WT mice. A chronic treatment induced collagen deposition in fibrous septa that were made of thinner and irregular fibers in TS2(-/-) mice. The rate of collagen deposition was slower in TS2(-/-) mice, and at an equivalent degree of fibrosis, the resorption of fibrous septa was slightly faster. Most of the genes involved in the development and reversion of the fibrosis were similarly regulated in TS2(-/-) and WT mice.


CONCLUSIONS
These data indicate that the extent of fibrosis is reduced in TS2(-/-) mice in comparison with their WT littermates. Inhibiting the maturation of fibrillar collagens may be a beneficial therapeutic approach to interfering with the development of fibrotic lesions.
Kesteloot
Frédéric
F
Laboratory of Connective Tissues Biology, Interdisciplinary Cluster for Applied Genoproteomics/Center for Experimental Cancer Research, University of Liège, Liège, Belgium.
Desmoulière
Alexis
A
Leclercq
Isabelle
I
Thiry
Marc
M
Arrese
Jorge E
JE
Prockop
Darwin J
DJ
Lapière
Charles M
CM
Nusgens
Betty V
BV
Colige
Alain
A
D051722:ADAM Proteins / Q000037:antagonists & inhibitors*; D000071096:ADAMTS Proteins; D000071121:ADAMTS4 Protein; D000818:Animals; D002251:Carbon Tetrachloride / Q000008:administration & dosage / Q000633:toxicity; D003094:Collagen / Q000648:ultrastructure; D005786:Gene Expression Regulation; D007274:Injections, Intraperitoneal; D008099:Liver / Q000648:ultrastructure; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D011348:Procollagen N-Endopeptidase / Q000037:antagonists & inhibitors*
D003094:Collagen; D002251:Carbon Tetrachloride; D051722:ADAM Proteins; D000071096:ADAMTS Proteins; C000609308:Adamts2 protein, mouse; D011348:Procollagen N-Endopeptidase; D000071121:ADAMTS4 Protein