{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nGremlin‐1, encoded by GREM1, is a secreted glycoprotein that primarily acts as a bone morphogenetic protein (BMP) antagonist to regulate cellular differentiation, proliferation, and tissue homeostasis. In several cancer settings, abnormal GREM1 expression—whether through duplications, noncoding polymorphisms, or epigenetic alterations—disturbs normal morphogen gradients and promotes neoplastic transformation. For example, in hereditary mixed polyposis syndrome and colorectal cancer, ectopic and elevated Gremlin‐1 levels disrupt epithelial cell fate and stimulate proliferation by counteracting BMP‐dependent differentiation signals. Similar oncogenic roles have been described in basal cell carcinoma, glioblastoma, and breast and lung cancers, where Gremlin‐1 contributes to the tumor microenvironment and may support cancer stem cell maintenance. In addition, genetic variants near GREM1 associate with developmental abnormalities such as orofacial clefts, highlighting its importance in embryonic patterning."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "17"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its contribution to tumorigenesis, Gremlin‐1 is a key mediator of fibrotic and remodeling processes in several organs. In response to profibrotic stimuli—including high glucose, interleukin‐6 and transforming growth factor–β (TGF–β)—Gremlin‐1 is up‐regulated in epithelial, mesangial, and stellate cells. This induction triggers Smad‐dependent signaling that promotes epithelial–mesenchymal transition (EMT) and extracellular matrix deposition, thereby contributing to conditions such as diabetic nephropathy, idiopathic pulmonary fibrosis, chronic pancreatitis, and even osteoarthritic cartilage hypertrophy. Experimental studies in animal models have further shown that elevated Gremlin‐1 diminishes osteoblastic differentiation and perturbs normal developmental programs in tissues such as kidney and liver, while genetic variants in GREM1 have been linked to congenital anomalies like CAKUT. Collectively, these findings underscore the role of Gremlin‐1 as a pivotal driver of tissue remodeling and fibrosis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "18", "end_ref": "33"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its roles in cell fate determination and fibrotic remodeling, Gremlin‐1 significantly influences angiogenesis and inflammatory pathways. By binding to receptors such as vascular endothelial growth factor receptor–2 (VEGFR2), Gremlin‐1 activates non‐BMP signaling cascades that stimulate endothelial cell proliferation, vessel formation, and inflammatory cell recruitment. These pathways contribute to vascular remodeling in conditions such as pulmonary arterial hypertension, atherosclerosis, and even ocular abnormalities related to extracellular matrix remodeling. Structural studies have revealed that Gremlin‐1 can form oligomeric complexes, which may further diversify its interactions with BMPs and other signaling molecules, thereby fine‐tuning its impact on both angiogenic and inflammatory responses."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "34", "end_ref": "41"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Bo Chen, Meropi Athanasiou, Qiuping Gu, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Common genetic variants at the CRAC1 (HMPS) locus on chromosome 15q13.3 influence colorectal cancer risk."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Genet (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ng.2007.41"}], "href": "https://doi.org/10.1038/ng.2007.41"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18084292"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18084292"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Iris J H van Vlodrop, Marcella M L Baldewijns, Kim M Smits, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Enrichment map profiling of the cancer invasion front suggests regulation of colorectal cancer progression by the bone morphogenetic protein antagonist, gremlin-1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Oncol (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.molonc.2013.04.002"}], "href": "https://doi.org/10.1016/j.molonc.2013.04.002"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23659962"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23659962"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Kenneth Yan, Qiulian Wu, Diana H Yan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Glioma cancer stem cells secrete Gremlin1 to promote their maintenance within the tumor hierarchy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Genes Dev (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1101/gad.235515.113"}], "href": "https://doi.org/10.1101/gad.235515.113"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24788093"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24788093"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Annabelle Lewis, Luke Freeman-Mills, Elisa de la Calle-Mustienes, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Cancer-associated fibroblast-derived Gremlin 1 promotes breast cancer progression."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Breast Cancer Res (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/s13058-019-1194-0"}], "href": "https://doi.org/10.1186/s13058-019-1194-0"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31533776"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31533776"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Hiroki Kobayashi, Krystyna A Gieniec, Josephine A Wright, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The Balance of Stromal BMP Signaling Mediated by GREM1 and ISLR Drives Colorectal Carcinogenesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Gastroenterology (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1053/j.gastro.2020.11.011"}], "href": "https://doi.org/10.1053/j.gastro.2020.11.011"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33197448"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33197448"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Linxiang Lan, Theodore Evan, Huafu Li, et al. "}, {"type": "b", "children": [{"type": "t", "text": "GREM1 is required to maintain cellular heterogeneity in pancreatic cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nature (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41586-022-04888-7"}], "href": "https://doi.org/10.1038/s41586-022-04888-7"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "35768509"}], "href": "https://pubmed.ncbi.nlm.nih.gov/35768509"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Elisabetta Gazzerro, Renata C Pereira, Vanda Jorgetti, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Skeletal overexpression of gremlin impairs bone formation and causes osteopenia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Endocrinology (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1210/en.2004-0766"}], "href": "https://doi.org/10.1210/en.2004-0766"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15539560"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15539560"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "Vincent Dolan, Madeline Murphy, Denise Sadlier, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Expression of gremlin, a bone morphogenetic protein antagonist, in human diabetic nephropathy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Kidney Dis (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1053/j.ajkd.2005.03.014"}], "href": "https://doi.org/10.1053/j.ajkd.2005.03.014"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15957132"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15957132"}]}, {"type": "r", "ref": 20, "children": [{"type": "t", "text": "Willem Boers, Saida Aarrass, Chris Linthorst, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Transcriptional profiling reveals novel markers of liver fibrogenesis: gremlin and insulin-like growth factor-binding proteins."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M600711200"}], "href": "https://doi.org/10.1074/jbc.M600711200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16606614"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16606614"}]}, {"type": "r", "ref": 21, "children": [{"type": "t", "text": "Natasha Y Frank, Alvin T Kho, Tobias Schatton, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Regulation of myogenic progenitor proliferation in human fetal skeletal muscle by BMP4 and its antagonist Gremlin."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Biol (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1083/jcb.200511036"}], "href": "https://doi.org/10.1083/jcb.200511036"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17015616"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17015616"}]}, {"type": "r", "ref": 22, "children": [{"type": "t", "text": "Sergio Mezzano, Alejandra Droguett, M Eugenia Burgos, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Expression of gremlin, a bone morphogenetic protein antagonist, in glomerular crescents of pauci-immune glomerulonephritis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nephrol Dial Transplant (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/ndt/gfm145"}], "href": "https://doi.org/10.1093/ndt/gfm145"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17403698"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17403698"}]}, {"type": "r", "ref": 23, "children": [{"type": "t", "text": "Marjukka Myllärniemi, Pamela Lindholm, Merja J Ryynänen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Gremlin-mediated decrease in bone morphogenetic protein signaling promotes pulmonary fibrosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Respir Crit Care Med (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1164/rccm.200706-945OC"}], "href": "https://doi.org/10.1164/rccm.200706-945OC"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17975199"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17975199"}]}, {"type": "r", "ref": 24, "children": [{"type": "t", "text": "David W Walsh, Sarah A Roxburgh, Paul McGettigan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Co-regulation of Gremlin and Notch signalling in diabetic nephropathy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochim Biophys Acta (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbadis.2007.09.005"}], "href": "https://doi.org/10.1016/j.bbadis.2007.09.005"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17980714"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17980714"}]}, {"type": "r", "ref": 25, "children": [{"type": "t", "text": "Christine M Costello, Katherine Howell, Edwina Cahill, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Lung-selective gene responses to alveolar hypoxia: potential role for the bone morphogenetic antagonist gremlin in pulmonary hypertension."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Physiol Lung Cell Mol Physiol (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1152/ajplung.00358.2007"}], "href": "https://doi.org/10.1152/ajplung.00358.2007"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18469115"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18469115"}]}, {"type": "r", "ref": 26, "children": [{"type": "t", "text": "Marc Fajardo, Chuan-Ju Liu, Kenneth Egol "}, {"type": "b", "children": [{"type": "t", "text": "Levels of expression for BMP-7 and several BMP antagonists may play an integral role in a fracture nonunion: a pilot study."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Orthop Relat Res (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s11999-009-0981-9"}], "href": "https://doi.org/10.1007/s11999-009-0981-9"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19597895"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19597895"}]}, {"type": "r", "ref": 27, "children": [{"type": "t", "text": "Laszlo Farkas, Daniela Farkas, Jack Gauldie, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Transient overexpression of Gremlin results in epithelial activation and reversible fibrosis in rat lungs."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Respir Cell Mol Biol (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1165/rcmb.2010-0070OC"}], "href": "https://doi.org/10.1165/rcmb.2010-0070OC"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20705941"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20705941"}]}, {"type": "r", "ref": 28, "children": [{"type": "t", "text": "M Heron, C H M van Moorsel, J C Grutters, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Genetic variation in GREM1 is a risk factor for fibrosis in pulmonary sarcoidosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Tissue Antigens (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1399-0039.2010.01590.x"}], "href": "https://doi.org/10.1111/j.1399-0039.2010.01590.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21214523"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21214523"}]}, {"type": "r", "ref": 29, "children": [{"type": "t", "text": "Jeroen C H Leijten, Steffan D Bos, Ellie B M Landman, et al. "}, {"type": "b", "children": [{"type": "t", "text": "GREM1, FRZB and DKK1 mRNA levels correlate with osteoarthritis and are regulated by osteoarthritis-associated factors."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Arthritis Res Ther (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/ar4306"}], "href": "https://doi.org/10.1186/ar4306"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24286177"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24286177"}]}, {"type": "r", "ref": 30, "children": [{"type": "t", "text": "Steven O'Reilly, Marzena Ciechomska, Rachel Cant, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Mild recessive mutations in six Fraser syndrome-related genes cause isolated congenital anomalies of the kidney and urinary tract."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Am Soc Nephrol (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1681/ASN.2013101103"}], "href": "https://doi.org/10.1681/ASN.2013101103"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24700879"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24700879"}]}, {"type": "r", "ref": 32, "children": [{"type": "t", "text": "Raquel Rodrigues-Diez, Raúl R Rodrigues-Diez, Carolina Lavoz, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Gremlin activates the Smad pathway linked to epithelial mesenchymal transdifferentiation in cultured tubular epithelial cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biomed Res Int (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1155/2014/802841"}], "href": "https://doi.org/10.1155/2014/802841"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24949470"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24949470"}]}, {"type": "r", "ref": 33, "children": [{"type": "t", "text": "Dustin Staloch, Xuxia Gao, Ka Liu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Gremlin is a key pro-fibrogenic factor in chronic pancreatitis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Mol Med (Berl) (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00109-015-1308-9"}], "href": "https://doi.org/10.1007/s00109-015-1308-9"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26141517"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26141517"}]}, {"type": "r", "ref": 34, "children": [{"type": "t", "text": "Gulab S Zode, Abbot F Clark, Robert J Wordinger "}, {"type": "b", "children": [{"type": "t", "text": "Bone morphogenetic protein 4 inhibits TGF-beta2 stimulation of extracellular matrix proteins in optic nerve head cells: role of gremlin in ECM modulation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Glia (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/glia.20803"}], "href": "https://doi.org/10.1002/glia.20803"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19031438"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19031438"}]}, {"type": "r", "ref": 35, "children": [{"type": "t", "text": "Stefania Mitola, Cosetta Ravelli, Emanuela Moroni, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Gremlin-1 is an inhibitor of macrophage migration inhibitory factor and attenuates atherosclerotic plaque growth in ApoE-/- Mice."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M113.477745"}], "href": "https://doi.org/10.1074/jbc.M113.477745"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24003215"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24003215"}]}, {"type": "r", "ref": 37, "children": [{"type": "t", "text": "Michela Corsini, Emanuela Moroni, Cosetta Ravelli, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Gremlin1 preferentially binds to bone morphogenetic protein-2 (BMP-2) and BMP-4 over BMP-7."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem J (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1042/BJ20140771"}], "href": "https://doi.org/10.1042/BJ20140771"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25378054"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25378054"}]}, {"type": "r", "ref": 39, "children": [{"type": "t", "text": "Carolina Lavoz, Matilde Alique, Raquel Rodrigues-Diez, et al. 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