Thiazolidinediones induce osteocyte apoptosis and increase sclerostin expression.
OBJECTIVE
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.
Mabilleau
G
G
Nuffield Department of Orthopaedics, Institute of Musculoskeletal Sciences, University of Oxford, Oxford, UK. guillaume.mabilleau@ndorms.ox.ac.uk
Mieczkowska
A
A
Edmonds
M E
ME
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D019485:Bone Morphogenetic Proteins / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D005260:Female; D005819:Genetic Markers / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D010011:Osteocytes / Q000187:drug effects / Q000378:metabolism*; D017698:Postmenopause; D045162:Thiazolidinediones / Q000009:adverse effects* / Q000378:metabolism; D015854:Up-Regulation
D048868:Adaptor Proteins, Signal Transducing; D019485:Bone Morphogenetic Proteins; D005819:Genetic Markers; C422903:SOST protein, human; D045162:Thiazolidinediones