PAPP-A as a Potential Target in Thyroid Eye Disease.
J Clin Endocrinol Metab
; 2024 May 16.
Article
in En
| MEDLINE
| ID: mdl-38752390
ABSTRACT
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.DESIGN:
Informed consent was obtained from TED patients undergoing surgery, and retro-orbital tissue collected for fibroblast isolation and culture.SETTING:
Surgeries were performed in Mayo Clinic operating suites. Cell culture was performed in a sterile tissue culture facility. PATIENT SAMPLES Retro-orbital tissue was collected from 19 TED patients.INTERVENTIONS:
Treatment of TED fibroblasts with pro-inflammatory cytokines. Flow separation of CD34- and CD34+ orbital fibroblasts, the latter representing infiltrating fibrocytes into the orbit in TED. MAIN OUTCOMEMEASURES:
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.RESULTS:
Pro-inflammatory 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 TED patients. TED fibroblasts that were CD34+ represented â¼80% of the cells in culture and accounted for â¼70% of PAPP-A and IGF-IR expressing cells.CONCLUSIONS:
These results support a role for PAPP-A in TED pathogenesis and indicate the potential for novel therapeutic targeting of the IGF axis.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Language:
En
Journal:
J Clin Endocrinol Metab
Year:
2024
Type:
Article
Affiliation country:
United States