Gremlin1 and chronic pancreatitis: a new clinical target and biomarker?

Abstract

Chronic pancreatitis (CP) is a progressive inflammatory condition triggered by the loss of exocrine pancreatic acini and fibrosis or scarring of pancreas tissue [1]. The exocrine pancreas comprises about 90 % of total pancreas and releases digestive enzymes such as chymotrypsin, amylase and lipase in response to a meal. CP develops in 16 % of patients presenting with acute pancreatitis, a number which increases to 38 % upon second admission. The most common symptom of CP is abdominal pain, which can be both intermittent and persistent. Furthermore, 95 % of CP patients present with alcoholic or idiopathic disease [1]; however, excessive consumption of alcohol alone may not be the cause of CP. Additional causes of CP include gallstones, exposure to volatile hydrocarbons, viral infection and genetic mutations [2]. There are various genetic forms of CP including gain-of-function mutations in genes such as Prss1 which results in a form of trypsin that is resistant to degradation and can lead to an autosomal-dominant hereditary form of CP [1]. In contrast, loss-of-function mutations in genes such as Spink1 and Cftr, which is involved in the inactivation of pancreatic trypsin, are also associated with CP. The overall survival rate for CP patients is only 50 % at 20-25 years from diagnosis [3], and CP patients also have an increased risk of developing pancreatic cancer [4].Current treatments for CP involve pain management with paracetamol and non-steroid anti-inflammatory drugs as first line, followed by mild opioids such as tramadol. An important clinical feature of CP is steatorrhea, caused by reduced absorption of fat in the intestine. Supplementation of pancreatic enzymes such as lipase, together with H 2 histamine antagonists, is used to reduce this malabsorption of lipids [1]. Micronutrient therapy containing antioxidants such as Antox® (containing methyl and thiol moieties, as well as methionine and vitamin C) is now being tested, as it has been shown to control the pain and attacks associated with CP [1].

Human esophageal myofibroblast secretion of bone morphogenetic proteins and GREMLIN1 and paracrine regulation of squamous epithelial growth

“…Secreted active BMP4 can be inhibited at the extracellular level by interacting with secreted BMP4 antagonists such as GREM1 6 . High levels of Gremlin expression have been reported in neurons, alveolar epithelial cells, and goblet cells 17 and upregulation of GREM1 has been reported in fibrosis of the kidney, lung, heart, liver, and pancreas 18 . Immunohistochemistry performed on tissue microarrays has shown negative or weak GREM1 expression in the human esophagus 19 .…”

Gremlin Regulates Tubular Epithelial to Mesenchymal Transition via VEGFR2: Potential Role in Renal Fibrosis

“…Many experimental evidences suggest that Gremlin could be an important promoter of fibrosis in different pathologies, including liver fibrosis, lung diseases (particularly pulmonary hypertension and idiopathic pulmonary fibrosis), myocardial fibrosis, and chronic pancreatitis ( Khokha et al, 2003 ; Mueller et al, 2013 ; Brazil, 2015 ; Mezzano et al, 2018 ). In several human renal diseases, Gremlin was found overexpressed, mainly in areas of tubulointerstitial fibrosis ( Murphy et al, 2002 ; Dolan et al, 2005 ; Carvajal et al, 2008 ), suggesting that Gremlin could be involved in the fibrotic process during CKD.…”

“…Earlier studies demonstrate an important role of Gremlin in development, including nephrogenesis, acting as a BMP antagonist ( Merino et al, 1999 ; Khokha et al, 2003 ; Michos et al, 2004 ). More recently, Gremlin has been suggested as an important promoter of fibrosis in different pathological conditions including renal, liver, lung, and myocardial diseases ( Dolan et al, 2005 ; Carvajal et al, 2008 ; Mueller et al, 2013 ; Brazil, 2015 ; Erdmann et al, 2015 ; Mezzano et al, 2018 ). Moreover, in vitro studies have demonstrated direct effects of Gremlin in the regulation of profibrotic-related events ( Zode et al, 2009 ; Li et al, 2012 ; Rodrigues-Diez et al, 2012 ; Huang et al, 2013 ).…”

Anti-inflammation and anti-fibrosis with PEGylated, apigenin loaded PLGA nanoparticles in chronic pancreatitis disease

“…32, 33 We therefore used PLGA, a state-of-the-art material for drug delivery, to load the drug. 16,17 To enhance the drug delivery efficiency, the particles are therefore modied by PEG via biotin-avidin reactions (Fig. 16,17 To enhance the drug delivery efficiency, the particles are therefore modied by PEG via biotin-avidin reactions (Fig.…”

“…In this study, we employ PEGylated poly(lactic-co-glycolic acid) (PLGA) nanoparticles, a state-of-the-art material for drug delivery, 14,15 to improve the delivery efficiency and bioavailability of apigenin for CP treatment. Considering the signicant challenge, that there is currently no active target for CP treatment, 16,17 the particle surface was modied using PEGylation to enhance its in vivo circulation time and delivery efficiency. Studying at a cellular level nds that apigenin loaded nanoparticles can inhibit PSC proliferation and induce PSC apoptosis.…”