Abstract
Osteoclasts are giant bone cells formed by fusion from monocytes and uniquely capable of a complete destruction of mineralized tissues. Previously, we have demonstrated that in energy-rich environment not only osteoclast fusion index (the number of nuclei each osteoclast contains), but also cytoplasm volume per single nucleus was increased. The goal of this study was to investigate the regulation of metabolic sensor mTOR during osteoclast differentiation in energy-rich environment simulated by addition of pyruvate. We have found that in the presence of pyruvate, the proportion of mTOR associated with raptor increased, while mTOR-rictor-mediated Akt phosphorylation decreased. Inhibition of mTOR with rapamycin (10 nM) significantly interfered with all aspects of osteoclastogenesis. However, rapamycin at 1 nM, which preferentially targets mTOR-raptor complex, was only effective in control cultures, while in the presence of pyruvate osteoclast fusion index was successfully increased. Inhibition of Akt drastically reduced osteoclast fusion, however in energy-rich environment, osteoclasts of comparable size were formed through increased cytoplasm growth. These data suggest that mTOR-rictor mediated Akt signaling regulates osteoclast fusion, while mTOR-raptor regulation of protein translation contributes to fusion-independent cytoplasm growth. We demonstrate that depending on the bioenergetics microenvironment osteoclastogenesis can adjust to occur through preferential multinucleation or through cell growth, implying that attaining large cell size is part of the osteoclast differentiation program.
Highlights
Osteoclasts are bone cells uniquely capable of a complete destruction of mineralized tissues
Since mechanistic target of rapamycin (mTOR) is a known downstream target of AMP-activated protein kinase (AMPK), we considered its role in regulation of osteoclast size (Figure 2A). mTOR can form complex with raptor, mTORC1, which regulates protein synthesis, or with rictor, mTORC2, which regulates cytoskeleton organization
Taken together our data indicate that two distinct processes occur simultaneously during the formation of large osteoclasts: continuous fusion and fusion-independent cytoplasm growth
Summary
Osteoclasts are bone cells uniquely capable of a complete destruction of mineralized tissues. Osteoclasts are responsible for bone destruction in degenerative, inflammatory and metabolic bone disorders (Henriksen et al, 2011; Boyce, 2013). It has been demonstrated that large osteoclasts are more likely to be observed during pathological mTOR/Akt and Osteoclast Size bone resorption, and are more active and more responsive to environmental stimuli (Lees and Heersche, 1999, 2000; Lees et al, 2001; Trebec et al, 2007). The complete sequence of events leading from stimulation of osteoclastogenesis by receptor activator of nuclear factor κB ligand (RANKL) to formation of large polykarions capable of bone destruction is incompletely understood
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