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Thiazolidinediones induce osteocyte apoptosis and increase sclerostin expression
G Mabilleau1, A Mieczkowska, M E Edmonds
1Nuffield Department of Orthopaedics, Institute of Musculoskeletal Sciences, University of Oxford, Oxford, UK. guillaume.mabilleau@ndorms.ox.ac.uk
Aims:
Thiazolidinediones (TZDs) are associated with a higher risk of bone fracture in women compared with men. The aim of the present study was to investigate whether TZDs could influence osteocyte behaviour and contribute to the skeletal phenotype observed in TZD-treated patients.
Methods:
The murine MLO-Y4 cell line was used as a source of osteocytes. These cells were cultured for 24 h with 0, 10(-8) m, 10(-7) m, 10(-6) m, 10(-5) m or 10(-4) m of pioglitazone, rosiglitazone or troglitazone in the presence or absence of 17beta-oestradiol. The extent of osteocyte apoptosis was assessed, as was the expression of the bone formation inhibitor sclerostin and receptor activator for nuclear factor kappaB ligand (RANKL) also.
Results:
In the absence of 17beta-oestradiol, pioglitazone, rosiglitazone and troglitazone induced osteocyte apoptosis dose-dependently even at the lowest concentration of 10(-8) m. Furthermore, the expression of sclerostin but not RANKL was significantly increased in TZD-treated cultures compared with untreated cultures. The presence of 17beta-oestradiol significantly reduced TZD-induced osteocyte apoptosis and also sclerostin up-regulation.
Conclusions:
These findings therefore raise the potential concern of using TZDs in post-menopausal women where the lack of oestrogen would not prevent osteocyte apoptosis and sclerostin up-regulation and may aggravate the reduction in bone mass in these patients.
Insights
Thiazolidinediones (TZDs) increase osteocyte apoptosis and sclerostin expression, potentially worsening bone loss in post-menopausal women lacking estrogen. This highlights risks associated with TZD use in this demographic.
Area of Science:
- Endocrinology and Bone Biology
- Pharmacology and Toxicology
Background:
- Thiazolidinediones (TZDs) are linked to increased bone fracture risk in women.
- The impact of TZDs on osteocyte behavior and skeletal health requires further investigation.
Purpose of the Study:
- To investigate the effects of TZDs on osteocyte apoptosis and gene expression.
- To determine if TZDs contribute to the observed skeletal phenotype in patients.
Main Methods:
- Murine MLO-Y4 osteocyte cell line cultured with varying concentrations of pioglitazone, rosiglitazone, and troglitazone.
- Assessment of osteocyte apoptosis, sclerostin, and RANKL expression.
- Experiments conducted with and without 17beta-estradiol.
Main Results:
- TZDs induced dose-dependent osteocyte apoptosis, even at low concentrations, in the absence of 17beta-estradiol.
- Sclerostin expression was significantly increased by TZDs, while RANKL expression remained unchanged.
- 17beta-estradiol significantly attenuated TZD-induced apoptosis and sclerostin upregulation.
Conclusions:
- TZDs may pose a significant risk to bone health in post-menopausal women due to estrogen deficiency.
- The observed osteocyte apoptosis and sclerostin upregulation by TZDs could exacerbate bone mass reduction in this population.
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