{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T11:31:59Z","timestamp":1789471919005,"version":"build-2803163510"},"reference-count":46,"publisher":"The Endocrine Society","issue":"12","license":[{"start":{"date-parts":[[2024,5,16]],"date-time":"2024-05-16T00:00:00Z","timestamp":1715817600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012264","name":"NIH","doi-asserted-by":"publisher","award":["AI170571"],"award-info":[{"award-number":["AI170571"]}],"id":[{"id":"10.13039\/501100012264","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,11,18]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Context<\/jats:title>\n                  <jats:p>Proptosis in thyroid eye disease (TED) can result in facial disfigurement and visual dysfunction. Treatment with insulin-like growth factor I receptor (IGF-IR) inhibitors has been shown to be effective in reducing proptosis but with side effects.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Objective<\/jats:title>\n                  <jats:p>To test the hypothesis that inhibition of IGF-IR indirectly and more selectively with PAPP-A inhibitors attenuates IGF-IR signaling in TED. Informed consent was obtained from patients with TED undergoing surgery, and retro-orbital tissue was collected for fibroblast isolation and culture. Operations were performed in Mayo Clinic operating suites. Cell culture was performed in a sterile tissue culture facility. Retro-orbital tissue was collected from 19 patients with TED.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Treatment of TED fibroblasts with proinflammatory cytokines. Flow separation of CD34\u2212 and CD34+ orbital fibroblasts, the latter representing infiltrating fibrocytes into the orbit in TED. PAPP-A expression and proteolytic activity, IGF-I stimulation of phosphatidylinositol 3 kinase\/Akt pathway, and inhibition by immuno-neutralizing antibodies against PAPP-A, CD34+ status, and associated PAPP-A and IGF-IR expression were measured.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Proinflammatory cytokines markedly increased PAPP-A expression in TED fibroblasts. IGF-IR expression was not affected by cytokine treatment. Inhibition of PAPP-A's proteolytic activity suppressed IGF-IR activation in orbital fibroblasts from patients with TED. TED fibroblasts that were CD34+ represented \u223c80% of the cells in culture and accounted for \u223c70% of PAPP-A and IGF-IR\u2013expressing cells.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>These results support a role for PAPP-A in TED pathogenesis and indicate the potential for novel therapeutic targeting of the IGF axis.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1210\/clinem\/dgae339","type":"journal-article","created":{"date-parts":[[2024,5,15]],"date-time":"2024-05-15T20:40:51Z","timestamp":1715805651000},"page":"3119-3125","source":"Crossref","is-referenced-by-count":4,"title":["PAPP-A as a Potential Target in Thyroid Eye Disease"],"prefix":"10.1210","volume":"109","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4550-6633","authenticated-orcid":false,"given":"Cheryl A","family":"Conover","sequence":"first","affiliation":[{"name":"Division of Endocrinology, Mayo Clinic , Rochester, MN 55905 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurie K","family":"Bale","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Mayo Clinic , Rochester, MN 55905 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1408-8125","authenticated-orcid":false,"given":"Marius N","family":"Stan","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Mayo Clinic , Rochester, MN 55905 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","published-online":{"date-parts":[[2024,5,16]]},"reference":[{"issue":"8","key":"2024111804030142800_dgae339-B1","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1056\/NEJMra0905750","article-title":"Graves\u2019 ophthalmopathy","volume":"362","author":"Bahn","year":"2010","journal-title":"N Engl J Med"},{"issue":"3","key":"2024111804030142800_dgae339-B2","doi-asserted-by":"crossref","first-page":"1735","DOI":"10.1167\/iovs.14-14002","article-title":"Current concepts in the molecular pathogenesis of thyroid-associated ophthalmopathy","volume":"55","author":"Wang","year":"2014","journal-title":"Invest Ophthalmol Vis Sci"},{"issue":"3","key":"2024111804030142800_dgae339-B3","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1016\/j.beem.2011.11.007","article-title":"Evaluating Graves\u2019 orbitopathy","volume":"26","author":"Dolman","year":"2012","journal-title":"Best Pract Res Clin Endocrinol Metab"},{"key":"2024111804030142800_dgae339-B4","doi-asserted-by":"crossref","first-page":"739994","DOI":"10.3389\/fendo.2021.739994","article-title":"Orbital signaling in Graves\u2019 orbitopathy","volume":"12","author":"Draman","year":"2021","journal-title":"Front Endocrinol (Lausanne)"},{"issue":"2","key":"2024111804030142800_dgae339-B5","doi-asserted-by":"crossref","first-page":"101661","DOI":"10.1016\/j.beem.2022.101661","article-title":"Genetics and epigenetics of autoimmune thyroid diseases: translational implications","volume":"37","author":"Lee","year":"2023","journal-title":"Best Pract Res Clin Endocrinol Metab"},{"issue":"6","key":"2024111804030142800_dgae339-B6","doi-asserted-by":"crossref","first-page":"4397","DOI":"10.4049\/jimmunol.181.6.4397","article-title":"Evidence for an association between thyroid-stimulating hormone and insulin-like growth factor 1 receptors: a tale of two antigens implicated in Graves\u2019 disease","volume":"181","author":"Tsui","year":"2008","journal-title":"J Immunol"},{"key":"2024111804030142800_dgae339-B7","doi-asserted-by":"crossref","first-page":"653627","DOI":"10.3389\/fendo.2021.653627","article-title":"Insulin-like growth factor pathway and the thyroid","volume":"12","author":"Smith","year":"2021","journal-title":"Front Endocrinol (Lausanne)"},{"issue":"9","key":"2024111804030142800_dgae339-B8","doi-asserted-by":"crossref","first-page":"983","DOI":"10.1089\/thy.2007.0404","article-title":"Unique attributes of orbital fibroblasts and global alterations in IGF-1 receptor signaling could explain thyroid-associated ophthalmopathy","volume":"18","author":"Smith","year":"2008","journal-title":"Thyroid"},{"issue":"1","key":"2024111804030142800_dgae339-B9","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1210\/er.2018-00066","article-title":"Insulin-like growth factor-I receptor and thyroid-associated ophthalmopathy","volume":"40","author":"Smith","year":"2019","journal-title":"Endocr Rev"},{"key":"2024111804030142800_dgae339-B10","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.exer.2015.02.007","article-title":"Current perspectives on the role of orbital fibroblasts in the pathogenesis of Graves\u2019 ophthalmopathy","volume":"142","author":"Dik","year":"2016","journal-title":"Exp Eye Res"},{"issue":"12","key":"2024111804030142800_dgae339-B11","doi-asserted-by":"crossref","first-page":"6348","DOI":"10.4049\/jimmunol.170.12.6348","article-title":"Immunoglobulin activation of T cell chemoattractant expression in fibroblasts from patients with Graves\u2019 disease is mediated through the insulin-like growth factor I receptor pathway","volume":"170","author":"Pritchard","year":"2003","journal-title":"J Immunol"},{"issue":"4","key":"2024111804030142800_dgae339-B12","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1111\/bph.13693","article-title":"Inhibiting thyrotropin\/insulin-like growth factor 1 receptor crosstalk to treat Graves\u2019 ophthalmopathy: studies in orbital fibroblasts in vitro","volume":"174","author":"Place","year":"2017","journal-title":"Br J Pharmacol"},{"issue":"2","key":"2024111804030142800_dgae339-B13","doi-asserted-by":"crossref","first-page":"151902","DOI":"10.1016\/j.imbio.2019.151902","article-title":"Insulin-like growth factor-1 enhances the expression of functional TSH receptor in orbital fibroblasts from thyroid-associated ophthalmopathy","volume":"225","author":"Paik","year":"2020","journal-title":"Immunobiology"},{"issue":"9","key":"2024111804030142800_dgae339-B14","doi-asserted-by":"crossref","first-page":"E1635","DOI":"10.1210\/jc.2014-1580","article-title":"Teprotumumab, an IGF-1R blocking monoclonal antibody inhibits TSH and IGF-1 action in fibrocytes","volume":"99","author":"Chen","year":"2014","journal-title":"J Clin Endocrinol Metab"},{"issue":"2","key":"2024111804030142800_dgae339-B15","doi-asserted-by":"crossref","first-page":"383","DOI":"10.3390\/cells10020383","article-title":"Lessons learned from targeting IGF-I receptor in thyroid-associated ophthalmopathy","volume":"10","author":"Janssen","year":"2021","journal-title":"Cells"},{"issue":"18","key":"2024111804030142800_dgae339-B16","doi-asserted-by":"crossref","first-page":"1748","DOI":"10.1056\/NEJMoa1614949","article-title":"Teprotumumab for thyroid-associated ophthalmopathy","volume":"376","author":"Smith","year":"2017","journal-title":"N Engl J Med"},{"issue":"4","key":"2024111804030142800_dgae339-B17","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1056\/NEJMoa1910434","article-title":"Teprotumumab for the treatment of active thyroid eye disease","volume":"382","author":"Douglas","year":"2020","journal-title":"N Engl J Med"},{"issue":"11","key":"2024111804030142800_dgae339-B18","doi-asserted-by":"crossref","first-page":"1627","DOI":"10.1016\/j.ophtha.2021.04.024","article-title":"Teprotumumab: interpreting the clinical trials in the context of thyroid eye disease pathogenesis and current therapies","volume":"128","author":"Winn","year":"2021","journal-title":"Ophthalmology"},{"issue":"9","key":"2024111804030142800_dgae339-B19","doi-asserted-by":"crossref","first-page":"e654","DOI":"10.1210\/clinem\/dgad213","article-title":"The adverse effects profile of teprotumumab","volume":"108","author":"Stan","year":"2023","journal-title":"J Clin Endocrinol Metab"},{"issue":"6","key":"2024111804030142800_dgae339-B20","doi-asserted-by":"crossref","first-page":"3149","DOI":"10.1073\/pnas.96.6.3149","article-title":"The insulin-like growth factor (IGF)-dependent IGF binding protein-4 protease secreted by human fibroblasts is pregnancy-associated plasma protein-A","volume":"96","author":"Lawrence","year":"1999","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"5","key":"2024111804030142800_dgae339-B21","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1016\/j.tem.2012.02.008","article-title":"Key questions and answers about pregnancy-associated plasma protein-A","volume":"23","author":"Conover","year":"2012","journal-title":"Trends Endocrinol Metab"},{"key":"2024111804030142800_dgae339-B22","doi-asserted-by":"crossref","first-page":"1012","DOI":"10.1210\/endrev\/bnad017","article-title":"The pregnancy-associated plasma protein-A (PAPP-A) story","volume":"44","author":"Conover","year":"2023","journal-title":"Endocr Rev"},{"issue":"6","key":"2024111804030142800_dgae339-B23","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1093\/gerona\/glq032","article-title":"Longevity and age-related pathology of mice deficient in pregnancy-associated plasma protein-A","volume":"65","author":"Conover","year":"2010","journal-title":"J Gerontol A Biol Sci Med Sci"},{"issue":"1","key":"2024111804030142800_dgae339-B24","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1530\/JOE-13-0167","article-title":"Mice deficient in PAPP-A show resistance to the development of diabetic nephropathy","volume":"219","author":"Mader","year":"2013","journal-title":"J Endocrinol"},{"issue":"10","key":"2024111804030142800_dgae339-B25","doi-asserted-by":"crossref","first-page":"bqaa160","DOI":"10.1210\/endocr\/bqaa160","article-title":"Genetic and pharmacological inhibition of PAPP-A protects against visceral obesity in mice","volume":"161","author":"Ramakrishna","year":"2020","journal-title":"Endocrinology"},{"issue":"6","key":"2024111804030142800_dgae339-B26","doi-asserted-by":"crossref","first-page":"942","DOI":"10.1111\/j.1474-9726.2010.00630.x","article-title":"PAPP-A: a new anti-aging target?","volume":"9","author":"Conover","year":"2010","journal-title":"Aging Cell"},{"issue":"1","key":"2024111804030142800_dgae339-B27","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1007\/s12265-015-9666-9","article-title":"Targeted inhibition of pregnancy-associated plasma protein-A activity reduces atherosclerotic plaque burden in mice","volume":"9","author":"Conover","year":"2016","journal-title":"J Cardiovasc Transl Res"},{"issue":"12","key":"2024111804030142800_dgae339-B28","doi-asserted-by":"crossref","first-page":"1696","DOI":"10.1161\/CIRCRESAHA.106.146183","article-title":"Genetic deletion of pregnancy-associated plasma protein-A is associated with resistance to atherosclerotic lesion development in apolipoprotein E-deficient mice challenged with a high-fat diet","volume":"100","author":"Harrington","year":"2007","journal-title":"Circ Res"},{"issue":"3","key":"2024111804030142800_dgae339-B29","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1089\/105072502753600133","article-title":"Orbital fibroblasts exhibit a novel pattern of responses to proinflammatory cytokines: potential basis for the pathogenesis of thyroid-associated ophthalmopathy","volume":"12","author":"Smith","year":"2002","journal-title":"Thyroid"},{"key":"2024111804030142800_dgae339-B30","doi-asserted-by":"crossref","first-page":"654473","DOI":"10.3389\/fendo.2021.654473","article-title":"Cytokines as targets of novel therapies for Graves\u2019 ophthalmopathy","volume":"12","author":"Fallahi","year":"2021","journal-title":"Front Endocrinol (Lausanne)"},{"issue":"9","key":"2024111804030142800_dgae339-B31","first-page":"2620","article-title":"Evidence for cellular heterogeneity in primary cultures of human orbital fibroblasts","volume":"80","author":"Smith","year":"1995","journal-title":"J Clin Endocrinol Metab"},{"issue":"2","key":"2024111804030142800_dgae339-B32","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1210\/jc.2018-01493","article-title":"Potential roles of CD34+ fibrocytes masquerading as orbital fibroblasts in thyroid-associated ophthalmopathy","volume":"104","author":"Smith","year":"2019","journal-title":"J Clin Endocrinol Metab"},{"issue":"1","key":"2024111804030142800_dgae339-B33","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1210\/jc.2009-1614","article-title":"Increased generation of fibrocytes in thyroid-associated ophthalmopathy","volume":"95","author":"Douglas","year":"2010","journal-title":"J Clin Endocrinol Metab"},{"key":"2024111804030142800_dgae339-B34","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.exer.2012.11.014","article-title":"Insulin-like growth factor 1 promotes the proliferation and adipogenesis of orbital adipose-derived stromal cells in thyroid-associated ophthalmopathy","volume":"107","author":"Zhao","year":"2013","journal-title":"Exp Eye Res"},{"issue":"4","key":"2024111804030142800_dgae339-B35","doi-asserted-by":"crossref","first-page":"1014","DOI":"10.18632\/oncotarget.1629","article-title":"Indirect targeting of IGF receptor signaling in vivo by substrate-selective inhibition of PAPP-A proteolytic activity","volume":"5","author":"Mikkelsen","year":"2014","journal-title":"Oncotarget"},{"issue":"24","key":"2024111804030142800_dgae339-B36","doi-asserted-by":"crossref","first-page":"16772","DOI":"10.1074\/jbc.M802429200","article-title":"Inhibition of the proteolytic activity of pregnancy-associated plasma protein-A by targeting substrate exosite binding","volume":"283","author":"Mikkelsen","year":"2008","journal-title":"J Biol Chem"},{"issue":"2","key":"2024111804030142800_dgae339-B37","doi-asserted-by":"crossref","first-page":"930","DOI":"10.1210\/jc.2003-031427","article-title":"Evidence for enhanced adipogenesis in the orbits of patients with Graves\u2019 ophthalmopathy","volume":"89","author":"Kumar","year":"2004","journal-title":"J Clin Endocrinol Metab"},{"issue":"3","key":"2024111804030142800_dgae339-B38","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1530\/JME-11-0006","article-title":"A stimulatory TSH receptor antibody enhances adipogenesis via phosphoinositide 3-kinase activation in orbital preadipocytes from patients with Graves\u2019 ophthalmopathy","volume":"46","author":"Kumar","year":"2011","journal-title":"J Mol Endocrinol"},{"issue":"4","key":"2024111804030142800_dgae339-B39","doi-asserted-by":"crossref","first-page":"e14006","DOI":"10.14814\/phy2.14006","article-title":"Cellular characterization of human epicardial adipose tissue: highly expressed PAPP-A regulates insulin-like growth factor I signaling in human cardiomyocytes","volume":"7","author":"Conover","year":"2019","journal-title":"Physiol Rep"},{"key":"2024111804030142800_dgae339-B40","doi-asserted-by":"crossref","first-page":"111548","DOI":"10.1016\/j.exger.2021.111548","article-title":"Brain-specific PAPP-A knock-out mice?","volume":"154","author":"Bale","year":"2021","journal-title":"Exp Gerontol"},{"issue":"1","key":"2024111804030142800_dgae339-B41","doi-asserted-by":"crossref","first-page":"T69","DOI":"10.1530\/JME-17-0311","article-title":"IGF1 receptor signaling pathways","volume":"61","author":"Hakuno","year":"2018","journal-title":"J Mol Endocrinol"},{"issue":"5","key":"2024111804030142800_dgae339-B42","doi-asserted-by":"crossref","first-page":"E796","DOI":"10.1210\/jc.2013-3072","article-title":"Human fibrocytes express multiple antigens associated with autoimmune endocrine diseases","volume":"99","author":"Fernando","year":"2014","journal-title":"J Clin Endocrinol Metab"},{"issue":"8","key":"2024111804030142800_dgae339-B43","doi-asserted-by":"crossref","first-page":"895","DOI":"10.3390\/cells8080895","article-title":"Therapeutic targeting of the IGF axis","volume":"8","author":"Osher","year":"2019","journal-title":"Cells"},{"issue":"4","key":"2024111804030142800_dgae339-B44","doi-asserted-by":"crossref","first-page":"973","DOI":"10.1158\/1535-7163.MCT-14-0880","article-title":"A novel neutralizing antibody targeting pregnancy-associated plasma protein-a inhibits ovarian cancer growth and ascites accumulation in patient mouse tumorgrafts","volume":"14","author":"Becker","year":"2015","journal-title":"Mol Cancer Ther"},{"issue":"5","key":"2024111804030142800_dgae339-B45","doi-asserted-by":"crossref","first-page":"1681","DOI":"10.1210\/jc.2011-2890","article-title":"A stimulatory thyrotropin receptor antibody enhances hyaluronic acid synthesis in Graves\u2019 orbital fibroblasts: inhibition by an IGF-I receptor blocking antibody","volume":"97","author":"Kumar","year":"2012","journal-title":"J Clin Endocrinol Metab"},{"issue":"10","key":"2024111804030142800_dgae339-B46","doi-asserted-by":"crossref","first-page":"5076","DOI":"10.1210\/jc.2004-0716","article-title":"Immunoglobulins from patients with Graves\u2019 disease induce hyaluronan synthesis in their orbital fibroblasts through the self-antigen, insulin-like growth factor-I receptor","volume":"89","author":"Smith","year":"2004","journal-title":"J Clin Endocrinol Metab"}],"container-title":["The Journal of Clinical Endocrinology &amp; Metabolism"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jcem\/advance-article-pdf\/doi\/10.1210\/clinem\/dgae339\/58374449\/dgae339.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jcem\/article-pdf\/109\/12\/3119\/60680506\/dgae339.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jcem\/article-pdf\/109\/12\/3119\/60680506\/dgae339.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,11,18]],"date-time":"2024-11-18T04:04:14Z","timestamp":1731902654000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jcem\/article\/109\/12\/3119\/7675084"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,5,16]]},"references-count":46,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2024,5,16]]},"published-print":{"date-parts":[[2024,11,18]]}},"URL":"https:\/\/doi.org\/10.1210\/clinem\/dgae339","relation":{},"ISSN":["0021-972X","1945-7197"],"issn-type":[{"value":"0021-972X","type":"print"},{"value":"1945-7197","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2024,12]]},"published":{"date-parts":[[2024,5,16]]}}}