Inhibition of Osteocyte Apoptosis Prevents the Increase in Osteocytic Receptor Activator of Nuclear Factor κB Ligand (RANKL) but Does Not Stop Bone Resorption or the Loss of Bone Induced by Unloading

Plotkin, Lilian I.; Gortázar, Arancha R.; Davis, Hannah M.; Condon, Keith W.; Gabilondo, Hugo; Maycas, Marta; Allen, Matthew R.; Bellido, Teresita

doi:10.1074/jbc.m115.642090

Cited by 79 publications

(76 citation statements)

References 40 publications

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“…This notion is supported by the fact that inhibition of apoptosis by administering anti-apoptotic bisphosphonates or caspase inhibitors blocks the increase in osteocytic RANKL found in the above described animal models. 90–92, 94, 95 Further, deletion of RANKL from osteocytes and mature osteoblasts prevents the decrease in bone mass and the increase in osteoclast number in tail-suspended mice. 82 Moreover, inhibition of osteocyte/osteoblast apoptosis with a bisphosphonate that does not affect osteoclasts or with a pan caspase inhibitor prevented the increase in osteocytic RANKL induced by unloading.…”

Section: Molecular and Functional Signature Of Osteocytesmentioning

confidence: 99%

“…82 Moreover, inhibition of osteocyte/osteoblast apoptosis with a bisphosphonate that does not affect osteoclasts or with a pan caspase inhibitor prevented the increase in osteocytic RANKL induced by unloading. 94 However, the bisphosphonate did not prevent the loss of bone 94 whereas the caspase inhibitor did. 95 Nevertheless, these findings demonstrate a cause-effect relationship between osteocyte apoptosis and osteocytic RANKL and suggest that at least under certain unloading conditions osteocytic RANKL is central for osteoclast formation and bone resorption.…”

Section: Molecular and Functional Signature Of Osteocytesmentioning

confidence: 99%

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Osteocytic signalling pathways as therapeutic targets for bone fragility

2016

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Osteocytes are differentiated osteoblasts that become surrounded by matrix during the process of bone formation. The acquisition of the osteocyte phenotype is achieved by profound modifications in gene expression that confer adaptation to the changing cellular functions and constitute the molecular signature of osteocytes. The levels of expression of genes characteristic of osteoblasts is altered; and the expression of genes/proteins that impart dendritic cellular morphology, regulate matrix mineralization, and control the function of bone surface cells, is orderly modulated during osteocytogenesis. The discovery of human mutations of osteocytic genes had contributed to a large extent to reveal the role of osteocytes in bone homeostasis. Osteocytes are targets of mechanical force imposed to the skeleton and also play a critical role in integrating mechanosensory pathways with the action of hormones, thereby leading to the orchestrated response of bone to environmental cues. Current, novel therapeutic approaches harness this accumulating knowledge by targeting osteocytic signaling pathways and messengers to improve skeletal health.

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Section: Molecular and Functional Signature Of Osteocytesmentioning

confidence: 99%

Section: Molecular and Functional Signature Of Osteocytesmentioning

confidence: 99%

Osteocytic signalling pathways as therapeutic targets for bone fragility

2016

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“…Previously, Aguirre and colleagues (17) had shown that osteocyte apoptosis occurs in vertebral bone of tail-suspended, hindlimb-unloaded mice, indicating adverse effects on osteocyte integrity in this model. A recent study by Plotkin and colleagues (18) further concluded that dying osteocytes in lumbar vertebrae of hindlimb-unloaded mice do not significantly influence bone resorption. Here we report that, in contrast, both resorption activation and bone loss in long bones of mice subjected to hindlimb unloading are fully dependent on osteocyte apoptosis.…”

Section: Introductionmentioning

confidence: 99%

“…(13–15) In each instance, the activation of bone remodeling has been spatially and temporally associated with osteocyte apoptosis, (6,16–18) which precedes the recruitment of osteoclasts that resorb the region of bone containing the apoptotic osteocytes. (6,17–20) Moreover, this osteocyte apoptosis plays a central and controlling role in triggering bone resorption in response to microdamage and estrogen loss.…”

Section: Introductionmentioning

confidence: 99%

Osteocyte Apoptosis Caused by Hindlimb Unloading is Required to Trigger Osteocyte RANKL Production and Subsequent Resorption of Cortical and Trabecular Bone in Mice Femurs

Cabahug‐Zuckerman

Frikha-Benayed

Majeska

et al. 2016

Journal of Bone and Mineral Research

141

130

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Osteocyte apoptosis is essential to activate bone remodeling in response to fatigue microdamage and estrogen withdrawal, such that apoptosis inhibition in vivo prevents the onset of osteoclastic resorption. Osteocyte apoptosis has also been spatially linked to bone resorption owing to disuse, but whether apoptosis plays a similar controlling role is unclear. We, therefore, 1) evaluated the spatial and temporal effects of disuse from hindlimb unloading (HLU) on osteocyte apoptosis, receptor activator of NF-κB ligand (RANKL) expression, bone resorption, and loss in mouse femora, and 2) tested whether osteocyte apoptosis was required to activate osteoclastic activity in cortical and trabecular bone by treating animals subjected to HLU with the pan-caspase apoptosis inhibitor, QVD (quinolyl-valyl-O-methylaspartyl-[-2,6-difluorophenoxy]-methylketone). Immunohistochemistry was used to identify apoptotic and RANKL-producing osteocytes in femoral diaphysis and distal trabecular bone, and μCT was used to determine the extent of trabecular bone loss owing to HLU. In both cortical and trabecular bone, 5 days of HLU increased osteocyte apoptosis significantly (3- and 4-fold, respectively, p < 0.05 versus Ctrl). At day 14, the apoptotic osteocyte number in femoral cortices declined to near control levels but remained elevated in trabeculae (3-fold versus Ctrl, p < 0.05). The number of osteocytes producing RANKL in both bone compartments was also significantly increased at day 5 of HLU (>1.5-fold versus Ctrl, p <0.05) and further increased by day 14. Increases in osteocyte apoptosis and RANKL production preceded increases in bone resorption at both endocortical and trabecular surfaces. QVD completely inhibited not only the HLU-triggered increases in osteocyte apoptosis but also RANKL production and activation of bone resorption at both sites. Finally, μCT studies revealed that apoptosis inhibition completely prevented the trabecular bone loss caused by HLU. Together these data indicate that osteocyte apoptosis plays a central and controlling role in triggering osteocyte RANKL production and the activation of new resorption leading to bone loss in disuse.

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“…Apoptosis of osteoblasts is a significant event in bone, as approximately 70% of osteoblasts are thought to undergo apoptosis in the process of bone remodeling[18]. In bone tissue, regulation of osteoblast apoptosis is thought to play a key role in the maintenance of healthy bone and skeletal architectural integrity[19–21]. …”

Section: Introductionmentioning

confidence: 99%

Cyclic Compressive Stress Regulates Apoptosis in Rat Osteoblasts: Involvement of PI3K/Akt and JNK MAPK Signaling Pathways

et al. 2016

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It is widely accepted that physiological mechanical stimulation suppresses apoptosis and induces synthesis of extracellular matrix by osteoblasts; however, the effect of stress overloading on osteoblasts has not been fully illustrated. In the present study, we investigated the effect of cyclic compressive stress on rat osteoblasts apoptosis, using a novel liquid drop method to generate mechanical stress on osteoblast monolayers. After treatment with different levels of mechanical stress, apoptosis of osteoblasts and activations of mitogen-activated protein kinases (MAPKs) and PI3-kinase (PI3K)/Akt signaling pathways were investigated. Osteoblasts apoptosis was observed after treated with specific inhibitors prior to mechanical stimulation. Protein levels of Bax/Bcl-2/caspase-3 signaling were determined using western blot with or without inhibitors of PI3K/Akt and phosphorylation of c-jun N-terminal kinase (JNK) MAPK. Results showed that mechanical stimulation led to osteoblasts apoptosis in a dose-dependent manner and a remarkable activation of MAPKs and PI3K/Akt signaling pathways. Activation of PI3K/Akt protected against apoptosis, whereas JNK MAPK increased apoptosis via regulation of Bax/Bcl-2/caspase-3 activation. In summary, the PI3K/Akt and JNK MAPK signaling pathways played opposing roles in osteoblasts apoptosis, resulting in inhibition of apoptosis upon small-magnitude stress and increased apoptosis upon large-magnitude stress.

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Inhibition of Osteocyte Apoptosis Prevents the Increase in Osteocytic Receptor Activator of Nuclear Factor κB Ligand (RANKL) but Does Not Stop Bone Resorption or the Loss of Bone Induced by Unloading

Cited by 79 publications

References 40 publications

Osteocytic signalling pathways as therapeutic targets for bone fragility

Osteocytic signalling pathways as therapeutic targets for bone fragility

Osteocyte Apoptosis Caused by Hindlimb Unloading is Required to Trigger Osteocyte RANKL Production and Subsequent Resorption of Cortical and Trabecular Bone in Mice Femurs

Cyclic Compressive Stress Regulates Apoptosis in Rat Osteoblasts: Involvement of PI3K/Akt and JNK MAPK Signaling Pathways

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