Background & Aims: Liver fibrosis is characterized by significant accumulation of extracellular matrix (ECM) proteins, mainly fibrillar collagen-I, as a result of persistent liver injury. Cartilage oligomeric matrix protein (COMP) is largely found in the ECM of skeletal tissue. Increased COMP expression has been associated with fibrogenesis in systemic sclerosis, lung fibrosis, chronic pancreatitis, cirrhosis and hepatocellular carcinoma. We hypothesized that COMP could induce fibrillar collagen-I deposition and participate in matrix remodeling thus contributing to the pathophysiology of liver fibrosis.
Methods: Thioacetamide (TAA) and carbon tetrachloride (CCl) were used to induce liver fibrosis in wild-type (WT) and Comp mice. In vitro experiments were performed with primary hepatic stellate cells (HSCs).
Results: COMP expression was detected in livers from control WT mice and was upregulated in response to either TAA or CCl-induced liver fibrosis. TAA-treated or CCl-injected Comp mice showed less liver injury, inflammation and fibrosis compared to their corresponding control WT mice. Challenge of HSCs with recombinant COMP (rCOMP) induced intra- plus extracellular collagen-I deposition and increased matrix metalloproteinases (MMPs) 2, 9 and 13, albeit similar expression of transforming growth factor beta (TGFβ) protein, in addition to Tgfβ, tumour necrosis factor alpha (Tnfα) and tissue inhibitor of metalloproteinases-1 (Timp1) mRNAs. We demonstrated that COMP binds collagen-I; yet, it does not prevent collagen-I cleavage by MMP1. Last, rCOMP induced collagen-I expression in HSCs via CD36 receptor signaling and activation of the MEK1/2-pERK1/2 pathway.
Conclusion: These results suggest that COMP contributes to liver fibrosis by regulating collagen-I deposition.
Lay Summary: Cartilage oligomeric matrix protein (COMP) induces fibrillar collagen-I deposition via the CD36 receptor signaling and activation of the MEK1/2-pERK1/2 pathway, and participates in extracellular matrix remodeling contributing to the pathophysiology of liver fibrosis.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5831373 | PMC |
http://dx.doi.org/10.1016/j.jhep.2016.06.003 | DOI Listing |
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