The authors have no conflict of interest
Serotonin Regulates Osteoclast Differentiation Through Its Transporter†
Article first published online: 21 JUN 2004
Copyright © 2004 ASBMR
Journal of Bone and Mineral Research
Volume 19, Issue 9, pages 1420–1431, September 2004
How to Cite
Battaglino, R., Fu, J., Späte, U., Ersoy, U., Joe, M., Sedaghat, L. and Stashenko, P. (2004), Serotonin Regulates Osteoclast Differentiation Through Its Transporter. J Bone Miner Res, 19: 1420–1431. doi: 10.1359/JBMR.040606
- Issue published online: 2 DEC 2009
- Article first published online: 21 JUN 2004
- Manuscript Accepted: 7 MAY 2004
- Manuscript Revised: 9 APR 2004
- Manuscript Received: 16 FEB 2004
- neural regulation
5-HTT mediates antidepressant-sensitive clearance of 5-HT after its release into neural synapses. We found increased expression of 5-HTT in RANKL-induced osteoclast-like cells. Fluoxetine, an inhibitor of 5-HTT, reduced osteoclast differentiation but not activation. Reserpine, an inhibitor of 5-HT intracellular transport, potentiated differentiation. These results indicate a role for 5-HTT in osteoclast function and suggest that commonly used antidepressive agents may affect bone mass.
Introduction: Interactions between the serotonergic and skeletal systems are suggested by various clinical observations but are poorly understood.
Materials and Methods: Using gene microarrays, we found that the serotonin transporter (5-HTT) was strongly expressed in RANKL-induced osteoclasts. Using RANKL stimulation of RAW264.7 cells and mouse bone marrow cells as a model system for osteoclast differentiation, we studied the possible role/s of the different components of the serotonin (5-HT) system on the differentiation process.
Results: Osteoclast 5-HTT exhibited typical 5-HT uptake activity that was inhibitable by fluoxetine (Prozac). Fluoxetine reduced osteoclast differentiation but did not inhibit the activation of preformed osteoclasts, whereas the addition of 5-HT itself enhanced differentiation. Fluoxetine-treated osteoclast precursors had reduced NF-κB activation and elevated inhibitory protein κBα (IκBα) levels compared with untreated cells. 5-HT, on the other hand, resulted in activation of NF-κB. Reserpine inhibition of intracellular transport of 5-HT into cytoplasmic vesicles potentiated RANKL-induced osteoclast formation, suggesting the importance of intracellular 5-HT in regulating osteoclast differentiation. Reserpine also modestly enhanced the expression of the osteoclast marker TRACP in the absence of RANKL.
Conclusions: Taken together, these data suggest that the 5-HT system plays an important role in bone homeostasis through effects on osteoclast differentiation and implies that commonly used antidepressive agents may affect bone mass.