Abstract
ABSTRACTMechanical stress stimulates bone remodeling, which occurs through bone formation and resorption, resulting in bone adaptation in response to the mechanical stress. Osteocytes perceive mechanical stress loaded to bones and promote bone remodeling through various cellular processes. Osteocyte apoptosis is considered a cellular process to induce bone resorption during mechanical stress‐induced bone remodeling, but the underlying molecular mechanisms are not fully understood. Recent studies have demonstrated that neuropeptides play crucial roles in bone metabolism. The neuropeptide, methionine enkephalin (MENK) regulates apoptosis positively and negatively depending on cell type, but the role of MENK in osteocyte apoptosis, followed by bone resorption, in response to mechanical stress is still unknown. Here, we examined the roles and mechanisms of MENK in osteocyte apoptosis induced by compressive force. We loaded compressive force to mouse parietal bones, resulting in a reduction of MENK expression in osteocytes. A neutralizing connective tissue growth factor (CTGF) antibody inhibited the compressive force‐induced reduction of MENK. An increase in osteocyte apoptosis in the compressive force‐loaded parietal bones was inhibited by MENK administration. Nuclear translocation of NFATc1 in osteocytes in the parietal bones was enhanced by compressive force. INCA‐6, which inhibits NFAT translocation into nuclei, suppressed the increase in osteocyte apoptosis in the compressive force‐loaded parietal bones. NFATc1‐overexpressing MLO‐Y4 cells showed increased expression of apoptosis‐related genes. MENK administration reduced the nuclear translocation of NFATc1 in osteocytes in the compressive force‐loaded parietal bones. Moreover, MENK suppressed Ca2+ influx and calcineurin and calmodulin expression, which are known to induce the nuclear translocation of NFAT in MLO‐Y4 cells. In summary, this study shows that osteocytes expressed MENK, whereas the MENK expression was suppressed by compressive force via CTGF signaling. MENK downregulated nuclear translocation of NFATc1 probably by suppressing Ca2+ signaling in osteocytes and consequently inhibiting compressive force‐induced osteocyte apoptosis, followed by bone resorption. © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
Highlights
V ertebrate skeletons are influenced by various kinds of mechanical stress during daily activities
Osteocytes express receptor activator of nuclear factor kappa B ligand (RANKL), an essential factor for osteoclastogenesis.[6] osteocytes are considered critical for osteoclastogenesis and bone resorption.[7,8] Importantly, living osteocytes, but osteocytes undergoing apoptosis promote bone resorption.[9,10,11] We previously reported that compressive force induces osteocyte apoptosis in the alveolar bones during experimental tooth movement in mice and in cell culture of chick calvaria-derived osteocytes.[12,13] Our data suggest that osteocyte apoptosis occurs in response to compressive force and induces bone resorption
methionine enkephalin (MENK) is expressed in non-nervous tissue, such as bone, heart, pancreas, and kidneys.[18,19,20,21] Its analgesic property is a major function of MENK; MENK has other functions, including anti-inflammatory effects and regulation of embryonic organ development.[22,23] On the other hand, long-term administration of opioids to alleviate cancer pain reduces bone mass, suggesting that opioids have a close relationship with bone remodeling.[24]. MENK is expressed in osteoblasts and mesenchymal stem cells, which are precursors of osteoblasts.[21,25] In addition, MENK inhibits osteoblast differentiation.[26]. These findings suggest the inhibitory effect of MENK on bone formation regulating osteoblast differentiation during bone remodeling
Summary
V ertebrate skeletons are influenced by various kinds of mechanical stress during daily activities. Mechanical stress stimulates bone remodeling, which occurs through bone formation and resorption, resulting in bone adaptation to the mechanical stress.[1] Osteocytes are the most abundant cells in bones and are embedded in bone matrices. Osteocytes have their dendritic processes through canaliculi to form an intercellular communication network via gap junctions.[2,3] Osteocytes perceive mechanical stress as mechanosensors, transform into biochemical signals, and regulate bone 1 of 13 n remodeling by transmitting signals related to bone formation and resorption.[4,5]. The role of MENK in bone resorption is still unknown
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