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Locally produced insulin-like growth factor-1 by orbital fibroblasts as implicative pathogenic factor rather than systemically circulated IGF-1 for patients with thyroid-associated ophthalmopathy

  • Oculoplastics and Orbit
  • Published:
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Abstract

Background

To determine the correlation between clinical activity scores (CAS) of thyroid-associated ophthalmology (TAO) patients and their locally produced and/or systemically circulating insulin-like growth factor-1 (IGF-1), and to assess the possible pathogenic role of IGF-1 in TAO.

Methods

Eighteen patients with TAO, and 16 age- and gender-matched controls were included in the present study. Among them, orbital tissue surgically collected from five TAO patients and five healthy controls was used for orbital fibroblasts (OFs) culture and in vitro study. Total and free IGF-1 in serum levels were determined by an ELISA kit for all the participants in this study. The IGF-1 concentration in culture media of OFs was determined using a noncompetitive time-resolved radioimmunoassay kit. The effect of octreotide (OCT), a somatostatin analog, on proliferation of OFs was assessed using the MTT assay. IGF-1 mRNA levels were measured by real-time polymerase chain reaction (PCR).

Results

Cultured OFs from both TAO patients and normal donors secreted IGF-1, and the secretion continued over a 72 hour period in vitro. IGF-1 secretion by OFs was elevated in the TAO group. Both the elevated secretion of IGF-1 and proliferation of OFs from TAO patients could be inhibited by OCT. Result of quantitative PCR showed that IGF-1 mRNA expression by OFs in TAO patients was up-regulated more than 2-fold compared with normal controls (P < 0.05), and this up-regulation was prevented by OCT treatment. Total and free serum IGF-1 levels in TAO patients were similar to those of normal controls. However, the IGF-1 level in cultured medium of OFs from TAO patients, but not serum levels of IGF-1, was positively correlated with CAS (r = 0.97, P = 0.017).

Conclusions

Local production of IGF-1 by cultured OFs may be positively correlated with CAS, whereas systemically circulating IGF-1 may remain unchanged in TAO patients. Thus, locally produced IGF-1 may develop a role in the pathogenesis of TAO in an autocrine or paracrine fashion. The inhibitory effect of OCT on proliferating and IGF-1 mRNA levels of cultured OFs from TAO patients may be used as the mechanistic explanation for somatostatin analog as a valuable option in the treatment of TAO.

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Abbreviations

IGF-1:

insulin-like growth factor-1

OFs:

orbital fibroblasts

TAO:

thyroid-associated ophthalmopathy

OCT:

octreotide

PCR:

polymerase chain reaction

GD:

Graves’ disease

CAS:

clinical activity score

PUMCH:

Peking Union Medical College Hospital

MTT:

tetrazolium salts

ANOVA:

analysis of variance

TSH:

thyroid-stimulating hormone

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Acknowledgement

We thank Dr. Fang Qi (Department of E.N.T. in PUMCH) for tissue collection and Dr. Xiaolan Lian (Department of Endocrinology in PUMCH) for the diagnosis and consultation of patients with GD and Dr. Gui-shuang Ying (The Center for Preventive Ophthalmology and Biostatistics, University of Pennsylvania Perelman School of Medicine) for biostatistics analysis. We acknowledge the help of Dr. Wenchao Song (Institute for the Translational Medicine and Therapeutics, University of Pennsylvania Perelman School of Medicine) for preparing this paper. This study was supported by the unrestricted grant from Peking Union Medical College Hospital and State Scholarship Fund (File No. 2010621116) of China Scholarship Council, Ministry of Education of the P. R. China.

Disclosure

The authors have no financial conflict of interest. The authors confirm that they have full control to all data in the study, and agree to allow Graefe’s Archive for Clinical and Experimental Ophthalmology to review data upon request.

Author information

Authors and Affiliations

  1. The F. M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA

    Delu Song

  2. Department of Ophthalmology, Drexel University College of Medicine, Philadelphia, PA, 19129, USA

    Weiye Li

  3. Department of Ophthalmology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, China

    Delu Song, Renyan Wang, Yong Zhong, Weiye Li, Hui Li & Fangtian Dong

  4. Department of Ophthalmology, Peking Union Medical College Hospital, 1# Dongdan Shuaifuyuan, Beijing, 100730, China

    Yong Zhong

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  1. Delu Song
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  2. Renyan Wang
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  3. Yong Zhong
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Corresponding author

Correspondence to Yong Zhong.

Additional information

Clinical trial registration: ISRCTN34713784 (http://www.controlled-trials.com/ISRCTN34713784/)

This is the first study that demonstrated locally produced IGF-1 may be involved in the pathogenesis of TAO through an autocrine/paracrine mechanism.

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Song, D., Wang, R., Zhong, Y. et al. Locally produced insulin-like growth factor-1 by orbital fibroblasts as implicative pathogenic factor rather than systemically circulated IGF-1 for patients with thyroid-associated ophthalmopathy. Graefes Arch Clin Exp Ophthalmol 250, 433–440 (2012). https://doi.org/10.1007/s00417-011-1876-5

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  • DOI: https://doi.org/10.1007/s00417-011-1876-5

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