Serotonin regulates osteoclast differentiation through its transporter

被引:159
作者
Battaglino, R [1 ]
Fu, J [1 ]
Späte, U [1 ]
Ersoy, U [1 ]
Joe, M [1 ]
Sedaghat, L [1 ]
Stashenko, P [1 ]
机构
[1] Forsyth Inst, Dept Cytokine Biol, Boston, MA 02115 USA
关键词
bone; osteoclasts; differentiation; serotonin; neural regulation;
D O I
10.1359/JBMR.040606
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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-kappaB activation and elevated inhibitory protein kappaBalpha (1kappaBalpha) levels compared with untreated cells. 5-HT, on the other hand, resulted in activation of NF-kappaB. 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 inarker TRACP in the absence of RANKL. Conclusions: Taken together, these data suggest that the 5-HT system plays an important role in bone horneostasis through effects on osteoclast differentiation and implies that commonly used antidepressive agents may affect bone mass.
引用
收藏
页码:1420 / 1431
页数:12
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