{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Bone morphogenetic protein 9 (BMP9), also known as growth differentiation factor 2 (GDF2), is a multifunctional cytokine that plays pivotal roles in vascular, skeletal, hepatic, and lymphatic physiology. BMP9 is a high‐affinity ligand for the endothelial‐specific receptor ALK1, and its signaling promotes vascular quiescence by inhibiting endothelial cell migration, proliferation, and sprouting, thereby regulating angiogenesis and maintaining vessel homeostasis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": " In models of pulmonary arterial hypertension, BMP9 not only protects endothelial integrity but also reverses established disease, underscoring its therapeutic potential."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Beyond the vasculature, BMP9 is one of the most potent osteogenic factors. It synergizes with other pathways—including Wnt signaling and growth hormone—to induce early and late markers of osteogenic differentiation in mesenchymal stem/progenitor cells and thereby promote robust bone formation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "10"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Moreover, BMP9 contributes to systemic iron homeostasis by regulating hepcidin expression in hepatocytes"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": ", and it modulates lymphatic endothelial function by attenuating the expression of markers such as LYVE-1 and by promoting proper valve formation, thus influencing blood/lymphatic vessel separation and lymphatic drainage."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In addition, BMP9 exerts proliferative effects in ovarian epithelial cells through ALK2/Smad1/Smad4 signaling, suggesting a role in ovarian physiology"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": ", and it is produced by hepatocytes and biliary epithelial cells where, in its mature active form, it helps to stabilize hepatocyte metabolic functions and modulate responses to injury."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Finally, genetic studies have linked mutations in GDF2/BMP9 to vascular anomaly syndromes, including variants of pulmonary arterial hypertension."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "16"}]}, {"type": "t", "text": " Collectively, these findings highlight the multifunctional nature of GDF2/BMP9 in orchestrating angiogenesis, osteogenesis, iron metabolism, lymphatic development, and hepatic homeostasis, and they underscore its promise as a target for therapeutic intervention in diverse disease settings.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Laurent David, Christine Mallet, Sabine Mazerbourg, et al. 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