Treatment with Anti–Gremlin 1 Antibody Ameliorates Chronic Hypoxia/SU5416–Induced Pulmonary Arterial Hypertension in Mice

Ciuclan, Loredana; Sheppard, Kelly-Ann; Dong, Liqun; Sutton, Daniel; Duggan, Nicholas; Hussey, Martin; Simmons, Jenny; Morrell, Nicholas W.; Járai, Gábor; Edwards, Matthew; Dubois, Gerald; Thomas, Matthew; Heeke, Gino Van; England, Karen

doi:10.1016/j.ajpath.2013.07.017

Cited by 56 publications

(55 citation statements)

References 35 publications

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“…Small molecules such as tilerone (which induces BMP-7) and Thr123 (which activates the Alk3 BMP receptor) have been shown to reduce kidney fibrosis in vivo [47,48]. Together with a recent report showing that an anti-Grem1 antibody can reduce fibrosis in a model of pulmonary artery hypertension (PAH) [49], these data illustrate that manipulation of the Grem1-BMP signalling axis may still be a useful therapeutic avenue for the treatment of diabetic kidney disease. A recent paper identified that twisted gastrulation (Twsg1) is the most abundant BMP antagonist expressed in cultured kidney podocytes, and could inhibit both BMP-4 and BMP-7 in these cells [20].…”

Section: Discussionmentioning

confidence: 74%

Gremlin1 preferentially binds to bone morphogenetic protein-2 (BMP-2) and BMP-4 over BMP-7

Church

Krishnakumar

Urbanek

et al. 2015

Biochemical Journal

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Section: Discussionmentioning

confidence: 74%

Gremlin1 preferentially binds to bone morphogenetic protein-2 (BMP-2) and BMP-4 over BMP-7

Church

Krishnakumar

Urbanek

et al. 2015

Biochemical Journal

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“…The roles of these BMP antagonists in diseases such as diabetes, liver fibrosis, cancer, and right ventricular hypertrophy and failure demonstrate their importance in disease pathophysiology (27)(28)(29)(30). Currently, there is mounting evidence that altered BMP signaling may result from factors independent of BMPR2 mutations in IPAH (31)(32)(33)(34). Indeed, the modes of BMP activation and signaling must have multiples stages of regulation.…”

Section: Pulmonary Arterial Hypertension (Pah)mentioning

confidence: 99%

Bone Morphogenic Protein Type 2 Receptor Mutation-Independent Mechanisms of Disrupted Bone Morphogenetic Protein Signaling in Idiopathic Pulmonary Arterial Hypertension

Barnes¹,

Kucera²,

Tian³

et al. 2016

Am J Respir Cell Mol Biol

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Altered bone morphogenic protein (BMP) signaling, independent of BMPR2 mutations, can result in idiopathic pulmonary arterial hypertension (IPAH). Glucose dysregulation can regulate multiple processes in IPAH. However, the role of glucose in BMP antagonist expression in IPAH has not been characterized. We hypothesized that glucose uptake regulates BMP signaling through stimulation of BMP antagonist expression in IPAH. Using human plasma, lung tissue, and primary pulmonary arterial smooth muscle cells (PASMCs), we examined the protein expression of BMP2, BMP-regulated Smads, and Smurf-1 in patients with IPAH and control subjects. Gremlin-1 levels were elevated in patients with IPAH compared with control subjects, whereas expression of BMP2 was not different. We demonstrate increased Smad polyubiquitination in IPAH lung tissue and PASMCs that was further enhanced with proteasomal inhibition. Examination of the Smad ubiquitin-ligase, Smurf-1, showed increased protein expression in IPAH lung tissue and localization in the smooth muscle of the pulmonary artery. Glucose dose dependently increased Smurf-1 protein expression in control PASMCs, whereas Smurf-1 in IPAH PASMCs was increased and sustained. Conversely, phosphoSmad1/5/8 levels were reduced in IPAH compared with control PASMCs at physiological glucose concentrations. Interestingly, high glucose concentrations decreased phosphorylation of Smad1/5/8 in control PASMCs. Blocking glucose uptake had opposing effects in IPAH PASMCs, and inhibition of Smurf-1 activity resulted in partial rescue of Smad1/5/8 activation and cell migration rates. Collectively, these data suggest that BMP signaling can be regulated through BMPR2 mutation-independent mechanisms. Gremlin-1 (synonym: induced-in-high-glucose-2 protein) and Smurf-1 may function to inhibit BMP signaling as a consequence of the glucose dysregulation described in IPAH.

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“…Given the wealth of data implicating Gremlin1 in fibrosis of the kidney, lung, heart, liver and now pancreas, it would seem that strategies to inhibit Gremlin1 would have obvious clinical potential. This view was supported by a report from a Novartis group who demonstrated that antibody-mediated targeting of Gremlin1 reduced vascular remodelling and improved the outcome of mice with PAH [22]. This paper provides an important proof-ofconcept for those researchers interested in developing pharmacological tools aimed at targeting Gremlin1 action in fibrosis in CP patients.…”

mentioning

confidence: 52%

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

Brazil

2015

J Mol Med

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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].

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Treatment with Anti–Gremlin 1 Antibody Ameliorates Chronic Hypoxia/SU5416–Induced Pulmonary Arterial Hypertension in Mice

Cited by 56 publications

References 35 publications

Gremlin1 preferentially binds to bone morphogenetic protein-2 (BMP-2) and BMP-4 over BMP-7

Gremlin1 preferentially binds to bone morphogenetic protein-2 (BMP-2) and BMP-4 over BMP-7

Bone Morphogenic Protein Type 2 Receptor Mutation-Independent Mechanisms of Disrupted Bone Morphogenetic Protein Signaling in Idiopathic Pulmonary Arterial Hypertension

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

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