Objective: Cysteine-rich protein 61 (CCN1/CYR61) is a matricellular protein of the CCN family
that comprises six secreted CCN proteins in mammals [1]. In adults, CCN1/CYR61 expression
is associated with inflammation and injury repair. Recent studies showed that CCN1/CYR61
limits fibrosis in models of cutaneous wound healing by inducing cellular senescence
in myofibroblasts of the granulation tissue which thereby transform into an extracellular
matrix (ECM)-degrading phenotype. In fibrotic livers, hepatic stellate cells (HSC)
and periportal myofibroblasts (pMF) are considered to produce ECM. Design and Results: We here measured CCN1/CYR61 expression in HSC and pMF. We found a dramatic increase
during activation of HSC and a subsequent decline in fully transdifferentiated myofibroblasts
(MFB). In contrast, CCN1/CYR61 levels in primary hepatocytes were only marginal compared
to the levels found in HSC and pMF. Quantitative RT-PCR using RNA isolated from livers
of animals that were subjected to bile duct ligation (BDL) and repeatedly applications
of CCl4 showed increased CCN1/CYR61 mRNA quantities compared to livers taken from
untreated controls. In these models, elevated levels of CCN1/CYR61 were particularly
found during early periods of liver injury, while the expression declined during prolonged
phases of fibrogenesis. In line, Western blot analysis further revealed that the protein
quantities of CCN1/CYR61 declined at later stages of BDL. The initial CCN1/CYR61 upregulation
correlated well with the expression of α-smooth muscle actin (α-SMA) and collagen
type I (col1α) in early stages of in vivo liver fibrogenesis. Likewise, we observed
a correlation to the acute phase response protein Lipocalin 2 (LCN2) that was recently
shown to be linked to acute and chronic liver damage and controlled by interleukin-1beta
via the nuclear factor-kappaB (NF-kappaB) pathway [2]. Immunohistochemistry confirmed
the initial elevation and subsequent decline of CCN1/CYR61 expression in respective
injury models. Conclusions: CCN1/CYR61 is obviously linked to the pathogenesis of hepatic fibrogenesis and most
likely involved in the control of senescence in transdifferentiated MFB and pMF.
References:
[1] Weiskirchen R. Front Biosci. 2011;16:1939–1961.
[2] Borkham-Kamphorst E et al. Liver Int. 2011;31:656–665.
