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The Effects of Retinoic Acid on the Insulin-like Growth Factor Axis in Primary Tissue Culture from Hyperparathyroidism

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Abstract

Background

The importance of the IGF system in HPT has been previously demonstrated. Additionally, the role of vitamin A in HPT has been reported. Retinoic acid (RA), a derivative of vitamin A, is a ligand for the IGF II receptor (IGF2R). We have evaluated the interactions of RA with the IGF system in a primary parathyroid cell culture model.

Materials and Methods

Primary cell cultures were prepared from nine patients. Following adhesion, the cells were transferred to serum-free medium and dosed once with growth factors ± RA for 96 hours. Proliferation was assessed by measuring tritiated thymidine incorporation.

Results

Compared with the control group (100%), both IGF I and II increased DNA synthesis significantly. Retinoic acid significantly reduced the basal DNA synthesis to 82.2% ± 4.2% compared with control (P < 0.05). Retinoic acid ×10−5 M completely abrogated the proliferative actions of IGF II (70.2% ± 9.7%, P < 0.05) but had no significant effect on the IGF I response (P > 0.05). To evaluate the role of IGF2R or IGFBPs in mediating the actions of RA, the IGF II analogs [Leu27]IGF II (10–20-fold reduced IGF I receptor affinity) and des(1–6) IGF II (lower IGFBP binding affinity) were used. The IGF II inhibitory effect of RA was enhanced in the presence of analogs [Leu27]IGF II (P = 0.052) but not with des(1–6)IGF II (P > 0.05), compared with wild-type IGF II.

Conclusions

These data implicate a novel antiproliferative role for RA in enhancing the pericellular clearance of IGF II via the IGF2R preventing ligand activation of the IGF I receptor. This may have broader implications for RA effects in other tumors.

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Acknowledgments

This research was supported by grants from The Royal College of Surgeons Research Fellowship, Mason’s Medical Research Foundation, the Hamamelis Trust, Royal Society, the Lord Dowding Fund for Humane Research.

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Authors and Affiliations

  1. Division of Surgery, University of Bristol, Bristol Royal Infirmary, Marlborough Street, Bristol, United Kingdom, BS2 8HW

    Chris K.M. Wong PhD, Teresa Lai BSc, Jeffrey M.P. Holly BSc, PhD & John R. Farndon MD

  2. Department of Endocrine Surgery, University Hospital of Wales, Cardiff, United Kingdom, CF14 1XW

    Malcolm H. Wheeler MD

  3. Department of Exercise and Sport Science, MMU Cheshire, Hassall Road, Alsager, Cheshire, United Kingdom, ST7 2HL

    Claire E.H. Stewart BSc, PhD

Authors
  1. Chris K.M. Wong PhD
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  2. Teresa Lai BSc
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  3. Jeffrey M.P. Holly BSc, PhD
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  4. Malcolm H. Wheeler MD
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  5. Claire E.H. Stewart BSc, PhD
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  6. John R. Farndon MD
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Corresponding author

Correspondence to Chris K.M. Wong PhD.

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Wong, C.K., Lai, T., Holly, J.M. et al. The Effects of Retinoic Acid on the Insulin-like Growth Factor Axis in Primary Tissue Culture from Hyperparathyroidism. World J. Surg. 30, 714–720 (2006). https://doi.org/10.1007/s00268-005-0340-2

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