Serotonin Regulates Osteoclast Differentiation Through Its Transporter

Abstract

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-B activation and elevated inhibitory protein B␣ (IB␣) levels compared with untreated cells. 5-HT, on the other hand, resulted in activation of NF-B. 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.

A link between depression and bone metabolism: what are the implications for treatment?

“…Receptors for serotonin have been found on osteoblasts [36], and several studies have reported that SSRIs induce a loss of bone mass in mice [35,37]. This is consistent with evidence from observational studies in humans, which report that SSRI use among older adults is associated with low BMD, independent of the effects of depression [38], and heightened BMD loss over time [39].…”

Spinal cord injury causes rapid osteoclastic resorption and growth plate abnormalities in growing rats (SCI-induced bone loss in growing rats)

“…Bone is densely innervated, and the observation of direct contact of nerve fibers and bone cells strongly supports a role of innervation in bone cell functions. A number of neuromediators have also been detected by immunocytochemistry in nerve fibers in bone [18][19][20][21][22][23]. These studies suggest an important role of the neural system in regulating bone cell functions, and ultimately in influencing bone homeostasis.…”

The antidepressant bupropion exerts alleviating properties in an ovariectomized osteoporotic rat model

“…Animal studies also indicated that serotonin may influence bone mass. Battaglino et al [27] demonstrated that mice injected daily with fluoxetine had increased bone formation. However, these effects are not observed in estrogen deficient animals; this finding suggests that the effect of antidepressants on bone metabolism may depend on sex steroids [28] .…”