{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nBMPER (also known as Crossveinless‐2 or CV2) is a secreted modulator of bone morphogenetic protein (BMP) signaling that plays an essential role in embryonic organogenesis and skeletal development. In several model systems, it has been shown to enhance BMP activity in a spatially restricted fashion, thereby supporting cartilage differentiation, vertebral formation, and proper axial patterning. Its expression is tightly linked with BMP ligands during early development, underscoring its importance in establishing the morphogenetic fields that drive organ formation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMechanistically, BMPER is a context‐dependent regulator of BMP signaling. At low to moderate concentrations it acts as a BMP agonist, promoting downstream Smad1/5 activation, while at high molar ratios it switches to an inhibitory role—often through facilitating endocytic clearance of BMP ligands. Moreover, BMPER interacts with extracellular partners such as Twisted Gastrulation (Tsg) to concentrate BMP–ligand complexes and fine‐tune the BMP gradient during processes like vertebral patterning and nephrogenesis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the vascular system, BMPER exerts profound effects on endothelial function by modulating angiogenesis and inflammation. It promotes the formation of new blood vessels, helps maintain endothelial homeostasis, and counteracts proinflammatory signals—functions that are critical in processes ranging from coronary artery formation to mitigating atherosclerotic inflammation. In addition, BMPER’s regulatory impact on BMP-dependent signaling underlies its roles in tumor progression and liver iron metabolism via hepcidin suppression."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "9", "end_ref": "13"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond vascular regulation, BMPER is critical in cellular differentiation and tissue remodeling. It influences cardiomyocyte differentiation—by interacting with BMP10 and modulating Smad signaling—to promote cardiac mesoderm specification, while also regulating hematopoietic stem cell maturation in the aorta–gonad–mesonephros region. BMPER additionally governs progenitor cell functions in the lung and pericardial adipose tissue, where its proper expression is necessary for maintaining tissue integrity and promoting adipogenesis. Its regulatory versatility extends to numerous developmental contexts, underscoring its role as a master modulator of BMP signals."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "14", "end_ref": "20"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFinally, emerging evidence indicates that BMPER has important roles in metabolic regulation and vascular repair. By directly engaging with intracellular partners such as NPC1 and IGFBP4, BMPER can activate insulin signaling and favor a contractile phenotype in vascular smooth muscle cells—thereby preventing neointima formation in occlusive diseases. These properties, along with its ability to modulate cerebral responses following ischemic injury and to drive adipogenesis in visceral fat depots, suggest that BMPER holds considerable potential as a therapeutic target in diabetes, cardiovascular disease, and regenerative medicine."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "21", "end_ref": "24"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Mika Kamimura, Ken Matsumoto, Kazuko Koshiba-Takeuchi, et al. 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