Modulation of expression of somatostatin receptor subtypes in Graves' ophthalmopathy orbits: relevance to novel analogs.
Apart from evaluating orbital inflammation in Graves' ophthalmopathy (GO), somatostatin (SST) analogs have been proposed as a therapy, but recent trials were disappointing. We aimed to measure somatostatin receptor (SSTR) expression in orbital tissues ex vivo and determine whether the new broad-affinity analog SOM230 might be of therapeutic use. Orbital adipose/connective tissues from 29 GO patients and 10 normal individuals were analyzed. Transcripts were quantified using SYBR Green and a light cycler. In vitro models were used to investigate whether thyrotropin receptor activation (as occurs via thyroid stimulating antibodies) or adipogenesis affected SSTR expression in primary preadipocytes and to compare the biological activity of octreotide and SOM230 in their modulation. The expression of SSTR1 was significantly higher in GO patients than normal controls (P = 0.024). Although differences in the expression of SSTR2 were not significant, 39% of GO samples had levels above the 97th percentile of the controls. SSTR3, -4, and -5 were at or below the limit of detection (LOD). The lymphocyte contribution was minimal, since CD3alpha transcripts were at the LOD. TSH receptor activation did not modulate SSTR expression. An in vitro model of adipogenesis indicated upregulation of SSTR1 and SSTR2 during differentiation. SOM230 produced significantly greater inhibition of orbital preadipocyte proliferation than octreotide. Ex vivo analysis of orbital tissues reveals upregulation of SSTR1 and -2 in a group of GO patients. Adipogenesis, a process occurring in GO orbits, provides one possible explanation for some of the observed increase.
Cozma
Irina
I
School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK.
Zhang
Lei
L
Uddin
James
J
Lane
Carol
C
Rees
Aled
A
Ludgate
Marian
M
D017667:Adipocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000368:Aged; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D015870:Gene Expression; D049970:Graves Ophthalmopathy / Q000188:drug therapy / Q000235:genetics*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D015282:Octreotide / Q000494:pharmacology; D009915:Orbit / Q000378:metabolism*; D047495:PPAR gamma / Q000235:genetics; D017481:Receptors, Somatostatin / Q000235:genetics*; D011989:Receptors, Thyrotropin / Q000235:genetics; D013004:Somatostatin / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D014162:Transfection
D022782:CCAAT-Enhancer-Binding Protein-beta; D047495:PPAR gamma; D017481:Receptors, Somatostatin; D011989:Receptors, Thyrotropin; C101130:somatostatin receptor type 1; D013004:Somatostatin; C517782:pasireotide; D015282:Octreotide