{Reference Type}: Journal Article
{Title}: PAPP-A as a Potential Target in Thyroid Eye Disease.
{Author}: Conover CA;Bale LK;Stan MN;
{Journal}: J Clin Endocrinol Metab
{Volume}: 0
{Issue}: 0
{Year}: 2024 May 16
{Factor}: 6.134
{DOI}: 10.1210/clinem/dgae339
{Abstract}: BACKGROUND: 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.
METHODS: Informed consent was obtained from TED patients undergoing surgery, and retro-orbital tissue collected for fibroblast isolation and culture.
METHODS: Surgeries were performed in Mayo Clinic operating suites. Cell culture was performed in a sterile tissue culture facility.
METHODS: Retro-orbital tissue was collected from 19 TED patients.
METHODS: 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.
METHODS: 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 ∼80% of the cells in culture and accounted for ∼70% 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.