{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Bone morphogenetic protein‐4 (BMP4) is a multifaceted signaling molecule that plays diverse roles during embryonic development, adult tissue homeostasis, and disease. In the skin, BMP4 is expressed cyclically in the dermis where it works together with BMP2 to create a “BMP cycle” that partitions the resting (telogen) phase of hair follicles into refractory and competent states, thereby regulating the timing of hair regeneration."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In the context of skeletal repair, ex vivo gene therapy studies show that targeted expression of BMP4 in muscle‐derived stem cells can synergize with angiogenic factors such as VEGF to enhance mesenchymal stem cell recruitment, promote cartilage formation at early stages, and ultimately augment endochondral bone formation and healing."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n During limb development, BMP4, together with other BMP family members (notably BMP2), establishes a requisite signaling threshold for chondrogenesis, and its deficiency (especially in combination with loss of BMP2) results in severe deficits in osteogenesis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " In parallel, in differentiating human embryonic stem cells (hESCs), BMP4 functions as a ventral mesoderm inducer that not only supports hematopoietic commitment and enhances progenitor self‐renewal but also, when integrated with core pluripotency networks, helps specify distinct developmental fates"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": ";"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": ";."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Genetic studies have further implicated BMP4 in disease pathogenesis; a common variant at the BMP4 locus has been associated with an increased risk of colorectal cancer, highlighting its potential contribution to oncogenesis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " \n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n BMP4 also serves as a critical mediator in organogenesis. In the kidney, it is induced downstream of sonic hedgehog signaling in the renal stroma and ureteral mesenchyme, although it does not appear to drive mesenchymal proliferation per se."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " In craniofacial development, BMP4 expression in the palatal mesenchyme—regulated by the oocyte‐restricted transcription factor Msx1—is essential for the propagation of signals (including those from Shh and BMP2) that promote cell proliferation and proper palate formation"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": ", while in cardiac development, myocardial BMP4 functions as a paracrine signal that directly mediates atrioventricular septation, and its dysregulation can recapitulate congenital atrioventricular canal defects."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Finally, in the vasculature and craniofacial structures associated with the dentition, BMP4 is dynamically regulated by extrinsic cues. Oscillatory shear stress in endothelial cells induces BMP4 expression, which in turn generates reactive oxygen species leading to pro‐inflammatory responses implicated in early atherogenic events"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": ", and during tooth development, BMP4 is a key morphogenetic regulator acting downstream of Wnt/β‐catenin signals to guide tooth bud formation, cusp patterning, and overall dental morphogenesis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": " \n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Overall, BMP4 emerges as a pivotal factor whose context‐dependent signaling orchestrates a wide array of cellular processes—from stem cell fate determination and tissue regeneration to the patterning of complex organs and the modulation of disease states.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Maksim V Plikus, Julie Ann Mayer, Damon de la Cruz, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Cyclic dermal BMP signalling regulates stem cell activation during hair regeneration."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nature (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nature06457"}], "href": "https://doi.org/10.1038/nature06457"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18202659"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18202659"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Hairong Peng, Vonda Wright, Arvydas Usas, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Synergistic enhancement of bone formation and healing by stem cell-expressed VEGF and bone morphogenetic protein-4."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Invest (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1172/JCI15153"}], "href": "https://doi.org/10.1172/JCI15153"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12235106"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12235106"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Amitabha Bandyopadhyay, Kunikazu Tsuji, Karen Cox, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Genetic analysis of the roles of BMP2, BMP4, and BMP7 in limb patterning and skeletogenesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS Genet (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pgen.0020216"}], "href": "https://doi.org/10.1371/journal.pgen.0020216"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17194222"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17194222"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Kristin Chadwick, Lisheng Wang, Li Li, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Cytokines and BMP-4 promote hematopoietic differentiation of human embryonic stem cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Blood (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1182/blood-2003-03-0832"}], "href": "https://doi.org/10.1182/blood-2003-03-0832"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12702499"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12702499"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Zheng Wang, Efrat Oron, Brynna Nelson, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Distinct lineage specification roles for NANOG, OCT4, and SOX2 in human embryonic stem cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Stem Cell (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.stem.2012.02.016"}], "href": "https://doi.org/10.1016/j.stem.2012.02.016"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22482508"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22482508"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Xiaoxia Qi, Teng-Guo Li, Jing Hao, et al. "}, {"type": "b", "children": [{"type": "t", "text": "BMP4 supports self-renewal of embryonic stem cells by inhibiting mitogen-activated protein kinase pathways."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.0401367101"}], "href": "https://doi.org/10.1073/pnas.0401367101"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15075392"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15075392"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Richard S Houlston, Emily Webb, Peter Broderick, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Meta-analysis of genome-wide association data identifies four new susceptibility loci for colorectal cancer."}]}, {"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.262"}], "href": "https://doi.org/10.1038/ng.262"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19011631"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19011631"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Jing Yu, Thomas J Carroll, Andrew P McMahon "}, {"type": "b", "children": [{"type": "t", "text": "Sonic hedgehog regulates proliferation and differentiation of mesenchymal cells in the mouse metanephric kidney."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Development (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1242/dev.129.22.5301"}], "href": "https://doi.org/10.1242/dev.129.22.5301"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12399320"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12399320"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Zunyi Zhang, Yiqiang Song, Xiang Zhao, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Rescue of cleft palate in Msx1-deficient mice by transgenic Bmp4 reveals a network of BMP and Shh signaling in the regulation of mammalian palatogenesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Development (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1242/dev.129.17.4135"}], "href": "https://doi.org/10.1242/dev.129.17.4135"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12163415"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12163415"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Kai Jiao, Holger Kulessa, Kevin Tompkins, et al. "}, {"type": "b", "children": [{"type": "t", "text": "An essential role of Bmp4 in the atrioventricular septation of the mouse heart."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Genes Dev (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1101/gad.1124803"}], "href": "https://doi.org/10.1101/gad.1124803"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12975322"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12975322"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "George P Sorescu, Hannah Song, Sarah L Tressel, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Bone morphogenic protein 4 produced in endothelial cells by oscillatory shear stress induces monocyte adhesion by stimulating reactive oxygen species production from a nox1-based NADPH oxidase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Circ Res (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1161/01.RES.0000145728.22878.45"}], "href": "https://doi.org/10.1161/01.RES.0000145728.22878.45"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15388638"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15388638"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Fei Liu, Emily Y Chu, Brenda Watt, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Wnt/beta-catenin signaling directs multiple stages of tooth morphogenesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Dev Biol (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ydbio.2007.10.016"}], "href": "https://doi.org/10.1016/j.ydbio.2007.10.016"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18022614"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18022614"}]}]}]}