Bone Marrow Mononuclear Cell Transplantation Increases Metalloproteinase-9 and 13 and Decreases Tissue Inhibitors of Metalloproteinase-1 and 2 Expression in the Liver of Cholestatic Rats

Abstract

Liver fibrosis results from chronic injury followed by activation of macrophages and fibrogenic cells like myofibroblasts and activated hepatic stellate cells. These fibrogenic cells express α-smooth muscle actin (α-SMA) and produce excessive extracellular matrix (ECM), with disorganization and loss of function of hepatic parenchyma. It is known that increased levels of metalloproteinases (MMPs) in liver fibrosis are associated with reduction of the pathologic ECM and fibrosis resolution. Recently, it has been shown that bone marrow mononuclear cells (BMMNCs) may reduce collagen and α-SMA expression, and ameliorate liver function in cholestatic rats. Therefore, this study aimed to analyze MMP-2, MMP-9 and MMP-13, and tissue inhibitors of MMPs (TIMPs)-1 and TIMP-2 in the liver of cholestatic rats transplanted with BMMNC. Animals were divided into normal rats, cholestatic rats obtained after 14 and 21 days of bile duct ligation (BDL), and rats obtained after 14 days of BDL that received BMMNCs and were killed after 7 days. MMP and TIMP expression was assessed by Western blotting, along with α-SMA, CD68 and CD11b expression by confocal microscopy. Western blotting analysis showed that 14-day BDL animals had significantly reduced amounts of MMP-2 and MMP-13, but increased amounts of MMP-9 compared to normal rats. After 21 days of BDL, overall MMP amounts were decreased and TIMPs were increased. BMMNC transplantation significantly increased MMP-9 and MMP-13, and decreased TIMP expression. Increased MMP activity was confirmed by zymography. MMP-9 and MMP-13 were expressed by macrophages near fibrotic septa, suggesting BMMNC may stimulate MMP production in fibrotic livers, contributing to ECM degradation and hepatic regeneration.

Aerobic exercise training in the treatment of non‐alcoholic fatty liver disease related fibrosis

“…; Nunes de Carvalho et al . ). MMPs do not respond uniformly during pathology and some MMPs promote fibrogenesis, whereas others contribute to fibrolysis.…”

“…Another means by which NASH related fibrosis may be regulated is via alterations in extracellular matrix remodelling proteins because of their ability to regulate collagen turnover. Circulating MMPs are increased in NASH (D'Amico et al 2010), whereas models of liver fibrosis have increased the hepatic expression of MMPs (Wanninger et al 2011;Nunes de Carvalho et al 2013). MMPs do not respond uniformly during pathology and some MMPs promote fibrogenesis, whereas others contribute to fibrolysis.…”

Microsphere-Based Rapamycin Delivery, Systemic Versus Local Administration in a Rat Model of Renal Ischemia/Reperfusion Injury

“…The discrepancy between high collagen levels and decreased α-SMA positive myofibroblasts may therefore also be explained if α-SMA myofibroblasts have decreased already, while collagen has not been cleared yet. Since matrix metalloproteinases (MMPs) are normally mostly produced by macrophages ( 23 , 24 ), and macrophages were also decreased by rapamycin treatment in our study, it is possible that the deposited collagen was not cleared due to a lack of MMPs. However, an increased deposition of collagen by other cell types than myofibroblasts cannot be excluded based on our findings.…”

Salvianolic acid B prevents steroid-induced osteonecrosis of the femoral head via PPARγ expression in rats

“…Runx2 and Osterix are considered to be the most important transcription factors that regulate the stereotype and differ- entiation of osteoblasts, which are the key site for a variety of hormones that regulate the osteoblast differentiation and bone formation of local and external regulatory factors (24). Scholars have confirmed that high-concentration hormones are able to inhibit the expression and activity of osteoblast phenotype markers Runx2 and Osterix by investigating in-vitro cell culture and the molecular and genetic level (25). In present study, pretreatment with Sal B significantly increased Runx2 and Col I protein expression levels in steroid-induced osteonecrosis rats.…”