{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPregnancy‐associated plasma protein‑A (PAPP‑A) is a zinc‐binding metalloproteinase of the metzincin superfamily that plays a central role in modulating local insulin‐like growth factor (IGF) bioavailability. It does so primarily through the proteolytic cleavage of IGF‑binding proteins (especially IGFBP‑4), thereby releasing IGFs to interact with their receptors. Detailed structural and mechanistic studies have revealed that PAPP‑A possesses several conserved domains – including distinctive Lin‑Notch repeat modules – that are essential for substrate recognition, cell‐surface binding (mediated by heparan sulfate proteoglycans), and even its regulation by endogenous inhibitors such as the proform of major basic protein (proMBP) and possibly stanniocalcins. In several cell systems including dermal fibroblasts, osteoblasts, and myoblasts, its proteolytic activity is tightly regulated (e.g., by cytokines or by redox status), thereby orchestrating diverse processes such as wound healing, bone remodeling, and skeletal myogenesis through targeted enhancement of IGF actions."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nOutside of its fundamental biochemical role, PAPP‑A is widely exploited as a biomarker in pregnancy because its local IGF‑modulatory activity is crucial at the maternal–fetal interface. It is expressed by trophoblasts and decidual cells to facilitate trophoblast invasion and placental development, and altered circulating levels of PAPP‑A during the first trimester are strongly associated with adverse obstetrical outcomes such as pre‑eclampsia, fetal growth restriction, gestational diabetes, preterm birth, and even chromosomal abnormalities. In addition, recent work highlights novel regulatory mechanisms – including modulation by microRNAs, circRNAs, and nuclear receptors such as PPAR‑γ – that further influence placental expression and function of PAPP‑A. These findings underscore its diagnostic value in early pregnancy screening, placental morphometry assessments, and in the evaluation of abnormal placentation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "10", "end_ref": "26"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond pregnancy, PAPP‑A is emerging as an important factor in cardiovascular disease and cancer. In patients with coronary and atherosclerotic disease, elevated circulating or locally secreted PAPP‑A is linked to plaque instability, local IGF‑mediated smooth muscle cell proliferation, and accelerated lesion progression. In parallel, aberrant expression and secretion of PAPP‑A have been implicated in diverse malignancies—including lung, ovarian, and breast cancers—where enhanced IGF signaling can promote tumor growth and progression. Moreover, recent studies indicate that PAPP‑A may also participate in adipose tissue remodeling and systemic metabolic regulation, further broadening its pathophysiological significance and potential as a therapeutic target."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "27", "end_ref": "42"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Lisbeth S Laursen, Michael T Overgaard, Kathrin Weyer, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Cell surface targeting of pregnancy-associated plasma protein A proteolytic activity. 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