Abstract
The maintenance of bone homeostasis is largely dependent upon cellular communication between osteoclasts and osteoblasts. Microvesicles (MVs) represent a novel mechanism for osteoblasts and osteoclasts communication, as has been demonstrated in our previous study. Sphingomyelinases catalyze the hydrolysis of sphingomyelin, which leads to increased membrane fluidity and facilitates MV generation. This effect can be inhibited by imipramine, an inhibitor of acid sphingomyelinase (ASM), which is also known as a member of tricyclic antidepressants (TCAs). A recent study has reported that in vitro treatment of imipramine blocked MVs release from glial cells. However, whether imipramine has this effect on osteoblast-derived MVs and whether it is involved in MV generation in vivo is unclear. Here, our investigations found that imipramine slightly reduced the expression of osteoblast differentiation of related genes, but did not impact parathyroid hormone (PTH) regulation for these genes and also did not affect receptor activator of nuclear factor-κB ligand (RANKL)-mediated osteoclast formation; however, imipramine treatment blocked MVs released from osteoblasts and inhibited MV-induced osteoclast formation. In vivo, mice administrated with imipramine were protected from ovariectomy-induced bone loss as evaluated by various bone structural parameters and serum levels of biochemical markers. Our results suggest that inhibiting the production of MVs containing RANKL in vivo is very important for preventing bone loss.
Highlights
Bone remodeling is the predominant metabolic process regulating bone structure and function during adult life
We demonstrated that MVs shed from osteoblasts contain the cell-specific surface membrane receptor, RANKL protein, and can transfer to the surface of osteoclast precursors through receptor-ligand interaction (RANKL–RANK), leading to the activation of the RANKL–RANK signaling pathway to facilitate osteoclast formation [14]
Based on nanoparticle tracking analysis (NTA), we showed that a typical total number of MVs shed from 4 × UAMS-32P cells was about 5.65 × particles, while the number was decreased to 2.54 × 108 particles with imipramine treatment
Summary
Bone remodeling is the predominant metabolic process regulating bone structure and function during adult life. MVs typically range in size from 100 to about 1000 nm in diameter and are formed by the direct budding of the plasma membrane into the extracellular space, while exosomes are significantly smaller than MVs, averaging 30 to 100 nm in size, and are produced within the cell and released through exocytosis events. We demonstrated that MVs shed from osteoblasts contain the cell-specific surface membrane receptor, RANKL (receptor activator of nuclear factor-κB ligand) protein, and can transfer to the surface of osteoclast precursors through receptor-ligand interaction (RANKL–RANK), leading to the activation of the RANKL–RANK signaling pathway to facilitate osteoclast formation [14]. As very few articles reported the direct effect of imipramine on bone, before in vivo study, we firstly observed the influence of imipramine on osteoblast genes expression and osteoclast formation in vitro
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