Gremlin is a key pro-fibrogenic factor in chronic pancreatitis

Abstract

The current study aims to identify the pro-fibrogenic role of Gremlin, an endogenous antagonist of bone morphogenetic proteins (BMPs) in chronic pancreatitis (CP). CP is a highly debilitating disease characterized by progressive pancreatic inflammation and fibrosis that ultimately leads to exocrine and endocrine dysfunction. While transforming growth factor (TGF)-β is a known key pro-fibrogenic factor in CP, the TGF-β superfamily members BMPs exert an anti-fibrogenic function in CP reported by our group recently. To investigate how BMP signaling is regulated in CP by BMP antagonists, the mouse CP model induced by cerulein was used. During CP induction, TGF-β1 mRNA increased 156-fold in two weeks, a BMP antagonist Gremlin 1 (Grem1) mRNA levels increased 145-fold at three weeks, and increases in Grem1 protein levels correlated with increases in collagen deposition. Increased Grem1 was also observed in human CP pancreata compared to normal. Grem1 knockout in Grem1+/− mice revealed a 33.2% reduction in pancreatic fibrosis in CP compared to wild-type littermates. In vitro in isolated pancreatic stellate cells, TGF-β induced Grem1 expression. Addition of the recombinant mouse Grem1 protein blocked BMP2-induced Smad1/5 phosphorylation and abolished BMP2's suppression effects on TGF-β-induced collagen expression. Evidences presented herein demonstrate that Grem1, induced by TGF-β, is pro-fibrogenic by antagonizing BMP activity in CP.

Induction of chronic pancreatitis by pancreatic duct ligation activates BMP2, apelin, and PTHrP expression in mice

“…Additionally, PTHrP stimulated gremlin production. Gremlin is a documented inhibitor of BMP2 activity (21,22,28,37). Together, these cross-talk findings imply that PTHrP acted as an intermediate in the proinflammatory effects of TGF-␤ and in regulation of a novel pancreatic BMP2-apelin axis, which was protective.…”

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

“…BMP-2 inhibits TGF-β1 activation of pancreatic stellate cell and extracellular matrix secretion [21]. During CP progression, BMP activity is reduced and TGF-β1 activity is increased, causing fibrosis and CP progression [20]. The current report from Staloch and colleagues suggests that upregulation of Gremlin1 represents a mechanism by which anti-fibrotic BMP action is inhibited during CP, allowing the pro-fibrotic action of TGF-β1 to dominate.…”

“…Importantly, levels of Gremlin1 have been shown to be elevated in human biopsies from patients with DN [11], pulmonary arterial hypertension (PAH) [10], non-ischaemic heart failure [18] and liver fibrosis [19]. In this issue of J Mol Med, Staloch and colleagues have identified a new role for Gremlin1 as a novel biomarker and potential therapeutic target in CP [20]. The molecular targets of Gremlin1, BMPs, have been shown to antagonise the profibrotic action of TGF-β1 in fibrosis [20].…”

“…In this issue of J Mol Med, Staloch and colleagues have identified a new role for Gremlin1 as a novel biomarker and potential therapeutic target in CP [20]. The molecular targets of Gremlin1, BMPs, have been shown to antagonise the profibrotic action of TGF-β1 in fibrosis [20]. BMP-2 inhibits TGF-β1 activation of pancreatic stellate cell and extracellular matrix secretion [21].…”

“…CP can be induced in mice via intraperitoneal injection of the cholecystokinin analogue cerulein [20]. Marked collagen deposition was evident in pancreatic sections of ceruleininjected mice.…”