scholarly journals Blackcurrant Supplementation Improves Trabecular Bone Mass in Young but Not Aged Mice

Nutrients ◽  
2018 ◽  
Vol 10 (11) ◽  
pp. 1671 ◽  
Author(s):  
Junichi Sakaki ◽  
Melissa Melough ◽  
Sang Lee ◽  
Judy Kalinowski ◽  
Sung Koo ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Bone Loss ◽  
Bone Mass ◽  
Trabecular Bone ◽  
Chow Diet ◽  
Type I ◽  
Aged Mice ◽  
Age Related ◽  
Standard Chow Diet ◽  
Young Mice

Due to deleterious side effects of currently available medications, the search for novel, safe, and effective preventive agents for improving bone health in aging continues and is urgently needed. This study aimed to determine whether dietary blackcurrants (BC), an anthocyanin-rich berry, can improve bone mass in a mouse model of age-related bone loss. Thirty-five female C57BL/6J mice, 3 months old (n = 20) and 18 months old (n = 15), were randomized to consume either a standard chow diet or a standard chow diet with 1% (w/w) BC for four months. Dual-energy X-ray absorptiometry, Micro computed tomography (µCT), and histomorphometric analyses were conducted to assess bone parameters on femurs. Biochemical assays were conducted to determine bone resorption, antioxidant activity, and inflammation in humerus homogenates. Trabecular bone volume (BV/TV) was significantly lower in aged mice compared to young mice (young control, 3.7 ± 0.4% vs aged control, 1.5 ± 0.5%, mean ± SEM (standard error of mean), p < 0.01; young BC, 5.3 ± 0.6% vs aged BC, 1.1 ± 0.3%, p < 0.001). µCT analysis revealed that BC supplementation increased trabecular BV/TV in young mice by 43.2% (p < 0.05) compared to controls. Histomorphometric analysis revealed a 50% increase, though this effect was not statistically significant (p = 0.07). The osteoblast surface increased by 82.5% in aged mice with BC compared to controls (p < 0.01). In humerus homogenates of young mice, BC consumption reduced C-telopeptide of type I collagen by 12.4% (p < 0.05) and increased glutathione peroxidase by 96.4% (p < 0.05). In humerus homogenates of aged mice, BC consumption increased catalase by 12% (p = 0.09). Aged mice had significantly elevated concentrations of tumor necrosis factor α (TNF-α), a pro-inflammatory cytokine contributing to bone resorption, which was reduced by 43.3% with BC consumption (p = 0.06). These results suggest that early consumption of BC may protect from aging-associated bone loss.

scholarly journals Age-related trabecular bone loss is associated with a decline in serum Galectin-1 level

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Wenting Xu ◽  
Cheng Ni ◽  
Yuxuan Wang ◽  
Guoqing Zheng ◽  
Jinshan Zhang ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Loss ◽  
Protein Expression ◽  
Trabecular Bone ◽  
Hematopoietic Stem ◽  
Aged Mice ◽  
Age Related ◽  
Trabecular Bone Loss ◽  
The Relationship ◽  
Young Mice

Abstract Background Senile osteoporosis with age-related bone loss is diagnosed depending on radiographic changes of bone and bone mineral density (BMD) measurement. However, radiographic alterations are usually signs of medium-late stage osteoporosis. Therefore, biomarkers have been proposed as indicators of bone loss. In the current study, Galectin-1 (Gal-1) showed age-related decline in mice serum. The role of Gal-1 in osteoporosis has not been investigated so far. Hence, the current study illustrated the relationship of serum Gal-1 level with bone loss. Methods We employed 6- and 18-month-old mice to establish an animal model of age-related trabecular bone loss, whose bone density and microstructure were investigated by micro-CT. ELISA was used to measure the levels of Gal-1 in serum. The correlation analysis was performed to illustrate the relationship between serum Gal-1 levels and trabecular bone loss. In addition, immunohistochemistry was used to investigate the abundance of Gal-1 in bone marrow of mice. ELISA and western blot were performed to measure the secretion ability and protein expression of Gal-1 in bone marrow stromal cells (BMSC), hematopoietic stem cells (HSC) and myeloid progenitor (MP) respectively. Flow cytometry was used to measure BMSC number in bone marrow. Finally, male volunteers with age-related BMD decrease were recruited and the relationship between serum Gal-1 and BMD was analyzed. Results Gal-1 showed age-related decline in mice serum. Serum Gal-1 was positively associated with BV/TV of femur, tibia and L1 vertebrae in mice. BMSC secreted more Gal-1 compared with HSC and MP. BMSC number in bone marrow was significantly lower in aged mice compared with young mice. Significant attenuation of Gal-1 protein expression was observed in BMSC and HSC from aged mice compared with young mice. Further, we found a decline in serum Gal-1 levels in men with age-related BMD decrease. There was positive correlation between BMD and serum Gal-1 levels in these men. Conclusions Age-related trabecular bone loss is associated with a decline in serum Gal-1 level in mice and men. Our study suggested Gal-1 had great potential to be a biomarker for discovering BMSC senescence, diagnosing early osteoporosis and monitoring trabecular bone loss.

scholarly journals Porcupine inhibitors impair trabecular and cortical bone mass and strength in mice

2018 ◽  
Vol 238 (1) ◽  
pp. 13-23 ◽  
Author(s):  
Thomas Funck-Brentano ◽  
Karin H Nilsson ◽  
Robert Brommage ◽  
Petra Henning ◽  
Ulf H Lerner ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Bone Loss ◽  
Bone Formation ◽  
Bone Mass ◽  
Trabecular Bone ◽  
Cortical Bone ◽  
Bone Strength ◽  
Bending Test ◽  
Bone Homeostasis ◽  
Mineral Density

WNT signaling is involved in the tumorigenesis of various cancers and regulates bone homeostasis. Palmitoleoylation of WNTs by Porcupine is required for WNT activity. Porcupine inhibitors are under development for cancer therapy. As the possible side effects of Porcupine inhibitors on bone health are unknown, we determined their effects on bone mass and strength. Twelve-week-old C57BL/6N female mice were treated by the Porcupine inhibitors LGK974 (low dose = 3 mg/kg/day; high dose = 6 mg/kg/day) or Wnt-C59 (10 mg/kg/day) or vehicle for 3 weeks. Bone parameters were assessed by serum biomarkers, dual-energy X-ray absorptiometry, µCT and histomorphometry. Bone strength was measured by the 3-point bending test. The Porcupine inhibitors were well tolerated demonstrated by normal body weight. Both doses of LGK974 and Wnt-C59 reduced total body bone mineral density compared with vehicle treatment (P < 0.001). Cortical thickness of the femur shaft (P < 0.001) and trabecular bone volume fraction in the vertebral body (P < 0.001) were reduced by treatment with LGK974 or Wnt-C59. Porcupine inhibition reduced bone strength in the tibia (P < 0.05). The cortical bone loss was the result of impaired periosteal bone formation and increased endocortical bone resorption and the trabecular bone loss was caused by reduced trabecular bone formation and increased bone resorption. Porcupine inhibitors exert deleterious effects on bone mass and strength caused by a combination of reduced bone formation and increased bone resorption. We suggest that cancer targeted therapies using Porcupine inhibitors may increase the risk of fractures.

scholarly journals Protective Effects of Curcumin and Broccoli Seed Extract Against Age-Related Bone Loss in Mice

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 46-46
Author(s):  
Jing Li ◽  
Dong Zhang ◽  
Yiping Ren ◽  
Zhongdong Qiao ◽  
Doug Stevenson ◽  
...  
Keyword(s):  
Bone Loss ◽  
Seed Extract ◽  
Control Group ◽  
Protective Effects ◽  
Trabecular Thickness ◽  
Time Points ◽  
Aged Mice ◽  
Funding Sources ◽  
Age Related ◽  
Young Mice

Abstract Objectives Age-related bone loss occurs in both men and women, and is the leading cause of elderly disability. An age-related bone loss model was established in mice to investigate the protective effects of curcumin and broccoli seed extract. Methods 20 young (6-month-old) male C57BL/6 J mice after administration with vehicle once daily were sacrificed at four time points: day 0, 30, 60 and 90. 8 out of the 109 aged (18-month-old) male C57BL/6 J mice were sacrificed at the beginning and used as control. The rest of these aged mice were then randomly divided into four groups: one group served as control (vehicle), the other three groups were administrated with curcumin (CMN) and/or broccoli seed extract (BSE) by oral gavage. Mice in each group were sacrificed at four time points: day 0, 30, 60 and 90. L2 vertebrae of mice were fixed with paraformaldehyde and scanned with a Scanco Medical μCT40 scanner. Quantitative analyses of bone volume (BV), tissue volume (TV), trabecular number (Tb.N), trabecular thickness (Tb.Th) and trabecular spacing (Tb.Sp) were performed with the Scanco Medical's software. Results BV/TV of the young mice group were significantly higher compared to the aged mice group at all four time points. Similarly, Tb.N and Tb.Th were also higher in the young mice group compared to the aged mice group. In contrast, Tb.Sp was lower in the young mice group. When comparing different groups in the aged mice, we found that mice administered with CMN had a higher BV/TV value compared to the mice in the control group at all three time points. Such a difference is significant by day 30. The mice administered with combined CMN and BSE also showed significant increase in BV/TV on day 30. For Tb.N, both mice administered with either CMN or BSE had higher values at all three time points. But no obvious difference in Tb.N was found for mice administered with combined CMN and BSE. For Tb.Th, both mice administered with CMN and with combined CMN and BSE had higher values compared to the control. For Tb.Sp, both mice administered with either CMN or BSE had lower values compared to the control. Conclusions This study showed that curcumin could slow down bone loss in the mouse model. There is no obvious positive effect with broccoli seed extract or with curcumin and broccoli seed extract combined. The curcumin used in this study may shed light on the alleviation of bone loss in humans. Funding Sources Nu Skin Enterprises.

scholarly journals Age dependence of systemic bone loss and recovery following femur fracture in mice

2018 ◽  
Author(s):  
Armaun J. Emami ◽  
Chrisoula A. Toupadakis ◽  
Stephanie M. Telek ◽  
David P. Fyhrie ◽  
Clare E. Yellowley ◽  
...  
Keyword(s):  
Bone Loss ◽  
Fracture Risk ◽  
Trabecular Bone ◽  
Voluntary Movement ◽  
Whole Body ◽  
Middle Aged ◽  
Aged Mice ◽  
Future Fracture ◽  
Systemic Bone Loss ◽  
Young Mice

AbstractThe most reliable predictor of future fracture risk is a previous fracture of any kind. The etiology of this increased fracture risk is not fully known, but it is possible that fracture initiates systemic bone loss leading to greater fracture risk at all skeletal sites. In this study we investigated systemic bone loss and recovery following femoral fracture in young (3 month old) and middle-aged (12 month old) mice. Transverse femur fractures were created using a controlled impact, and whole-body bone mineral density (BMD), trabecular and cortical microstructure, bone mechanical properties, bone formation and resorption rates, mouse voluntary movement, and systemic inflammation were quantified at multiple time points post-fracture. We found that fracture led to decreased whole-body BMD in both young and middle-aged mice 2 weeks post-fracture; this bone loss was recovered by 6 weeks in young, but not middle-aged mice. Similarly, trabecular bone volume fraction (BV/TV) of the L5 vertebral body was significantly reduced in fractured mice relative to control mice 2 weeks post-fracture (−11% for young mice, −18% for middle-aged mice); this bone loss was fully recovered by 6 weeks post-fracture in young mice. At 3 days post-fracture we observed significant increases in serum levels of interleukin-6 and significant decreases in voluntary movement in fractured mice compared to control mice, with considerably greater changes in middle-aged mice than in young mice. At this time point we also observed increased osteoclast number on L5 vertebral body trabecular bone of fractured mice compared to control mice. These data show that systemic bone loss occurs after fracture in both young and middle-aged mice, and recovery from this bone loss may vary with age. This systemic response could contribute to increased future fracture risk following fracture, and these data may inform clinical treatment of fractures with respect to improving long-term skeletal health.

scholarly journals Erythropoietin (EPO) Regulates Bone Mass Via EPO Receptors on Myeloid and Lymphocytic Cells

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 846-846
Author(s):  
Sahar Hiram-Bab ◽  
Albert Kolomansky ◽  
Naamit Deshet-Unger ◽  
Nathalie Ben-Califa ◽  
Tamar Liron ◽  
...  
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
Bone Resorption ◽  
Bone Loss ◽  
Bone Mass ◽  
B Cell ◽  
Trabecular Bone ◽  
Conflicts Of Interest ◽  
New Findings ◽  
Equal Contribution

Abstract Background and aims: Erythropoietin (EPO) is the key regulator of red blood cell production. In response to hypoxia, EPO levels can increase 1000-fold and remain high for weeks to promote hematopoiesis. Therapeutically, the introduction of EPO and erythropoietic stimulating agents into clinical practice has revolutionized the treatment of anemia despite certain concerns regarding the safety of the therapy. Recent studies demonstrate that EPO has activities in addition to hematopoiesis, and modulates bone remodeling by increasing bone resorption and decreasing bone formation, leading to trabecular bone loss. In vitro, EPO directly inhibits murine osteoblast differentiation and mineralization at doses relatively lower than those shown to stimulate osteoclastogenesis. The aim of this study was to investigate the dose-response relationship between EPO dose, hemoglobin (Hgb) levels, and the extent of bone loss, as well as to examine the role of the monocytic and B cell EPO receptor (EPOR) in bone metabolism. Results: Treating mice for 2 weeks with escalating doses of EPO, ranging from 6-540 IU/week, led to a dose-dependent increase in Hgb accompanied by a more dramatic decrease in trabecular bone mass; regression slopes of Hgb and bone volume/total volume (BV/TV, a measure of bone density) were 0.009 vs -0.09, respectively (p<0.05). These effects were associated with a significant increase in the number of preosteoclasts (CD115+ cells) in the bone marrow (r=0.74, p<0.05). To assess whether the osteoclast lineage contributes to EPO-induced bone loss, we generated mice lacking EPOR in the monocytic lineage (LysM-cre+/+;EPORflox/flox, cKO). At steady state, these mice and their LysM+/+;EPORwt/wt controls exhibited similar levels of Hgb (16.7±0.57 and 16.8 ±0.25 g/dL, respectively) and BV/TV (2.73%± 0.73 and 3.10%±0.76, respectively). Although not completely abolished, the bone loss induced by high EPO doses (540 IU/week) was significantly attenuated in cKO compared to control mice (60%±4.7 reduction versus 40%±13.2 reduction, respectively). At the same time, the levels of osteoclast precursors (CD115+ cells) increased from 3.08%±1.12 to 4.67%±0.92 in EPO-treated control mice, although there was no change in bone marrow preosteoclasts and preosteoblasts (defined as CD11b-/ALP+) in EPO-treated cKO mice. This suggests that osteoclast EPOR is responsible, at least in part, for mediating the effect of EPO on bone mass. Adding to the complexity of EPO's osteoimmunological roles, new findings suggest that EPO also regulates bone resorption via EPOR signaling in B cells. EPO stimulated surface expression of the osteoclastogenic RANKL in B cells (MFI: 2.6%±0.1 to 3.13%±0.09 P<0.05) and we found a higher bone mass in mice with conditional EPOR KO in B cells (MB1-cre+/-;EPORflox/flox) (vBMD, 52.2±15.1 versus 40.8±8.8 mg HA/cm3 in MB1-Cre+/-;EPORwt/wt, p<0.05). Conclusions: Our data demonstrate the complexity of EPO-induced bone loss mediated at least partly by EPOR signaling in both myeloid and B cell lineages. Furthermore, since patients who require treatment with EPO are prone to osteoporosis, our data suggest that using the lowest effective EPO dose would not only decrease the risk of thromboembolic complications but also minimize adverse skeletal outcomes. SHB and AK - Equal contribution; YG and DN - Equal contribution Funded by the German Israel Foundation, Grant # 01021017 to YG, DN, MR and BW and the Israel Science Foundation, Grant # 343/17 to DN. Disclosures No relevant conflicts of interest to declare.

scholarly journals Bcl-2-dependent autophagy disruption during aging impairs amino acid utilization that is restored by hochuekkito

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Miwa Nahata ◽  
Sachiko Mogami ◽  
Hitomi Sekine ◽  
Seiichi Iizuka ◽  
Naoto Okubo ◽  
...  
Keyword(s):  
Amino Acid ◽  
Energy Homeostasis ◽  
Mitochondrial Dynamics ◽  
Negative Regulator ◽  
Aged Mice ◽  
Glucose Levels ◽  
Therapeutic Benefits ◽  
Age Related ◽  
Daily Food ◽  
Young Mice

AbstractChronic undernutrition contributes to the increase in frailty observed among elderly adults, which is a pressing issue in the sector of health care for older people worldwide. Autophagy, an intracellular recycling system, is closely associated with age-related pathologies. Therefore, decreased autophagy in aging could be involved in the disruption of energy homeostasis that occurs during undernutrition; however, the physiological mechanisms underlying this process remain unknown. Here, we showed that 70% daily food restriction (FR) induced fatal hypoglycemia in 23–26-month-old (aged) mice, which exhibited significantly lower hepatic autophagy than 9-week-old (young) mice. The liver expressions of Bcl-2, an autophagy-negative regulator, and Beclin1–Bcl-2 binding, were increased in aged mice compared with young mice. The autophagy inducer Tat-Beclin1 D11, not the mTOR inhibitor rapamycin, decreased the plasma levels of the glucogenic amino acid and restored the blood glucose levels in aged FR mice. Decreased liver gluconeogenesis, body temperature, physical activity, amino acid metabolism, and hepatic mitochondrial dynamics were observed in the aged FR mice. These changes were restored by treatment with hochuekkito that is a herbal formula containing several autophagy-activating ingredients. Our results indicate that Bcl-2 upregulation in the liver during the aging process disturbs autophagy activation, which increases the vulnerability to undernutrition. The promotion of liver autophagy may offer clinical therapeutic benefits to frail elderly patients.

scholarly journals Combination treatment with pioglitazone and fenofibrate attenuates pioglitazone-mediated acceleration of bone loss in ovariectomized rats

2011 ◽  
Vol 212 (2) ◽  
pp. 179-186 ◽  
Author(s):  
Rana Samadfam ◽  
Malaika Awori ◽  
Agnes Bénardeau ◽  
Frieder Bauss ◽  
Elena Sebokova ◽  
...  
Keyword(s):  
Bone Loss ◽  
Bone Mass ◽  
Trabecular Bone ◽  
Bone Mineral ◽  
Combination Treatment ◽  
Mass Gain ◽  
Ovariectomized Rats ◽  
Concomitant Treatment ◽  
Mineral Density ◽  
Ovx Rats

Peroxisome proliferator-activated receptor (PPAR) γ agonists, such as pioglitazone (Pio), improve glycemia and lipid profile but are associated with bone loss and fracture risk. Data regarding bone effects of PPARα agonists (including fenofibrate (Feno)) are limited, although animal studies suggest that Feno may increase bone mass. This study investigated the effects of a 13-week oral combination treatment with Pio (10 mg/kg per day)+Feno (25 mg/kg per day) on body composition and bone mass parameters compared with Pio or Feno alone in adult ovariectomized (OVX) rats, with a 4-week bone depletion period, followed by a 6-week treatment-free period. Treatment of OVX rats with Pio+Feno resulted in ∼50% lower fat mass gain compared with Pio treatment alone. Combination treatment with Pio+Feno partially prevented Pio-induced loss of bone mineral content (∼45%) and bone mineral density (BMD; ∼60%) at the lumbar spine. Similar effects of treatments were observed at the femur, most notably at sites rich in trabecular bone. At the proximal tibial metaphysis, concomitant treatment with Pio+Feno prevented Pio exacerbation of ovariectomy-induced loss of trabecular bone, resulting in BMD values in the Pio+Feno group comparable to OVX controls. Discontinuation of Pio or Feno treatment of OVX rats was associated with partial reversal of effects on bone loss or bone mass gain, respectively, while values in the Pio+Feno group remained comparable to OVX controls. These data suggest that concurrent/dual agonism of PPARγ and PPARα may reduce the negative effects of PPARγ agonism on bone mass.

scholarly journals Hypothalamic leptin gene therapy reduces body weight without accelerating age-related bone loss

2015 ◽  
Vol 227 (3) ◽  
pp. 129-141 ◽  
Author(s):  
Russell T Turner ◽  
Michael Dube ◽  
Adam J Branscum ◽  
Carmen P Wong ◽  
Dawn A Olson ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Body Weight ◽  
Bone Loss ◽  
Bone Mass ◽  
Bone Turnover ◽  
Cancellous Bone ◽  
Mass Density ◽  
Female Rats ◽  
Bone Mass Density ◽  
Age Related

Excessive weight gain in adults is associated with a variety of negative health outcomes. Unfortunately, dieting, exercise, and pharmacological interventions have had limited long-term success in weight control and can result in detrimental side effects, including accelerating age-related cancellous bone loss. We investigated the efficacy of using hypothalamic leptin gene therapy as an alternative method for reducing weight in skeletally-mature (9 months old) female rats and determined the impact of leptin-induced weight loss on bone mass, density, and microarchitecture, and serum biomarkers of bone turnover (CTx and osteocalcin). Rats were implanted with cannulae in the 3rd ventricle of the hypothalamus and injected with either recombinant adeno-associated virus encoding the gene for rat leptin (rAAV-Leptin,n=7) or a control vector encoding green fluorescent protein (rAAV-GFP,n=10) and sacrificed 18 weeks later. A baseline control group (n=7) was sacrificed at vector administration. rAAV-Leptin-treated rats lost weight (−4±2%) while rAAV-GFP-treated rats gained weight (14±2%) during the study. At study termination, rAAV-Leptin-treated rats weighed 17% less than rAAV-GFP-treated rats and had lower abdominal white adipose tissue weight (−80%), serum leptin (−77%), and serum IGF1 (−34%). Cancellous bone volume fraction in distal femur metaphysis and epiphysis, and in lumbar vertebra tended to be lower (P<0.1) in rAAV-GFP-treated rats (13.5 months old) compared to baseline control rats (9 months old). Significant differences in cancellous bone or biomarkers of bone turnover were not detected between rAAV-Leptin and rAAV-GFP rats. In summary, rAAV-Leptin-treated rats maintained a lower body weight compared to baseline and rAAV-GFP-treated rats with minimal effects on bone mass, density, microarchitecture, or biochemical markers of bone turnover.

Different responses of trabecular and cortical bone to 1,25(OH)2D3 infusion

1990 ◽  
Vol 259 (5) ◽  
pp. E715-E722
Author(s):  
D. D. Bikle ◽  
B. P. Halloran ◽  
C. McGalliard-Cone ◽  
E. Morey-Holton
Keyword(s):  
Bone Resorption ◽  
Bone Mass ◽  
Trabecular Bone ◽  
Cortical Bone ◽  
Particle Distribution ◽  
Proximal Tibia ◽  
Bone Maturation ◽  
Dihydroxyvitamin D3 ◽  
Per Se ◽  
Bone Particles

Previous studies regarding the effects of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] on bone have suggested that 1,25(OH)2D3 increases bone mass and calcium. Many of these studies have focused on trabecular or total bone without examining cortical bone per se. To determine whether the response of trabecular bone to 1,25(OH)2D3 differed from the response of cortical bone, we infused 1,25(OH)2D3 into rats and examined bone mass, 45Ca accumulation, and the density distribution of bone particles (as a measure of bone maturation) in both the proximal tibia and shaft. In the proximal tibia 1,25(OH)2D3 decreased 45Ca accumulation, yet increased bone mass and shifted the particle distribution to more mineralized fractions. In the shaft there was a redistribution of bone to less mineralized fractions that was not accompanied by a change in total bone mass or a decrease in 45Ca accumulation. Thus 1,25(OH)2D3 may retard bone maturation and mineralization throughout the tibia, but this effect in the proximal tibia appears to be overshadowed by a reduction in bone resorption resulting in an accumulation of well-mineralized bone in that region. Bone resorption, however, was not measured directly. The net result is an increase in bone mass and density of trabecular bone not seen in cortical bone.

scholarly journals Hedgehog Inhibitors Suppress Osteoclastogenesis in In Vitro Cultures, and Deletion of Smo in Macrophage/Osteoclast Lineage Prevents Age-Related Bone Loss

2020 ◽  
Vol 21 (8) ◽  
pp. 2745
Author(s):  
Yukihiro Kohara ◽  
Ryuma Haraguchi ◽  
Riko Kitazawa ◽  
Yuuki Imai ◽  
Sohei Kitazawa
Keyword(s):  
Bone Resorption ◽  
Bone Loss ◽  
Signaling Pathway ◽  
Early Stage ◽  
Osteoclast Differentiation ◽  
Osteoclast Formation ◽  
Age Related ◽  
Hh Signaling

The functional role of the Hedgehog (Hh)-signaling pathway has been widely investigated in bone physiology/development. Previous studies have, however, focused primarily on Hh functions in bone formation, while its roles in bone resorption have not been fully elucidated. Here, we found that cyclopamine (smoothened (Smo) inhibitor), GANT-58 (GLI1 inhibitor), or GANT-61 (GLI1/2 inhibitor) significantly inhibited RANKL-induced osteoclast differentiation of bone marrow-derived macrophages. Although the inhibitory effects were exerted by cyclopamine or GANT-61 treatment during 0–48 h (early stage of osteoclast differentiation) or 48–96 h (late stage of osteoclast differentiation) after RANKL stimulation, GANT-58 suppressed osteoclast formation only during the early stage. These results suggest that the Smo-GLI1/2 axis mediates the whole process of osteoclastogenesis and that GLI1 activation is requisite only during early cellular events of osteoclastogenesis. Additionally, macrophage/osteoclast-specific deletion of Smo in mice was found to attenuate the aging phenotype characterized by trabecular low bone mass, suggesting that blockage of the Hh-signaling pathway in the osteoclast lineage plays a protective role against age-related bone loss. Our findings reveal a specific role of the Hh-signaling pathway in bone resorption and highlight that its inhibitors show potential as therapeutic agents that block osteoclast formation in the treatment of senile osteoporosis.

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