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The present study aimed to evaluate whether <jats:italic>Pappa2<\/jats:italic> deficiency and pharmacological manipulation of GH\/IGF1 system are associated with sex-specific differences in growth-related signaling pathways.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Plasma, hypothalamus, pituitary gland and liver of <jats:italic>Pappa2<\/jats:italic><jats:sup>ko\/ko<\/jats:sup> mice of both sexes, showing reduced skeletal growth, and liver of these mice treated with rhGH, rhIGF1 and rhPAPP-A2 from postnatal day (PND) 5 to PND35 were analyzed.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Reduced body and femur length of <jats:italic>Pappa2<\/jats:italic><jats:sup>ko\/ko<\/jats:sup> mice was associated with increases in: (1) components of IGF1 ternary complexes (IGF1, IGFBP5\/<jats:italic>Igfbp5<\/jats:italic>, <jats:italic>Igfbp3<\/jats:italic>, <jats:italic>Igfals<\/jats:italic>) in plasma, hypothalamus and\/or liver; and (2) key signaling regulators (phosphorylated PI3K, AKT, mTOR, GSK3\u03b2, ERK1\/2 and AMPK\u03b1) in hypothalamus, pituitary gland and\/or liver, with <jats:italic>Pappa2<\/jats:italic><jats:sup>ko\/ko<\/jats:sup> females having a more prominent effect. Compared to rhGH and rhIGF1, rhPAPP-A2 specifically induced: (1) increased body and femur length, and reduced plasma total IGF1 and IGFBP5 concentrations in <jats:italic>Pappa2<\/jats:italic><jats:sup>ko\/ko<\/jats:sup> females; and (2) increased <jats:italic>Igf1<\/jats:italic> and <jats:italic>Igf1r<\/jats:italic> levels and decreased <jats:italic>Ghr<\/jats:italic>, <jats:italic>Igfbp3<\/jats:italic> and <jats:italic>Igfals<\/jats:italic> levels in the liver of <jats:italic>Pappa2<\/jats:italic><jats:sup>ko\/ko<\/jats:sup> females. These changes were accompanied by lower phospho-STAT5, phospho-AKT and phospho-ERK2 levels and higher phospho-AMPK levels in the liver of <jats:italic>Pappa2<\/jats:italic><jats:sup>ko\/ko<\/jats:sup> females.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>Sex-specific differences in IGF1 system and signaling pathways are associated with <jats:italic>Pappa2<\/jats:italic> deficiency, pointing to rhPAPP-A2 as a promising drug to alleviate postnatal growth retardation underlying low IGF1 bioavailability in a female-specific manner.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s13293-024-00603-5","type":"journal-article","created":{"date-parts":[[2024,4,8]],"date-time":"2024-04-08T11:02:02Z","timestamp":1712574122000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Sex-based differences in growth-related IGF1 signaling in response to PAPP-A2 deficiency: comparative effects of rhGH, rhIGF1 and rhPAPP-A2 treatments"],"prefix":"10.1186","volume":"15","author":[{"given":"Mar\u00eda del Mar","family":"Fern\u00e1ndez-Arjona","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan Antonio","family":"Navarro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio Jes\u00fas","family":"L\u00f3pez-Gambero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marialuisa","family":"de Ceglia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miguel","family":"Rodr\u00edguez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leticia","family":"Rubio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fernando","family":"Rodr\u00edguez de Fonseca","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vicente","family":"Barrios","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie A.","family":"Chowen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jes\u00fas","family":"Argente","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia","family":"Rivera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5254-9802","authenticated-orcid":false,"given":"Juan","family":"Su\u00e1rez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,4,8]]},"reference":[{"issue":"4","key":"603_CR1","doi-asserted-by":"publisher","first-page":"363","DOI":"10.15252\/emmm.201506106","volume":"8","author":"A Dauber","year":"2016","unstructured":"Dauber A, Mu\u00f1oz-Calvo MT, Barrios V, Domen\u00e9 HM, Kloverpris S, Serra-Juh\u00e9 C, Desikan V, Pozo J, Muzumdar R, Martos-Moreno G\u00c1, Hawkins F, Jasper HG, Conover CA, Frystyk J, Yakar S, Hwa V, Chowen JA, Oxvig C, Rosenfeld RG, P\u00e9rez-Jurado LA, Argente J. 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