Intermittent Hypoxia Effect on Osteoclastogenesis Stimulated by Neuroblastoma Cells

Bhaskara, Vasantha Kumar; Mohanam, Indra; Gujrati, Meena; Mohanam, Sanjeeva

doi:10.1371/journal.pone.0105555

Cited by 9 publications

(6 citation statements)

References 60 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…CM: conditioned media; mRNA: messenger RNA; RANKL: nuclear factor-κB ligand; siNC: HIF-1α silencer negative control; siRNA: small interfering RNA; TRAP: tartrate-resistant acid phosphatase [Color figure can be viewed at wileyonlinelibrary.com] (Johnson, Schipani, & Giaccia, 2015). It is been proven that HIF-1α also increases on exposure to osteoclastogenic cytokines during monocytes differentiating into osteoclasts (Bhaskara, Mohanam, Gujrati, & Mohanam, 2014;Utting, Flanagan, Brandaoburch, Orriss, & Arnett, 2010). Some evidence suggests that HIF-1α is also required for osteoclasts activation and bone loss in osteoporosis (Miyauchi et al, 2013;Tando et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

HIF‐1α facilitates osteocyte‐mediated osteoclastogenesis by activating JAK2/STAT3 pathway in vitro

Zhu

Tang

et al. 2019

Journal Cellular Physiology

View full text Add to dashboard Cite

Osteocytes, entrapped within the mineralized bone matrix, has been found to have numerous functions such as acting as an orchestrator of bone remodeling through regulation of both osteoclast and osteoblast activity and also functioning as an endocrine cell. Due to a specialized morphology and surrounding structure, osteocytes are more tolerant to hypoxia during osteoporosis, fracture, osteoarthritis, and orthodontic-orthognathic combination therapy. Hypoxia-inducible factor-1α (HIF-1α) is one of the master regulators of hypoxia reactions, playing an important role in bone modeling, remodeling, and homeostasis. This study aimed to investigate the pivotal functional role of HIF-1α in osteocytes initiating of bone remodeling under hypoxia. In the present study, the osteoclasts formation induced by RAW264.7 was significantly promoted in conditioned media (CM) from osteocytic MLO-Y4 exposed to hypoxia in vitro. Therefore, hypoxic MLO-Y4 cells simulated by 100 μmol/L CoCl 2 or 2% O 2 stably expressed HIF-1α proteins and upregulated the expression of receptor activator of nuclear factor-κB ligand (RANKL) at both the messenger RNA (mRNA) and protein level. Furthermore, with the Knockdown of HIF-1α, the expression of RANKL mRNA and protein decreased after transient transfection. In addition, the phosphorylation of Janus kinase 2 (JAK2) and signal transducer and activator of transcription (STAT3) was also correlated with HIF-1α and RANKL levels under hypoxia. Then AG490, a JAK2 inhibitor, inhibited p-JAK2, p-STAT3 and RANKL expression. It was possible that AG490 disturbed the contact of HIF-1α and RANKL by JAK2/STAT3 pathway, influencing osteoclastogenesis. Our findings suggested that HIF-1α promoted the expression of RANKL by activating JAK2/STAT3 pathway in MLO-Y4 cells, and enhanced osteocyte-mediated osteoclastic differentiation in vitro. K E Y W O R D Shypoxia-inducible factor-1α, JAK2/STAT3 pathway, osteoclastogenesis, osteocyte, receptor activator of nuclear factor-κB

show abstract

Section: Discussionmentioning

confidence: 99%

HIF‐1α facilitates osteocyte‐mediated osteoclastogenesis by activating JAK2/STAT3 pathway in vitro

Zhu

Tang

et al. 2019

Journal Cellular Physiology

View full text Add to dashboard Cite

show abstract

“…Obviously, in the in vivo situation, monocytes and osteoclasts do not exist in isolation but are surrounded by osteoblasts, fibroblasts, and other cellular components of the bone microenvironment that will also be exposed to local hypoxia. Co-culture of monocytes with stromal cells including osteoblasts, fibroblasts, and cancer cells has revealed that hypoxia stimulates local production of pro-osteoclastogenic cytokines including RANKL, 24 , 25 vascular endothelial growth factor (VEGF), 24 – 27 M-CSF, 27 insulin-like growth factor 2, 28 and growth differentiation factor 15, 29 as well as inhibiting production of osteoprotegerin (OPG), a soluble decoy receptor for RANKL that inhibits osteoclast formation and activity. 30 …”

Section: Hypoxia Stimulates Osteoblast-mediated Osteoclastogenesismentioning

confidence: 99%

Hypoxic regulation of osteoclast differentiation and bone resorption activity

Knowles¹

2015

View full text Add to dashboard Cite

Bone integrity is maintained throughout life via the homeostatic actions of bone cells, namely, osteoclasts, which resorb bone, and osteoblasts, which produce bone. Disruption of this balance in favor of osteoclast activation results in pathological bone loss, which occurs in conditions including osteoporosis, rheumatoid arthritis, primary bone cancer, and cancer metastasis to bone. Hypoxia also plays a major role in these conditions, where it is associated with disease progression and poor prognosis. In recent years, considerable interest has arisen in the mechanisms whereby hypoxia and the hypoxia-inducible transcription factors, HIF-1α and HIF-2α, affect bone remodeling and bone pathologies. This review summarizes the current evidence for hypoxia-mediated regulation of osteoclast differentiation and bone resorption activity. Role(s) of HIF and HIF target genes in the formation of multinucleated osteoclasts from cells of the monocyte–macrophage lineage and in the activation of bone resorption by mature osteoclasts will be discussed. Specific attention will be paid to hypoxic metabolism and generation of ATP by osteoclasts. Hypoxia-driven increases in both glycolytic flux and mitochondrial metabolic activity, along with consequent generation of mitochondrial reactive oxygen species, have been found to be essential for osteoclast formation and resorption activity. Finally, evidence for the use of HIF inhibitors as potential therapeutic agents targeting bone resorption in osteolytic disease will be discussed.

show abstract

“…Serum tartrate-resistant acid phosphatase (TRAP) is widely accepted in clinical practice and scientific research as a highly specific and sensitive index of bone metabolism reflecting changes in bone resorption [ 17 ]. Research data have indicated that the CIH of OSAS may affect the kidney, gastrointestinal tract, osteoblasts, osteoclasts, sympathetic nerves, leptin, and an inflammatory response resulting in abnormal bone metabolism [ 18 , 19 ]. However, changes in the biochemical indexes of bone metabolism in an environment of CIH are not fully understood.…”

Section: Introductionmentioning

confidence: 99%

CB1 receptor antagonist rimonabant protects against chronic intermittent hypoxia-induced bone metabolism disorder and destruction in rats

Dou

Gao

Jia³

et al. 2020

Sleep Breath

View full text Add to dashboard Cite

Objective The endocannabinoid system (ECS) regulates bone turnover and remodeling. Chronic intermittent hypoxia (CIH) occurring during obstructive sleep apnea (OSA) may lead to disorders of the ECS and bone metabolism abnormalities. This study aimed to investigate whether or not the cannabinoid receptor 1 (CB1R) antagonist rimonabant (Ri) alleviates bone metabolism abnormalities and bone destruction induced by chronic intermittent hypoxia (CIH). Methods Healthy male Sprague Dawley (SD) rats (n=48) were randomly divided into 6 groups of 8 rats: 2 normal control (NC) groups, 2 intermittent hypoxia (IH) groups, and 2 IH + Ri groups. Rats in NC groups breathed room air for 4 weeks (4w NC group) and 6 weeks (6w NC group). Rats in IH groups experienced IH environment for 4 weeks (4w IH group) and 6 weeks (6w IH group). In addition to the same IH exposure, rats in IH + Ri group were given daily intraperitoneal injection of Ri at the dosage of 1.5 mg/kg/d for 4 weeks (4w IH + Ri group) and 6 weeks (6w IH + Ri group). Levels of serum tartrate-resistant acid phosphatase (TRAP, a marker of bone resorption) were determined by ELISA. Hematoxylin and eosin (HE) staining was performed on bone sections to observe the changes in bone microstructure. Expression of CB1R in bone tissue was determined by immunohistochemistry. Results TRAP levels were higher in the 4w IH and 6w IH groups than in the 4w NC and 6w NC groups; TRAP levels were lower in the 4w IH + Ri and 6w IH + Ri groups than in the 4w IH and 6w IH groups. HE staining showed that the morphology of bone cells in the NC group was normal, but the 4w IH group had mild edema of bone cells, reduction in trabecular bone, and destruction of bone microstructure. Changes were more severe in the 6w IH group than 4w IH. The 4w IH + Ri group was slightly improved compared with the 4w IH group. The 6w IH + Ri group was improved compared with the 4w IH + Ri group. The results of immunohistochemistry showed that the expression of CB1R in IH group was significantly higher than that in NC group. The expression of CB1R in the IH + Ri group was lower than that in the IH group. With the prolongation of hypoxia, the expression of CB1R in bone cells of IH group increased. The expression level of CB1R in IH + Ri group decreased with the prolongation of intervention time. Correlation analysis showed that the expression rate of CB1R in bone cells was positively correlated with the level of TRAP in serum. Conclusion CIH increases serum TRAP levels and triggers metabolic bone disorder by activating bone CB1R. Intervention with CB1R antagonist (rimonabant) reduces the bone dysmetabolism in the CIH rat model. Keywords Obstructive sleep apnea syndrome (OSAS). Cannabinoid receptor 1 (CB1R). Tartrate-resistant acid phosphatase (TRAP). Rimonabant (Ri). Chronic intermittent hypoxia (CIH)

show abstract

Intermittent Hypoxia Effect on Osteoclastogenesis Stimulated by Neuroblastoma Cells

Cited by 9 publications

References 60 publications

HIF‐1α facilitates osteocyte‐mediated osteoclastogenesis by activating JAK2/STAT3 pathway in vitro

HIF‐1α facilitates osteocyte‐mediated osteoclastogenesis by activating JAK2/STAT3 pathway in vitro

Hypoxic regulation of osteoclast differentiation and bone resorption activity

CB1 receptor antagonist rimonabant protects against chronic intermittent hypoxia-induced bone metabolism disorder and destruction in rats

Contact Info

Product

Resources

About