Intermittent hypoxia retards mandibular growth and alters RANKL expression in adolescent and juvenile rats

2020 ◽  
Author(s):  
Haixin Hong ◽  
Jun Hosomichi ◽  
Hideyuki Maeda ◽  
Kochakorn Lekvijittada ◽  
Shuji Oishi ◽  
...  
Keyword(s):  
Intermittent Hypoxia ◽  
Bone Growth ◽  
Receptor Activation ◽  
Growth Stages ◽  
Mineral Density ◽  
Juvenile Rats ◽  
Mandibular Growth ◽  
Obstructive Sleep ◽  
Condylar Head ◽  
Adolescent Rats

Summary Objectives Chronic intermittent hypoxia (IH), a common state experienced in obstructive sleep apnoea (OSA), retards mandibular growth in adolescent rats. The aim of this study was to elucidate the differential effects of IH on mandibular growth in different growth stages. Materials and methods Three-week-old (juvenile stage) and 7-week-old (adolescent stage) male Sprague–Dawley rats underwent IH for 3 weeks. Age-matched control rats were exposed to room air. Mandibular growth was evaluated by radiograph analysis, micro-computed tomography, real-time polymerase chain reaction and immunohistology. Tibial growth was evaluated as an index of systemic skeletal growth. Results IH had no significant impact on the general growth of either the juvenile or adolescent rats. However, it significantly decreased the total mandibular length and the posterior corpus length of the mandible in the adolescent rats and the anterior corpus length in the juvenile rats. IH also increased bone mineral density (BMD) of the condylar head in adolescent rats but did not affect the BMD of the tibia. Immunohistological analysis showed that the expression level of receptor activation of nuclear factor-κB ligand significantly decreased (in contrast to its messenger ribonucleicacid level) in the condylar head of adolescent rats with IH, while the number of osteoprotegerin-positive cells was comparable in the mandibles of adolescent IH rats and control rats. Limitations The animal model could not simulate the pathological conditions of OSA completely and there were differences in bone growth between humans and rodents. Conclusions These results suggest that the susceptibility of mandibular growth retardation to IH depends on the growth stage of the rats.

scholarly journals Selective β2-Adrenoceptor Blockade Rescues Mandibular Growth Retardation in Adolescent Rats Exposed to Chronic Intermittent Hypoxia

2021 ◽  
Vol 12 ◽  
Author(s):  
Haixin Hong ◽  
Jun Hosomichi ◽  
Hideyuki Maeda ◽  
Yuji Ishida ◽  
Risa Usumi-Fujita ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Body Weight ◽  
Growth Retardation ◽  
Adrenergic Receptors ◽  
Intermittent Hypoxia ◽  
Skeletal Growth ◽  
Chronic Intermittent Hypoxia ◽  
Rankl Expression ◽  
Mandibular Growth ◽  
Condylar Head

Activation of the sympathoadrenal system is associated with sleep apnea-related symptoms and metabolic dysfunction induced by chronic intermittent hypoxia (IH). IH can induce hormonal imbalances and growth retardation of the craniofacial bones. However, the relationship between IH and β2-adrenergic receptor signaling in the context of skeletal growth regulation is unclear. This study aimed to investigate the role of β2-adrenergic receptors in IH-induced mandibular growth retardation and bone metabolic alterations. Male 7-week-old Sprague–Dawley rats were subjected to IH for 3 weeks. IH conditions were established using original customized hypoxic chambers; IH was induced at a rate of 20 cycles per hour (oxygen levels changed from 4 to 21% in one cycle) for 8 h per day during the 12 h “lights on” period. The rats received intraperitoneal administration of a β2-adrenergic antagonist (butoxamine) or saline. To exclude dietary effects on general growth, the normoxic rats with saline, normoxic rats with butoxamine, and IH rats with butoxamine were subjected to food restriction to match the body weight gains between IH and other three groups. Body weight, heart rate, blood pressure, and plasma concentrations of leptin, serotonin, and growth hormone were measured. Bone growth and metabolism were evaluated using radiography, microcomputed tomography, and immunohistochemical staining. Plasma leptin levels were significantly increased, whereas that of serotonin and growth hormone were significantly decreased following IH exposure. Leptin levels recovered following butoxamine administration. Butoxamine rescued IH-induced mandibular growth retardation, with alterations in bone mineral density at the condylar head of the mandible. Immunohistochemical analysis revealed significantly lower expression levels of receptor activator of nuclear factor-kappa B ligand (RANKL) in the condylar head of IH-exposed rats. Conversely, recovery of RANKL expression was observed in IH-exposed rats administered with butoxamine. Collectively, our findings suggest that the activation of β2-adrenergic receptors and leptin signaling during growth may be involved in IH-induced skeletal growth retardation of the mandible, which may be mediated by concomitant changes in RANKL expression at the growing condyle.

scholarly journals Edaravone mitigates cognitive impairment and hippocampal injury in juvenile rats with obstructive sleep apnea hypopnea syndrome via regulation of cAMP/PKACREB pathway

2021 ◽  
Vol 20 (11) ◽  
pp. 2299-2304
Author(s):  
Yongmei Zhao ◽  
Hongli Li ◽  
Yong Chen ◽  
Kexing Li ◽  
Sufei Yang
Keyword(s):  
Oxidative Stress ◽  
Obstructive Sleep Apnea ◽  
Cognitive Impairment ◽  
Sleep Apnea ◽  
Intermittent Hypoxia ◽  
New Drugs ◽  
Juvenile Rats ◽  
Protein Levels ◽  
Obstructive Sleep ◽  
Hypopnea Syndrome

Purpose: To investigate the influence of edaravone on cognitive impairment and hippocampal injury in juvenile rats with obstructive sleep apnea hypopnea syndrome (OSAHS), and the mechanism involved.Methods: Fifty-four young Wistar rats were randomly selected into control, intermittent hypoxia and edaravone groups. The contents of the antioxidants CAT, Mn-SOD, Cu/Zn SOD and oxidative stress products malondialdehyde (MDA) in hippocampus were assayed and compared. The expressions of brain-derived neurotrophic factor (BDNF), Bcl-2, CREB, p-CREB and PKAc were determined.Results: The times taken to cross the target quadrant and the platform; levels of CAT and Mn-SOD, as well as protein levels of BNDF, Bcl-2, p-CREB and PKAc were markedly lower in intermittent hypoxia group than in controls; and MDA contents, 8-OHdG and protein hydroxyl were markedly higher in intermittent hypoxic rats group than in controls. Time taken to cross the platform and quadrant; activities of CAT and Mn-SOD, and protein concentrations of BDNF, Bcl-2, p-CREB and PKAc were markedly higher in the edaravone-treated rats than in intermittent hypoxia rats.Conclusion: Edaravone significantly mitigated cognitive damage and hippocampal lesions in OSAHS rats via a mechanism related to alleviation of oxidative stress and up-regulation of the expressions of p-CREB and its downstream proteins BDNF and Bcl-2. This finding provides a theoretical basis for research and development of new drugs against OSAHS.

Effects of Amomum villosum on longitudinal bone growth in adolescent rats

Planta Medica ◽  
2012 ◽  
Vol 78 (11) ◽  
Author(s):  
JY Kim ◽  
SH Lee ◽  
J Park ◽  
MY Kim ◽  
GT Chang ◽  
...  
Keyword(s):  
Bone Growth ◽  
Longitudinal Bone Growth ◽  
Adolescent Rats ◽  
Amomum Villosum

scholarly journals Transcriptomic Changes of Murine Visceral Fat Exposed to Intermittent Hypoxia at Single Cell Resolution

2020 ◽  
Vol 22 (1) ◽  
pp. 261
Author(s):  
Abdelnaby Khalyfa ◽  
Wesley Warren ◽  
Jorge Andrade ◽  
Christopher A. Bottoms ◽  
Edward S. Rice ◽  
...  
Keyword(s):  
Intermittent Hypoxia ◽  
Cell Types ◽  
Cellular Level ◽  
Cellular Heterogeneity ◽  
Transcriptional Networks ◽  
Metabolic Dysfunction ◽  
Rna Seq ◽  
Obstructive Sleep ◽  
Differential Expressed Gene ◽  
Key Aspects

Intermittent hypoxia (IH) is a hallmark of obstructive sleep apnea (OSA) and induces metabolic dysfunction manifesting as inflammation, increased lipolysis and insulin resistance in visceral white adipose tissues (vWAT). However, the cell types and their corresponding transcriptional pathways underlying these functional perturbations are unknown. Here, we applied single nucleus RNA sequencing (snRNA-seq) coupled with aggregate RNA-seq methods to evaluate the cellular heterogeneity in vWAT following IH exposures mimicking OSA. C57BL/6 male mice were exposed to IH and room air (RA) for 6 weeks, and nuclei from vWAT were isolated and processed for snRNA-seq followed by differential expressed gene (DEGs) analyses by cell type, along with gene ontology and canonical pathways enrichment tests of significance. IH induced significant transcriptional changes compared to RA across 14 different cell types identified in vWAT. We identified cell-specific signature markers, transcriptional networks, metabolic signaling pathways, and cellular subpopulation enrichment in vWAT. Globally, we also identify 298 common regulated genes across multiple cellular types that are associated with metabolic pathways. Deconvolution of cell types in vWAT using global RNA-seq revealed that distinct adipocytes appear to be differentially implicated in key aspects of metabolic dysfunction. Thus, the heterogeneity of vWAT and its response to IH at the cellular level provides important insights into the metabolic morbidity of OSA and may possibly translate into therapeutic targets.

scholarly journals Micro-CT data of early physiological cancellous bone formation in the lumbar spine of female C57BL/6 mice

2021 ◽  
Vol 8 (1) ◽  
Author(s):  
Michael Zenzes ◽  
Paul Zaslansky
Keyword(s):  
Cancellous Bone ◽  
Structural Changes ◽  
Bone Growth ◽  
Post Partum ◽  
Three Dimensional ◽  
Lumbar Vertebra ◽  
Tissue Growth ◽  
Micro Ct ◽  
Mineral Density ◽  
Ct Data

AbstractMicro-CT provides critical data for musculoskeletal research, yielding three-dimensional datasets containing distributions of mineral density. Using high-resolution scans, we quantified changes in the fine architecture of bone in the spine of young mice. This data is made available as a reference to physiological cancellous bone growth. The scans (n = 19) depict the extensive structural changes typical for female C57BL/6 mice pups, aged 1-, 3-, 7-, 10- and 14-days post-partum, as they attain the mature geometry. We reveal the micro-morphology down to individual trabeculae in the spine that follow phases of mineral-tissue rearrangement in the growing lumbar vertebra on a micrometer length scale. Phantom data is provided to facilitate mineral density calibration. Conventional histomorphometry matched with our micro-CT data on selected samples confirms the validity and accuracy of our 3D scans. The data may thus serve as a reference for modeling normal bone growth and can be used to benchmark other experiments assessing the effects of biomaterials, tissue growth, healing, and regeneration.

Bone Mineral Density Attenuation in Obstructive Sleep Apnea by Derived Computed Tomography Screening

2021 ◽  
Author(s):  
Sharon Daniel ◽  
Yafit Cohen-Freud ◽  
Ilan Shelef ◽  
Ariel Tarasiuk
Keyword(s):  
Computed Tomography ◽  
Bone Mineral Density ◽  
Obstructive Sleep Apnea ◽  
Sleep Apnea ◽  
Bone Mineral ◽  
Clinical Information ◽  
Mineral Density ◽  
Peak Voltage ◽  
Arousal Index ◽  
Obstructive Sleep

Abstract The association between obstructive sleep apnea (OSA) and bone mineral density (BMD) is poorly elucidated with contradictory findings. We retrospectively explored the association between OSA and BMD by examining abdominal computed tomography (CT) vertebrae images using clinical information. We included 315 subjects (174 with OSA and 141 without OSA) who performed at least two CT scans (peak voltage of 120 kV). Bone mineral density was attenuated in those with OSA and increased age. BMD attenuation was not associated with the apnea–hypopnea score, nocturnal oxygen saturation, or arousal index. A multivariate linear regression indicated that OSA is associated with BMD attenuation after controlling for age, gender, and cardiovascular diseases. Here, we report that OSA is associated with BMD attenuation. Further studies are required to untangle the complex affect of OSA on BMD loss and possible clinical implication of vertebra depressed fracture or femoral neck fracture.

Reconstitution of the host holobiont in germ-free born male rats acutely increases bone growth and affects marrow cellular content

2021 ◽  
Author(s):  
Piotr J Czernik ◽  
Rachel M. Golonka ◽  
Saroj Chakraborty ◽  
Beng San Yeoh ◽  
Ahmed A Abokor ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Mass ◽  
Bone Growth ◽  
Elevated Serum ◽  
Male Rats ◽  
Bone Lengthening ◽  
Mineral Density ◽  
Germ Free ◽  
Hepatic Expression ◽  
Gut Colonization

Integration of microbiota in a host begins at birth and progresses during adolescence, forming a multidirectional system of physiologic interactions. Here, we present an instantaneous effect of natural, bacterial gut colonization on the acceleration of longitudinal and radial bone growth in germ-free born, 7-week-old male rats. Changes in bone mass and structure were analyzed after 10 days following the onset of colonization through cohousing with conventional rats and revealed unprecedented acceleration of bone accrual in cortical and trabecular compartments, increased bone tissue mineral density, improved proliferation and hypertrophy of growth plate chondrocytes, bone lengthening, and preferential deposition of periosteal bone in the tibia diaphysis. In addition, the number of small in size adipocytes increased, while the number of megakaryocytes decreased, in the bone marrow of conventionalized germ-free rats indicating that not only bone mass but also bone marrow environment is under control of gut microbiota signaling. The changes in bone status paralleled with a positive shift in microbiota composition toward short chain fatty acids (SCFA)-producing microbes and a considerable increase in cecal SCFA concentrations, specifically butyrate. Further, reconstitution of the host holobiont increased hepatic expression of IGF-1 and its circulating levels. Elevated serum levels of 25-hydroxy vitamin D and alkaline phosphatase pointed toward an active process of bone formation. The acute stimulatory effect on bone growth occurred independently of body mass increase. Overall, the presented model of conventionalized germ-free rats could be used to study microbiota-based therapeutics for combatting dysbiosis-related bone disorders.

Abstract 356: IKK-Beta Deletion Alleviates the Atherogenetic Effect of Intermittent Hypoxia Induced Macrophage Foam Cell Formation

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Toshihiro Imamura ◽  
Iain S Hartley ◽  
Abdull J Massri ◽  
Orit Poulsen ◽  
Dan Zhou ◽  
...  
Keyword(s):  
Gene Expression ◽  
Intermittent Hypoxia ◽  
Foam Cell ◽  
Cell Formation ◽  
Foam Cell Formation ◽  
Wild Type ◽  
Nf Kappa B ◽  
Macrophage Foam Cell ◽  
Obstructive Sleep ◽  
Intracellular Cholesterol

Background: Obstructive sleep apnea syndrome (OSAS) is a common sleeping disorder characterized by intermittent hypoxia (IH). Clinical studies have previously shown an independent association between obstructive sleep apnea and atherosclerosis. Furthermore, it has been previously shown that such a predisposition to atherosclerosis in OSAS patient can be caused by various inflammatory mediators, particularly the NF-kappa B (NF-kB) pathway. Foam cells or lipid-laden macrophages in the atherosclerotic lesion have been well documented as a hallmark of atherosclerosis; however, the contribution of IH, such as in OSAS, to foam cell formation is not yet fully understood. Previous observations have led us to hypothesized that IH induces macrophage foam cell formation due to the activation of NF-kappa B pathway. Methods: Myeloid restricted IKK-beta deleted mice were generated by a Cre/lox recombination system to inactivate the NF-kB pathway in macrophages. Thioglycollate-elicited peritoneal macrophages were incubated with 200 μg/ml of low-density lipoprotein and simultaneously exposed to either IH (Normoxia: 8min, 0.5% O2: 10min) or normoxia for 24 hours. After exposure, the extent of foam cell formation was assessed by quantification of intracellular cholesterol. Finally, we compared the differences in gene expression using RNA-seq between wild type and IKK-beta deleted macrophages exposed to either IH or normoxia for 24 hours. Results: IH significantly increased total cholesterol in wild type macrophages (63.4±3.3 μg/mg of cellular protein, n=9) in comparison to normoxia (51.2±1.6). Interestingly, such increase in intracellular cholesterol in response to IH-exposure was abolished by IKK-beta deletion (IH 52.4±1.1; normoxia 50.0±1.6 n=8), suggesting that NF-kB pathway regulated gene expression is critical for IH-induced foam cell formation. Indeed, we have found that NF-kB knockout abolished IH-induced expressional alterations in 364 genes, which are potential candidates for regulating intracellular cholesterol. Conclusion: NF-kB activation plays a critical role in IH-induced macrophage foam cell formation.

scholarly journals Evaluation of Bone Mineral Density by Computed Tomography in Patients with Obstructive Sleep Apnea

2016 ◽  
Vol 12 (01) ◽  
pp. 25-34 ◽  
Author(s):  
Satoshi Hamada ◽  
Kohei Ikezoe ◽  
Toyohiro Hirai ◽  
Tsuyoshi Oguma ◽  
Kiminobu Tanizawa ◽  
...  
Keyword(s):  
Computed Tomography ◽  
Bone Mineral Density ◽  
Obstructive Sleep Apnea ◽  
Sleep Apnea ◽  
Bone Mineral ◽  
Mineral Density ◽  
Obstructive Sleep
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