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Thiazolidinediones induce osteocyte apoptosis by a G protein-coupled receptor 40-dependent mechanism

Aleksandra Mieczkowska1, Michel F Baslé, Daniel Chappard

  • 1Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford OX3 7LD, United Kingdom.

The Journal of Biological Chemistry
|May 18, 2012
PubMed

Insights

Thiazolidinediones (TZDs) treatment for type 2 diabetes causes osteocyte apoptosis and sclerostin changes via distinct pathways. Understanding these mechanisms may reduce TZD-related bone fractures.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Endocrinology

Background:

  • Thiazolidinediones (TZDs) are used to treat type 2 diabetes mellitus.
  • Adverse effects including bone fractures have been linked to TZD use.
  • Previous studies indicated TZDs induce osteocyte apoptosis and sclerostin up-regulation, but mechanisms were unclear.

Purpose of the Study:

  • To elucidate the molecular mechanisms by which TZDs affect osteocytes.
  • To identify distinct signaling pathways responsible for TZD-induced osteocyte apoptosis and sclerostin up-regulation.

Main Methods:

  • Investigated TZD activation of Erk1/2 and p38 pathways.
  • Examined the role of Ras proteins and GPR40 in TZD signaling.
  • Assessed TZD activation of peroxisome proliferator-activated receptor-γ (PPARγ).

Main Results:

  • TZDs activated Erk1/2 and p38 pathways via Ras and GPR40, leading to osteocyte apoptosis.
  • TZDs activated PPARγ, leading to sclerostin up-regulation without inducing apoptosis.
  • Two distinct signaling pathways were identified in osteocytes responding to TZDs.

Conclusions:

  • TZDs activate separate molecular pathways in osteocytes, one causing cell death and another increasing sclerostin.
  • These distinct pathways may explain the increased risk of bone fractures observed in patients treated with TZDs.
  • Further research into these mechanisms could inform safer diabetes treatment strategies.

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