PAPPA2 (pappalysin 2) is a metalloproteinase that specifically cleaves insulin-like growth factor binding protein (IGFBP)-5 at the 163-Ser-|-Lys-164 bond, with limited activity toward IGFBP-3 1. By proteolytically releasing IGFBPs, PAPPA2 increases bioavailable IGF-I and IGF-II, thereby promoting IGF signaling crucial for growth and metabolic regulation 2. The enzyme is highly expressed in placental trophoblasts and is essential for trophoblast invasion and migration through MMP9 secretion regulation 3. PAPPA2 is a placental-enriched gene critical for normal placentation and fetal development 4. Functionally, PAPPA2 regulates IGF bioactivity within a regulatory axis involving stanniocalcin inhibition of pappalysins and IGFBP-IGF interactions 1. Disease relevance includes PAPPA2-associated short stature (Dauber-Argente type) 5, where reduced protease activity impairs growth, bone metabolism, and glucose homeostasis due to decreased free IGF-I bioavailability 2. PAPPA2 overexpression strongly predicts severe preeclampsia months before symptom onset and correlates with earlier delivery 6, and the gene serves as a validated diagnostic biomarker for preeclampsia with AUC values exceeding 0.83 7. PAPPA2 is also implicated in developmental dysplasia of the hip pathogenesis 8.