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Androgens and estrogens prevent rosiglitazone-induced adipogenesis in human mesenchymal stem cells
S Benvenuti1, I Cellai, P Luciani
1Endocrine Unit, Department of Clinical Physiopathology, Center for Research, Transfer and High Education on Chronic, Inflammatory, Degenerative and Neoplastic Disorders, University of Florence, Viale Pieraccini 6, Florence, Italy.
Abstract:
Thiazolidinediones (TZD), a class of anti-diabetic drugs, determine bone loss and increase fractures particularly in post-menopausal women, thus suggesting a protective role of sex steroids. We have previously demonstrated that the TZD rosiglitazone (RGZ) negatively affects bone mass by inhibiting osteoblastogenesis, yet inducing adipogenesis, in bone marrow-derived human mesenchymal stem cells (hMSC). The aim of this study was to determine whether estrogens and androgens are able to revert the effects of RGZ on bone. hMSC express estrogen receptor α and β and the androgen receptor. We found that 17β-estradiol (10 nM), the phytoestrogen genistein (10 nM), testosterone (10 nM) and the non-aromatizable androgens dihydrotestosterone (10 nM) and methyltrienolone (10 nM) effectively counteracted the adipogenic effect of RGZ (1 μM) in hMSC induced to differentiate into adipocytes, as determined by evaluating the expression of the adipogenic marker peroxisome proliferator-activated receptor γ and the percentage of fat cells. Furthermore, when hMSC were induced to differentiate into osteoblasts, all the above-mentioned molecules and also quercetin, another phytoestrogen, significantly reverted the inhibitory effect of RGZ on the expression of the osteogenic marker osteocalcin and decreased the number of fat cells observed after RGZ exposure. Our study represents, to our knowledge, the first demonstration in hMSC that androgens, independently of their aromatization, and estrogens are able to counteract the negative effects of RGZ on bone. Our data, yet preliminary, suggest the possibility to try to prevent the negative effects of TZD on bone, using steroid receptor modulators, such as plant-derived phytoestrogens, which lack evident adverse effects.
Insights
Sex steroids like estrogens and androgens, including phytoestrogens, can counteract bone loss caused by anti-diabetic drugs (TZDs). This study shows these compounds revert TZD-induced negative effects on bone cells.
Area of Science:
- Bone biology
- Endocrinology
- Pharmacology
Background:
- Thiazolidinediones (TZDs) are anti-diabetic drugs linked to bone loss and fractures, particularly in post-menopausal women.
- Previous research shows rosiglitazone (RGZ), a TZD, inhibits bone formation and promotes fat cell differentiation in human mesenchymal stem cells (hMSC).
- Sex steroids are suggested to play a protective role in bone health.
Purpose of the Study:
- To investigate if estrogens and androgens can reverse the detrimental effects of RGZ on bone.
- To explore the potential of phytoestrogens as therapeutic agents against TZD-induced bone loss.
Main Methods:
- Human mesenchymal stem cells (hMSC) were treated with RGZ and various sex steroids (17β-estradiol, testosterone, dihydrotestosterone, methyltrienolone) and phytoestrogens (genistein, quercetin).
- Cells were induced to differentiate into either adipocytes or osteoblasts.
- Adipogenesis was assessed by measuring peroxisome proliferator-activated receptor γ (PPARγ) expression and fat cell percentage.
- Osteogenesis was evaluated by measuring osteocalcin expression and assessing the number of fat cells.
Main Results:
- Estrogens (17β-estradiol, genistein) and androgens (testosterone, dihydrotestosterone, methyltrienolone) counteracted RGZ-induced adipogenesis in hMSC.
- These compounds, along with quercetin, reverted RGZ's inhibition of osteogenic marker osteocalcin expression.
- RGZ-induced increase in fat cells was reduced by estrogens and androgens.
Conclusions:
- Androgens, irrespective of aromatization, and estrogens effectively counteract RGZ's negative impact on bone cells (hMSC).
- Phytoestrogens show promise in preventing TZD-induced bone loss.
- This suggests potential therapeutic strategies using steroid receptor modulators, like phytoestrogens, to mitigate TZD side effects on bone.
