PAPP-A as a Potential Target in Thyroid Eye Disease.

Publisher: Oxford University Press Country of Publication: United States NLM ID: 0375362 Publication Model: Print Cited Medium: Internet ISSN: 1945-7197 (Electronic) Linking ISSN: 0021972X NLM ISO Abbreviation: J Clin Endocrinol Metab Subsets: MEDLINE

Publication: 2017- : New York : Oxford University Press
Original Publication: Springfield, Ill. : Charles C. Thomas

Graves Ophthalmopathy*/metabolism ; Graves Ophthalmopathy*/pathology ; Graves Ophthalmopathy*/drug therapy ; Fibroblasts*/metabolism ; Fibroblasts*/drug effects ; Receptor, IGF Type 1*/metabolism ; Receptor, IGF Type 1*/antagonists & inhibitors ; Pregnancy-Associated Plasma Protein-A*/metabolism; Humans ; Female ; Male ; Cells, Cultured ; Orbit/pathology ; Orbit/metabolism ; Signal Transduction/drug effects ; Middle Aged ; Insulin-Like Growth Factor I/metabolism ; Adult ; Cytokines/metabolism

Context: 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.
Objective: 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.
Methods: Treatment of TED fibroblasts with proinflammatory cytokines. Flow separation of CD34- 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.
Results: 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 ∼80% of the cells in culture and accounted for ∼70% of PAPP-A and IGF-IR-expressing cells.
Conclusion: These results support a role for PAPP-A in TED pathogenesis and indicate the potential for novel therapeutic targeting of the IGF axis.
(© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

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R03 AI170571 United States AI NIAID NIH HHS; AI170571 United States GF NIH HHS

Keywords: PAPP-A; fibrocytes; insulin-like growth factor; proinflammatory cytokines; thyroid eye disease

EC 2.7.10.1 (Receptor, IGF Type 1)
EC 3.4.24.- (Pregnancy-Associated Plasma Protein-A)
67763-96-6 (Insulin-Like Growth Factor I)
0 (Cytokines)
0 (IGF1R protein, human)

Date Created: 20240516 Date Completed: 20241117 Latest Revision: 20241120

20241120

PMC11570381

10.1210/clinem/dgae339

38752390