Cortical bone loss due to skeletal unloading in aldehyde dehydrogenase 2 gene knockout mice is associated with decreased PTH receptor expression in osteocytes

Tajima, Takafumi; Menuki, Kunitaka; Okuma, Kayoko Furukawa; Tsukamoto, Manabu; Fukuda, Hokuto; Okada, Yasuaki; Kosugi, Kenji; Yamanaka, Yoshiaki; Uchida, Soshi

doi:10.1016/j.bone.2018.02.020

Cited by 14 publications

(6 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…HLU, hindlimb unloading; WT, wild-type; µCT, micro-computed tomography; R, R76W; , 130-136; BV/TV, bone volume fraction; Tb.N, trabecular number; SMI, structure model index; Tb.Sp, trabecular separation; Tb.Th, trabecular thickness. more sensitive than cortical bone to unloading, as previously reported in rats (Jia et al, 2014) and mice (Tajima et al, 2018). Clinical studies have also demonstrated that reduced mechanical stimulation causes greater bone loss at trabecular rather than at cortical sites (Tervo et al, 2009).…”

Section: Discussionsupporting

confidence: 57%

“…This contradicts earlier findings (Lloyd et al, 2012(Lloyd et al, , 2013 of decreased cortical bone mass in both WT and osteoblastspecific Cx43 cKO mice during unloading. We speculated that the difference between WT mice following HLU in our study compared to that of Lloyd et al (2012Lloyd et al ( , 2013 was due to the age of the animals, as 7 and 10 week old (youth) mice were used in the studies by Tajima et al (2018) and ourselves, respectively, whereas Lloyd et al (2012Lloyd et al ( , 2013 used 6 month old (adult) mice, which may cause the different response to unloading in cortical bone. Compared to WT mice, we also found that Cx43 mutants exhibited greater cortical bone loss following HLU, which is not consistent with some previous studies.…”

Section: Discussionmentioning

confidence: 69%

See 1 more Smart Citation

Connexin 43 Channels in Osteocytes Regulate Bone Responses to Mechanical Unloading

Zhao

Liu

et al. 2020

Front. Physiol.

View full text Add to dashboard Cite

Connexin (Cx) 43 forms gap junctions and hemichannels that mediate communication between osteocytes and adjacent cells or the extracellular environment in bone, respectively. To investigate the role of each channel type in response to mechanical unloading, two transgenic mouse models overexpressing dominant-negative Cx43 predominantly in osteocytes driven by a 10 kb dentin matrix protein 1 (Dmp1) promoter were generated. The R76W mutation resulted in gap junction inhibition and enhancement of hemichannels, whereas the 130-136 mutation inhibited both gap junctions and hemichannels. Both mutations led to cortical bone loss with increased endocortical osteoclast activity during unloading. Increased periosteal osteoclasts with decreased apoptotic osteocytes were observed only in R76W mice. These findings indicated that inhibiting osteocytic Cx43 channels promotes bone loss induced by unloading, mainly in the cortical area; moreover, hemichannels protect osteocytes against apoptosis and promote periosteal bone remodeling, whereas gap junctions modulate endocortical osteoclast activity in response to unloading.

show abstract

Section: Discussionsupporting

confidence: 57%

Section: Discussionmentioning

confidence: 69%

Connexin 43 Channels in Osteocytes Regulate Bone Responses to Mechanical Unloading

Zhao

Liu

et al. 2020

Front. Physiol.

View full text Add to dashboard Cite

show abstract

“…Osteocytes inhabit the bone extracellular matrix (ECM) and are believed to play a pivotal role in mechanosensing and mechanotransduction [1][2][3][4] which ultimately result in well mechanically functionalized bone material under a specific mechanical environment. To date, the mechanisms by which osteocytes respond to mechanical stimulation to cause bone mechanical integration and resistance to breaking have been widely investigated using in vitro and in vivo assays at the genetic, cellular, and tissue level [5][6][7][8][9][10][11][12]. However, the major focus of these studies in bone adaptive responses was bone mass and/or BMD.…”

Section: Introductionmentioning

confidence: 99%

Quantitative Evaluation of Osteocyte Morphology and Bone Anisotropic Extracellular Matrix in Rat Femur

et al. 2021

View full text Add to dashboard Cite

Osteocytes are believed to play a crucial role in mechanosensation and mechanotransduction which are important for maintenance of mechanical integrity of bone. Recent investigations have revealed that the preferential orientation of bone extracellular matrix (ECM) mainly composed of collagen fibers and apatite crystallites is one of the important determinants of bone mechanical integrity. However, the relationship between osteocytes and ECM orientation remains unclear. In this study, the association between ECM orientation and anisotropy in the osteocyte lacuno-canalicular system, which is thought to be optimized along with the mechanical stimuli, was investigated using male rat femur. The degree of ECM orientation along the femur longitudinal axis was significantly and positively correlated with the anisotropic features of the osteocyte lacunae and canaliculi. At the femur middiaphysis, there are the osteocytes with lacunae that highly aligned along the bone long axis (principal stress direction) and canaliculi that preferentially extended perpendicular to the bone long axis, and the highest degree of apatite c-axis orientation along the bone long axis was shown. Based on these data, we propose a model in which osteocytes can change their lacuno-canalicular architecture depending on the mechanical environment so that they can become more susceptible to mechanical stimuli via fluid flow in the canalicular channel.

show abstract

“…Because the rationale for this work was to understand the physiology of the mice and to translate this to the physiology of humans with ALDH2 dysfunctional mutations, we employed whole body rather than muscle-specific KO mice. Whole body ALDH2-KO mice, which have been used in several avenues of research, were obtained from the RIKEN BioResource Center (Ibaraki, Japan) (24,34,43,47). The mice were housed (5-6 mice/ cage, cage size: 19.7 cm ϫ 37.5 cm ϫ 13.3 cm) on a 12-h light/dark cycle (dark 18:00 -06:00 h) in individually ventilated cages at 22°C.…”

Section: Animalsmentioning

confidence: 99%

“…The ALDH2*2 phenotype includes facial flushing and higher heart rate when alcohol is consumed. Beyond the response to alcohol, a growing body of epidemiological studies suggests that ALDH2*2 can increase the risk of several diseases, such as cancer, metabolic disorders, cardiac diseases, neurodegenerative diseases, and osteoporosis (16,47). However, there is little biological evidence to support these epidemiological findings.…”

Section: Introductionmentioning

confidence: 99%

Acetaldehyde dehydrogenase 2 deficiency increases mitochondrial reactive oxygen species emission and induces mitochondrial protease Omi/HtrA2 in skeletal muscle

Wakabayashi

Tamura

Kouzaki

et al. 2020

American Journal of Physiology-Regulatory, Integrative and Comp

Self Cite

View full text Add to dashboard Cite

Acetaldehyde dehydrogenase 2 (ALDH2) is an enzyme involved in redox homeostasis as well as the detoxification process in alcohol metabolism. Nearly 8% of the world’s population have an inactivating mutation in the ALDH2 gene. However, the expression patterns and specific functions of ALDH2 in skeletal muscles are still unclear. Herein, we report that ALDH2 is expressed in skeletal muscle and is localized to the mitochondrial fraction. Oxidative muscles had a higher amount of ALDH2 protein than glycolytic muscles. We next comprehensively investigated whether ALDH2 knockout in mice induces mitochondrial adaptations in gastrocnemius muscle (for example, content, enzymatic activity, respiratory function, supercomplex formation, and functional networking). We found that ALDH2 deficiency resulted in partial mitochondrial dysfunction in gastrocnemius muscle because it increased mitochondrial reactive oxygen species (ROS) emission (2′,7′-dichlorofluorescein and MitoSOX oxidation rate during respiration) and the frequency of regional mitochondrial depolarization. Moreover, we determined whether ALDH2 deficiency and the related mitochondrial dysfunction trigger mitochondrial stress and quality control responses in gastrocnemius muscle (for example, mitophagy markers, dynamics, and the unfolded protein response). We found that ALDH2 deficiency upregulated the mitochondrial serine protease Omi/HtrA2 (a marker of the activation of a branch of the mitochondrial unfolded protein response). In summary, ALDH2 deficiency leads to greater mitochondrial ROS production, but homeostasis can be maintained via an appropriate stress response.

show abstract

Cortical bone loss due to skeletal unloading in aldehyde dehydrogenase 2 gene knockout mice is associated with decreased PTH receptor expression in osteocytes

Cited by 14 publications

References 57 publications

Connexin 43 Channels in Osteocytes Regulate Bone Responses to Mechanical Unloading

Connexin 43 Channels in Osteocytes Regulate Bone Responses to Mechanical Unloading

Quantitative Evaluation of Osteocyte Morphology and Bone Anisotropic Extracellular Matrix in Rat Femur

Acetaldehyde dehydrogenase 2 deficiency increases mitochondrial reactive oxygen species emission and induces mitochondrial protease Omi/HtrA2 in skeletal muscle

Contact Info

Product

Resources

About