{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPregnancy‐associated plasma protein-A2 (PAPPA2) is a metzincin metalloproteinase that specifically cleaves insulin-like growth factor binding proteins—principally IGFBP-3 and IGFBP-5—to locally increase the bioavailability of IGFs. In doing so, it plays a critical role in regulating the growth hormone/IGF axis and is essential for normal placental development. Elevated PAPPA2 expression has been observed in placental tissues under pathologic conditions such as preeclampsia, suggesting that its upregulation may represent a compensatory response to reduced trophoblast invasion or hypoxia. These findings highlight PAPPA2’s dual role in both local (placental) and systemic growth regulation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nGenetic studies have demonstrated that loss-of-function mutations in PAPPA2 in humans result in syndromes characterized by postnatal growth failure, moderate microcephaly, reduced bone mineral density, and aberrant circulating levels of IGF-I and its binding proteins—findings that underscore its critical role in human growth. In parallel, analyses of placental expression show that PAPPA2 is predominantly synthesized by syncytiotrophoblasts and invasive trophoblasts, with its levels being modulated in response to hypoxic stress and trophoblast differentiation. Functional investigations further reveal that PAPPA2 influences trophoblast migration and invasion, potentially via modulation of matrix metalloproteinases and signaling pathways such as Hedgehog, thereby contributing to proper placentation and compensatory mechanisms in conditions like preeclampsia."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "11", "end_ref": "20"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its central role in fetal growth and placental development, PAPPA2 is emerging as a clinically significant biomarker in broader contexts including cardiovascular and metabolic disorders. Recent investigations have linked circulating PAPPA2 levels and genetic variants with conditions such as salt-sensitive hypertension and developmental dysplasia of the hip, while also exploring its utility in prenatal screening and the prediction of preeclampsia-related complications. The development of robust immunoassays now enables precise quantification of circulating PAPPA2, further establishing its importance as a modulator of IGF bioactivity with far-reaching implications in both development and long-term health."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "21", "end_ref": "31"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "M Buimer, R Keijser, J M Jebbink, et al. 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