scholarly journals A decrease in NAD+ contributes to the loss of osteoprogenitors and bone mass with aging

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Ha-Neui Kim ◽  
Filipa Ponte ◽  
Aaron Warren ◽  
Rebecca Ring ◽  
Srividhya Iyer ◽  
...  
Keyword(s):  
Bone Formation ◽  
Bone Mass ◽  
Bone Matrix ◽  
Cell Senescence ◽  
Dependent Manner ◽  
Nicotinamide Riboside ◽  
Age Related ◽  
Foxo Transcription Factors ◽  
Old Mice ◽  
Osteoblast Progenitors

AbstractAge-related osteoporosis is caused by a deficit in osteoblasts, the cells that secrete bone matrix. The number of osteoblast progenitors also declines with age associated with increased markers of cell senescence. The forkhead box O (FoxO) transcription factors attenuate Wnt/β-catenin signaling and the proliferation of osteoprogenitors, thereby decreasing bone formation. The NAD+-dependent Sirtuin1 (Sirt1) deacetylates FoxOs and β-catenin in osteoblast progenitors and, thereby, increases bone mass. However, it remains unknown whether the Sirt1/FoxO/β-catenin pathway is dysregulated with age in osteoblast progenitors. We found decreased levels of NAD+ in osteoblast progenitor cultures from old mice, associated with increased acetylation of FoxO1 and markers of cell senescence. The NAD+ precursor nicotinamide riboside (NR) abrogated FoxO1 and β-catenin acetylation and several marker of cellular senescence, and increased the osteoblastogenic capacity of cells from old mice. Consistent with these effects, NR administration to C57BL/6 mice counteracted the loss of bone mass with aging. Attenuation of NAD+ levels in osteoprogenitor cultures from young mice inhibited osteoblastogenesis in a FoxO-dependent manner. In addition, mice with decreased NAD+ in cells of the osteoblast lineage lost bone mass at a young age. Together, these findings suggest that the decrease in bone formation with old age is due, at least in part, to a decrease in NAD+ and dysregulated Sirt1/FoxO/β-catenin pathway in osteoblast progenitors. NAD+ repletion, therefore, represents a rational therapeutic approach to skeletal involution.

scholarly journals Overexpression of miR-125b in Osteoblasts Improves Age-Related Changes in Bone Mass and Quality through Suppression of Osteoclast Formation

2021 ◽  
Vol 22 (13) ◽  
pp. 6745
Author(s):  
Shota Ito ◽  
Tomoko Minamizaki ◽  
Shohei Kohno ◽  
Yusuke Sotomaru ◽  
Yoshiaki Kitaura ◽  
...  
Keyword(s):  
Bone Formation ◽  
Bone Mass ◽  
Trabecular Bone ◽  
Callus Formation ◽  
Bone Matrix ◽  
Age Groups ◽  
Osteoclast Formation ◽  
Mineral Apposition Rate ◽  
Age Related ◽  
Trabecular Bone Mass

We recently reported an unexpected role of osteoblast-derived matrix vesicles in the delivery of microRNAs to bone matrix. Of such microRNAs, we found that miR-125b inhibited osteoclast formation by targeting Prdm1 encoding a transcriptional repressor of anti-osteoclastogenesis factors. Transgenic (Tg) mice overexpressing miR-125b in osteoblasts by using human osteocalcin promoter grow normally but exhibit high trabecular bone mass. We have now further investigated the effects of osteoblast-mediated miR-125b overexpression on skeletal morphogenesis and remodeling during development, aging and in a situation of skeletal repair, i.e., fracture healing. There were no significant differences in the growth plate, primary spongiosa or lateral (periosteal) bone formation and mineral apposition rate between Tg and wild-type (WT) mice during early bone development. However, osteoclast number and medial (endosteal) bone resorption were less in Tg compared to WT mice, concomitant with increased trabecular bone mass. Tg mice were less susceptible to age-dependent changes in bone mass, phosphate/amide I ratio and mechanical strength. In a femoral fracture model, callus formation progressed similarly in Tg and WT mice, but callus resorption was delayed, reflecting the decreased osteoclast numbers associated with the Tg callus. These results indicate that the decreased osteoclastogenesis mediated by miR-125b overexpression in osteoblasts leads to increased bone mass and strength, while preserving bone formation and quality. They also suggest that, in spite of the fact that single miRNAs may target multiple genes, the miR-125b axis may be an attractive therapeutic target for bone loss in various age groups.

scholarly journals Ostm1 from Mouse to Human: Insights into Osteoclast Maturation

2020 ◽  
Vol 21 (16) ◽  
pp. 5600 ◽  
Author(s):  
Jean Vacher ◽  
Michael Bruccoleri ◽  
Monica Pata
Keyword(s):  
Bone Formation ◽  
Bone Mass ◽  
Bone Fractures ◽  
Bone Development ◽  
Bone Matrix ◽  
Adult Life ◽  
Cell Types ◽  
Severe Form ◽  
Isolation And Characterization

The maintenance of bone mass is a dynamic process that requires a strict balance between bone formation and resorption. Bone formation is controlled by osteoblasts, while osteoclasts are responsible for resorption of the bone matrix. The opposite functions of these cell types have to be tightly regulated not only during normal bone development, but also during adult life, to maintain serum calcium homeostasis and sustain bone integrity to prevent bone fractures. Disruption of the control of bone synthesis or resorption can lead to an over accumulation of bone tissue in osteopetrosis or conversely to a net depletion of the bone mass in osteoporosis. Moreover, high levels of bone resorption with focal bone formation can cause Paget’s disease. Here, we summarize the steps toward isolation and characterization of the osteopetrosis associated trans-membrane protein 1 (Ostm1) gene and protein, essential for proper osteoclast maturation, and responsible when mutated for the most severe form of osteopetrosis in mice and humans.

scholarly journals Acute fat loss does not affect bone mass

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Marie K. Lagerquist ◽  
Karin L. Gustafsson ◽  
Petra Henning ◽  
Helen Farman ◽  
Jianyao Wu ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Bone Mass ◽  
Fat Mass ◽  
Tissue Loss ◽  
Obese Mice ◽  
Long Term Effects ◽  
High Bone Mass ◽  
Age Related ◽  
Total Fat ◽  
Old Mice

AbstractObesity has previously been thought to protect bone since high body weight and body mass index are associated with high bone mass. However, some more recent studies suggest that increased adiposity negatively impacts bone mass. Here, we aimed to test whether acute loss of adipose tissue, via adipocyte apoptosis, alters bone mass in age-related obese mice. Adipocyte apoptosis was induced in obese male FAT-ATTAC mice through AP20187 dimerizer-mediated activation of caspase 8 selectively in adipocytes. In a short-term experiment, dimerizer was administered to 5.5 month-old mice that were terminated 2 weeks later. At termination, the total fat mass weighed 58% less in dimerizer-treated mice compared with vehicle-treated controls, but bone mass did not differ. To allow for the detection of long-term effects, we used 9-month-old mice that were terminated six weeks after dimerizer administration. In this experiment, the total fat mass weighed less (− 68%) in the dimerizer-treated mice than in the controls, yet neither bone mass nor biomechanical properties differed between groups. Our findings show that adipose tissue loss, despite the reduced mechanical loading, does not affect bone in age-related obese mice. Future studies are needed to test whether adipose tissue loss is beneficial during more severe obesity.

scholarly journals The aging mouse partially models the aging human spine: lumbar and coccygeal disc height, composition, mechanical properties, and Wnt signaling in young and old mice

2014 ◽  
Vol 116 (12) ◽  
pp. 1551-1560 ◽  
Author(s):  
Nilsson Holguin ◽  
Rhiannon Aguilar ◽  
Robin A. Harland ◽  
Bradley A. Bomar ◽  
Matthew J. Silva
Keyword(s):  
Wnt Signaling ◽  
Lumbar Vertebrae ◽  
Intervertebral Discs ◽  
Disc Height ◽  
Dependent Manner ◽  
Age Related ◽  
Intervertebral Disc Height ◽  
Spinal Region ◽  
The Impact ◽  
Old Mice

Murine lumbar and coccygeal (tail) regions of spines are commonly used to study cellular signaling of age-related disc diseases, but the tissue-level changes of aging intervertebral discs and vertebrae of each spinal region remain unclear. Furthermore, the impact of aging lumbar and coccygeal discs on Wnt/β-catenin signaling, which is putatively involved in the catabolism of intervertebral discs, is also unclear. We compared disc/vertebrae morphology and mechanics and biochemical composition of intervertebral discs from lumbar and coccygeal regions between young (4–5 mo) and old (20–22 mo) female C57BL/6 mice. Center intervertebral disc height from both regions was greater in old discs than young discs. Compared with young, old lumbar discs had a lower early viscous coefficient (a measure of stiffness) by 40%, while conversely old coccygeal discs were stiffer by 53%. Biochemically, old mice had double the collagen content in lumbar and coccygeal discs of young discs, greater glycosaminoglycan in lumbar discs by 37%, but less glycosaminoglycan in coccygeal discs by 32%. Next, we compared Wnt activity of lumbar and coccygeal discs of 4- to 5-mo and 12- to 14-mo TOPGAL mice. Despite the disc-specific changes, aging decreased Wnt signaling in the nucleus pulposus from both spinal regions by ≥64%. Compared with young, trabecular bone volume/tissue volume and ultimate force were less in old lumbar vertebrae, but greater in old coccygeal vertebrae. Thus intervertebral discs and vertebrae age in a spinal region-dependent manner, but these differential age-related changes may be uncoupled from Wnt signaling. Overall, lumbar and coccygeal regions are not interchangeable in modeling human aging.

scholarly journals Cortical bone gain following loading is site-specifically enhanced by prior and concurrent disuse in aged male mice

2019 ◽  
Author(s):  
Gabriel Galea ◽  
Peter J Delisser ◽  
Lee Meakin ◽  
Lance E Lanyon ◽  
Joanna S Price ◽  
...  
Keyword(s):  
Bone Mass ◽  
Cortical Bone ◽  
List Type ◽  
Male Mice ◽  
Site Specific ◽  
Female Mice ◽  
Age Related ◽  
Sciatic Neurectomy ◽  
Bone Gain ◽  
Old Mice

AbstractThe primary aim of bone anabolic therapies is to strategically increase bone mass in skeletal regions likely to experience high strains. This is naturally achieved by mechanical loading of the young healthy skeleton. However, these bone anabolic responses fail with age. Here, we applied site specificity analysis to map regional differences in bone anabolic responses to axial loading of the tibia (tri-weekly, for two weeks) between young (19-week-old) and aged (19-month-old), male and female mice. Loading increased bone mass specifically in the proximal tibia in both sexes and ages. Young female mice gained more cortical bone than young males in specific regions of the tibia. However, these site-specific sex difference were lost with age such that bone gain following loading was not significantly different between old males and females. Having previously demonstrated that prior and concurrent disuse enhances bone gain following loading in old females, we established whether this “rescue” is sex-specific. Old male mice were subjected to sciatic neurectomy or sham surgery, and tri-weekly loading was initiated four days after surgery. Disuse augmented cortical bone gain in response to loading in old male mice, but only in the regions of the tibia which were load-responsive in the young. Increased understanding of how locally-activated load-responsive processes lead to site-specific bone formation, and how the age-related diminution of these processes can be site-specifically enhanced by disuse, may lead to the next generation of strategic bone anabolic therapies.HighlightsSex differences in cortical tissue area of young and old mice are not site-specificThe loading response in young, but not old, mice is sex- and site-specificThe cortical loading response is site-specifically enhanced by disuse in old mice of both sexesThe trabecular loading response can be rescued by disuse in old male, but not female, mice

scholarly journals Adaptive Immune Responses Mediated Age-related Plasmodium yoelii 17XL and 17XNL Infections in 4 and 8-week-old BALB/c Mice

2020 ◽  
Author(s):  
Qiu-bo Wang ◽  
Yun-ting Du ◽  
Fei Liu ◽  
Xiao-dan Sun ◽  
Xun Sun ◽  
...  
Keyword(s):  
T Cells ◽  
Survival Rate ◽  
Plasmodium Yoelii ◽  
Th2 Cells ◽  
Dependent Manner ◽  
Adaptive Immune ◽  
Age Related ◽  
Specific Igg ◽  
Ifn Γ ◽  
Old Mice

Abstract Backgroud: As the quest to eradicate malaria continues, it is important to clarify the opposite clinical outcomes between children and adulthood. The relationship between adaptive immune response and age-related malaria infection remains unknown.Methods: 4 and 8-week-old mice were used to mimic children and adulthood, respectively. Parasitemia and the survival rate were monitored. The proportion and function of Th1 and Th2 cells were detected by FACS. The levels of IFN-γ, IL-4, total IgG, IgG1, IgG2a and Plasmodium yoelii MSP-1-specific IgG were measured by ELISA.Results: Our results found that childhood mice were more susceptible to P. yoelii 17XNL infection, with lower survival rate and higher parasitemia. The adult group showed greater resistance to P. yoelii 17XL infection, with lower parasitemia. Compared with 4-week-old mice, the percentage of CD4+T-bet+IFN-γ+ Th1 cells as well as IFN-γ production were significantly increased on day 5 p.i. in the 8-week-old mice after P. yoelii 17XNL infection. The percentage of CD4+GATA3+IL-4+ Th2 cells and CD4+CXCR5+ Tfh cells, and IL-4 production in the 8-week-old mice significantly increased on day 5 and day 10 after P. yoelii 17XNL infection. Notably, the levels of total IgG, IgG1, IgG2a and P. yoelii MSP-1-specific IgG were also significantly increased in the 8-week-old mice. PD-1, a marker of exhaustion, was up-regulated on CD4+ or activated CD4+ T cells in the 8-week-old mice as compared to the 4-week-old group.Conclusions: Thus, we consider that enhanced cellular and humoral adaptive immunity might contribute to rapid clearance of malaria among adults, likely in a PD-1-dependent manner due to induction of CD4+ T cells exhaustion in P. yoelii 17XNL infected 8-week-old mice.

scholarly journals Adaptive Immune Responses Mediated Age-related Plasmodium yoelii 17XL and 17XNL Infections in 4 and 8-week-old BALB/c Mice

2019 ◽  
Author(s):  
Qiu-bo Wang ◽  
Yun-ting Du ◽  
Fei Liu ◽  
Xiao-dan Sun ◽  
Xun Sun ◽  
...  
Keyword(s):  
T Cells ◽  
Survival Rate ◽  
Cd4 T Cells ◽  
Plasmodium Yoelii ◽  
Th2 Cells ◽  
Dependent Manner ◽  
Adaptive Immune ◽  
Age Related ◽  
Ifn Γ ◽  
Old Mice

Abstract Background As the quest to eradicate malaria continues, it is important to clarify the opposite clinical outcomes between childhood and adulthood. The relationship between adaptive immune response and age-related malaria infection remains unknown. Methods 4 and 8-week-old mice were used to mimic childhood and adulthood, respectively. Parasitemia and the survival rate were monitored. The proportion and function of Th1 and Th2 cells were detected by FACS. The levels of IFN-γ, IL-4, total IgG, IgG1, IgG2a and Plasmodium yoelii MSP-1-special IgG were measured by ELISA. Results Infant mice were more susceptible to P. yoelii 17XNL infection, with lower survival rate and higher parasitemia. The adult group showed greater resistance to P. yoelii 17XL infection, with lower parasitemia. Compared with 4-week-old mice, the percentage of CD4 + T-bet + IFN-γ + Th1 cells as well as IFN-γ production were significantly increased on day 5 p.i. in the 8-week-old mice after P. yoelii 17XNL infection. The percentage of CD4 + GATA3 + IL-4 + Th2 cells and CD4 + CXCR5 + Tfh cells, and IL-4 production in the 8-week-old mice obviously increased on day 5 and day 10 after P. yoelii 17XNL infection. Notably, the levels of total IgG, IgG1, IgG2a and P. yoelii MSP-1-special IgG were also significantly increased in the 8-week-old mice. PD-1, a marker of exhaustion, was up-regulated on CD4 + or activated CD4 + T cells in the 8-week-old mice as compared to the 4-week-old group. Conclusion We consider that enhanced cellular and humoral adaptive immunity might contribute to rapid clearance of malaria among adults, likely in a PD-1-dependent manner due to induction of CD4 + T cells exhaustion.

scholarly journals Adaptive Immune Responses Mediated Age-related Plasmodium yoelii 17XL and 17XNL Infections in 4 and 8-week-old BALB/c Mice

2020 ◽  
Author(s):  
Qiu-bo Wang ◽  
Yun-ting Du ◽  
Fei Liu ◽  
Xiao-dan Sun ◽  
Xun Sun ◽  
...  
Keyword(s):  
T Cells ◽  
Survival Rate ◽  
Plasmodium Yoelii ◽  
Th2 Cells ◽  
Dependent Manner ◽  
Adaptive Immune ◽  
Age Related ◽  
Specific Igg ◽  
Ifn Γ ◽  
Old Mice

Abstract Backgroud: As the quest to eradicate malaria continues, it is important to clarify the opposite clinical outcomes between childhood and adulthood. The relationship between adaptive immune response and age-related malaria infection remains unknown. Methods: 4 and 8-week-old mice were used to mimic childhood and adulthood, respectively. Parasitemia and the survival rate were monitored. The proportion and function of Th1 and Th2 cells were detected by FACS. The levels of IFN-γ, IL-4, total IgG, IgG1, IgG2a and Plasmodium yoelii MSP-1-specific IgG were measured by ELISA. Results: Our results found that childhood mice were more susceptible to P. yoelii 17XNL infection, with lower survival rate and higher parasitemia. The adult group showed greater resistance to P. yoelii 17XL infection, with lower parasitemia. Compared with 4-week-old mice, the percentage of CD4+T-bet+IFN-γ+ Th1 cells as well as IFN-γ production were significantly increased on day 5 p.i. in the 8-week-old mice after P. yoelii 17XNL infection. The percentage of CD4+GATA3+IL-4+ Th2 cells and CD4+CXCR5+ Tfh cells, and IL-4 production in the 8-week-old mice significantly increased on day 5 and day 10 after P. yoelii 17XNL infection. Notably, the levels of total IgG, IgG1, IgG2a and P. yoelii MSP-1-specific IgG were also significantly increased in the 8-week-old mice. PD-1, a marker of exhaustion, was up-regulated on CD4+ or activated CD4+ T cells in the 8-week-old mice as compared to the 4-week-old group. Conclusions: Thus, we consider that enhanced cellular and humoral adaptive immunity might contribute to rapid clearance of malaria among adults, likely in a PD-1-dependent manner due to induction of CD4+ T cells exhaustion in P. yoelii 17XNL infected 8-week-old mice.

scholarly journals Comparative Analysis of Age-Related Changes in Lacrimal Glands and Meibomian Glands of a C57BL/6 Male Mouse Model

2020 ◽  
Vol 21 (11) ◽  
pp. 4169 ◽  
Author(s):  
Chang Ho Yoon ◽  
Jin Suk Ryu ◽  
Ho Sik Hwang ◽  
Mee Kum Kim
Keyword(s):  
Oxidative Stress ◽  
Mouse Model ◽  
Dependent Manner ◽  
Ki 67 ◽  
Aged Mice ◽  
Age Related ◽  
Ifn Γ ◽  
One Year ◽  
Corneal Staining ◽  
Old Mice

It is not known how biological changes in the lacrimal (LGs) and meibomian (MGs) glands contribute to dry eye disease (DED) in a time-dependent manner. In this study, we investigated time-sequenced changes in the inflammation, oxidative stress, and senescence of stem cells in both glands of an aging-related DED mouse model. Eight-week (8W)-, one-year (1Y)-, and two-year (2Y)-old C57BL/6 male mice were used. MG areas of the upper and lower eyelids were analyzed by transillumination meibography imaging. The number of CD45+, 8-OHdG+, Ki-67+, and BrdU+ cells was compared in both glands. Increased corneal staining and decreased tear secretion were observed in aged mice. The MG dropout area increased with aging, and the age-adjusted MG area in lower lids was negatively correlated with the National Eye Institute (NEI) score. Increased CD4+ interferon (IFN)-γ+ cells in LGs were found in both aged mice. An increase in 8-OHdG+ cells in both glands was evident in 2Y-old mice. Reduced Ki-67+ cells, but no change in CD45+ cells, was observed in the MGs of 1Y-old mice. Increased BrdU+ cells were observed in the LGs of aged mice. This suggests that age-dependent DED in C57BL/6 mice is related to inflammation of the LGs, the development of MG atrophy, and oxidative stress in both glands.

scholarly journals Osteoblasts in osteoporosis: past, emerging, and future anabolic targets

2011 ◽  
Vol 165 (1) ◽  
pp. 1-10 ◽  
Author(s):  
Pierre J Marie ◽  
Moustapha Kassem
Keyword(s):  
Bone Resorption ◽  
Bone Loss ◽  
Bone Formation ◽  
Bone Matrix ◽  
Bone Fragility ◽  
Osteoblastic Cell ◽  
Medline Search ◽  
Cell Functions ◽  
Age Related ◽  
Increased Risk

ObjectiveAge-related bone loss is associated with significant changes in bone remodeling characterized by decreased trabecular and periosteal bone formation relative to bone resorption, resulting in bone fragility and increased risk of fractures. Prevention or reversal of age-related decrease in bone mass and increase in bone fragility has been based on inhibition of bone resorption using anticatabolic drugs. The current challenge is to promote osteoblastogenesis and bone formation to prevent age-related bone deterioration.MethodsA limited number of approved therapeutic molecules are available to activate bone formation. Therefore, there is a need for anabolic drugs that promote bone matrix apposition at the endosteal, endocortical, and periosteal envelopes by increasing the number of osteoblast precursor cells and/or the function of mature osteoblasts. In this study, we review current therapeutics promoting bone formation and anabolic molecules targeting signaling pathways involved in osteoblastogenesis, based on selected full-text articles searched on Medline search from 1990 to 2010.Results and discussionWe present current therapeutic approaches focused on intermittent parathyroid hormone and Wnt signaling agonists/antagonists. We also discuss novel approaches for prevention and treatment of defective bone formation and bone loss associated with aging and osteoporosis. These strategies targeting osteoblastic cell functions may prove to be useful in promoting bone formation and improving bone strength in the aging population.

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