Pregnancy-associated plasma protein A (PAPP-A) is a large placenta-derived glycoprotein. During pregnancy it is produced in high concentrations by the trophoblast and released into maternal circulation. In addition to trophoblasts, PAPP-A expression has been reported in various tissues, including endometrium, testis, kidney, bone, colon, and other adult and fetal tissues. PAPP-A is potentially proatherosclerotic and has been proposed as a new marker of inflammation, as high serum PAPP-A levels are observed in patients with renal impairment, asthma, lung cancer, etc. Studies suggest that the PAPP-A form in non-pregnant females and males is dimeric and is not complexed with proMBP.

References:
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PAPP-A (pico) CLIA AL-201
Kalra B, Kumar A, Tran A, Oxvig C, Shah S. Development of a fully characterized picoPAPP-A chemiluminescence assay for male and female serum evaluation. Poster session presented at American Association for Clinical Chemistry; 2012 Jul 16-19; Los Angeles, CA.

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PAPP-A (pico) ELISA AL-101
Al-Khafaji H, Noer PR, Alkharobi H, Alhodhodi A, Meade J, El-Gendy R, Oxvig C, Beattie J. A characteristic signature of insulin-like growth factor (IGF) axis expression during osteogenic differentiation of human dental pulp cells (hDPCs): Potential co-ordinated regulation of IGF action. Growth Horm IGF Res. 2018 Oct-Dec;42-43:14-21. doi: 10.1016/j.ghir.2018.07.003. Epub 2018 Jul 26. PMID: 30071469; PMCID: PMC6259625.

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Anastasilakis AD, Koulaxis D, Upadhyay J, Pagkalidou E, Kefala N, Perakakis N, Polyzos SA, Economou F, Mantzoros CS. Free IGF-1, Intact IGFBP-4, and PicoPAPP-A are Altered in Acute Myocardial Infarction Compared to Stable Coronary Artery Disease and Healthy Controls. Horm Metab Res. 2019 Feb;51(2):112-119.

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Becker M, Haluska P, Bale L, Oxvig C, Conover C. A Novel Neutralizing Antibody Targeting Pregnancy-Associated Plasma Protein-A Inhibits Ovarian Cancer Growth and Ascites Accumulation in Patient Mouse Tumorgrafts. Mol Cancer Ther. 2015 Apr;14(4):973-81. Epub 2015 Feb 18.

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Boldt H, Bale L, Resch Z, Exvig C, Overgaard M, Conover C. Effects of Mutated Pregnancy-Associated Plasma Protein-A on Atherosclerotic Lesion Development in Mice. Endocrinology. 2013 January; 154(1):246-252.

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Botkjaer JA, Borgbo T, Kloverpris S, Noer PR, Oxvig C, Andersen CY. Effect of pregnancy-associated plasma protein-A (PAPP-A) single-nucleotide polymorphisms on the level and activity of PAPP-A and the hormone profile in fluid from normal human small antral follicles. Fertil Steril. 2016 Dec;106(7):1778-1786.e8.

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Bøtkjær JA, Jeppesen JV, Wissing ML, Kløverpris S, Oxvig C, Mason JI, Borgbo T, Andersen CY. Pregnancy-associated plasma protein A in human ovarian follicles and its association with intrafollicular hormone levels. Fertil Steril. 2015 Nov;104(5):1294-301.e1. doi: 10.1016/j.fertnstert.2015.07.1152. Epub 2015 Aug 18. PMID: 26297643.

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Botkjær JA, Noer PR, Oxvig C, Yding Andersen C. A common variant of the pregnancy-associated plasma protein-A (PAPPA) gene encodes a protein with reduced proteolytic activity towards IGF-binding proteins. Sci Rep . 2019 Sep 13;9(1):13231. doi: 10.1038/s41598-019-49626-8.

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Brohus M, Gorbunova V, Faulkes C, Overgaard MT, Conover CA. The Insulin-Like Growth Factor System in the Long-Lived Naked Mole-Rat. PLOS ONE. 2015 December 22.

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Cediel G, Rueda F, Oxvig C, Oliveras T, Labata C, de Diego O, Ferrer M, Aranda-Nevado MC, Serra-Gregori J, Núñez J, García C, Bayes-Genis A. Prognostic value of the Stanniocalcin-2/PAPP-A/IGFBP-4 axis in ST-segment elevation myocardial infarction. Cardiovasc Diabetol. 2018 Apr 30;17(1):63. doi: 10.1186/s12933-018-0710-3.

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Davidge-Pitts C, Escande CJ, Conover CA. Preferential expression of PAPPA in human preadipocytes from omental fat. Journal of Endocrinology (2014) 222, 87–97.

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DiPrisco B, Kumar A, Kalra B, Savjani GV, Michael Z, Farr O, Papathanasiou AE, Christou H, Mantzoros C. Placental proteases PAPP-A and PAPP-A2, the binding proteins they cleave (IGFBP-4 and -5), and IGF-I and IGF-II: Levels in umbilical cord blood and associations with birth weight and length. Metabolism. 2019 Nov;100:153959. doi: 10.1016/j.metabol.2019.153959. Epub 2019 Aug 8.

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Hada M, Oh H, Pfeiffer RM, Falk RT, Fan S, Mullooly M, Pollak M, Geller B, Vacek PM, Weaver D, Shepherd J, Wang J, Fan B, Mahmoudzadeh AP, Malkov S, Herschorn S, Brinton LA, Sherman ME, Gierach GL. Relationship of circulating insulin-like growth factor-I and binding proteins 1-7 with mammographic density among women undergoing image-guided diagnostic breast biopsy. Breast Cancer Res. 2019 Jul 23;21(1):81. doi: 10.1186/s13058-019-1162-8. PMID: 31337427; PMCID: PMC6651938.

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Heitzeneder S, Shem J, Khan J, Mackall C. Pregnancy Associated Plasma Protein A (PAPP-A) Is A Novel Therapeutic Target In Ewing Sarcoma. Presented at 8th Ovarian Cancer Research; 2016 May 15-17; Niagra Falls, ON, Canada.

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Hjortebjerg R, Espelund U, Rasmussen TR, Folkersen B, Steiniche T, Georgsen JB, Oxvig C, Frystyk J. Pregnancy-Associated Plasma Protein-A2 Is Associated With Mortality in Patients With Lung Cancer. Front Endocrinol (Lausanne). 2020 Sep 2;11:614. doi: 10.3389/fendo.2020.00614. PMCID: PMC7492290.

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Hjortebjerg R, Høgdall C, Hansen KH, Høgdall E, Frystyk J. The IGF–PAPP-A–Stanniocalcin axis in serum and ascites associates with prognosis in patients with ovarian cancer. Int J Mol Sci. 2024;25(2014):1-16. doi:10.3390/ijms25042014.

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Jepsen MR, Kloverpris S, Mikkelsen JH, Pedersen JH, Fuchtbauer EM, Lisbeth S, Laursen LS, Oxvig C. Stanniocalcin-2 Inhibits Mammalian Growth by Proteolytic Inhibition of the Insulin-like Growth Factor Axis. J. Biol. Chem. 2015 290: 3430

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Kashyap S, Hein KZ, Chini CC, Lika J, Warner GM, Bale LK, Torres VE, Harris PC, Oxvig C, Conover CA, Chini EN. Metalloproteinase PAPP-A regulation of IGF-1 contributes to polycystic kidney disease pathogenesis. JCI Insight. 2020 Feb 27;5(4):e135700. doi: 10.1172/jci.insight.135700. PMID: 31990681; PMCID: PMC7101148.

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Marouli E, Graff M, Medina-Gomez C, et al. Rare and low-frequency coding variants alter human adult height. Nature. 2017 Feb 9;542(7640):186-190. doi: 10.1038/nature21039

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Mikkelsen JH1, Resch ZT, Kalra B, Savjani G, Kumar A, Conover CA, Oxvig C. Indirect targeting of IGF receptor signaling in vivo by substrate-selective inhibition of PAPP-A proteolytic activity. Oncotarget. 2014 Jan ; 5(4):1014-25.

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Thomsen J, Hjortebjerg R, Espelund U, Ørtoft G, Vestergaard P, Magnusson NE, Conover CA, Tramm T, Hager H, Høgdall C, Høgdall E, Oxvig C, Frystyk J. PAPP-A proteolytic activity enhances IGF bioactivity in ascites from women with ovarian carcinoma. Oncotarget. 2015 Oct 13;6(31):32266-78.

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Torres D, Hou X, Bale L, Heinzen EP, Maurer MJ, Zanfagnin V, Oberg AL, Conover C, Weroha SJ. . Overcoming platinum resistance in ovarian cancer by targeting pregnancy-associated plasma protein-A. PLoS One. 2019 Nov 21;14(11):e0224564. doi: 10.1371/journal.pone.0224564

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Zhong Q, Chu H, Wang G, Zhang C, Li R, Guo F, et al. Structural insights into the covalent regulation of PAPP-A activity by proMBP and STC2. Cell Discov. 2022;8(137):1-17. doi:10.1038/s41421-022-00502-2.

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