scholarly journals The Rho GTPase RAC1 in Osteoblasts Controls Their Function

2020 ◽  
Vol 21 (2) ◽  
pp. 385
Author(s):  
Katrin Huck ◽  
Carla Sens ◽  
Carina Wuerfel ◽  
Caren Zoeller ◽  
Inaam A. Nakchbandi
Keyword(s):  
Bone Mineral Density ◽  
Parathyroid Hormone ◽  
Signaling Pathways ◽  
Bone Mineral ◽  
Osteoblast Differentiation ◽  
Rho Gtpase ◽  
Mineral Density ◽  
Osteoblast Function

The regulation of the differentiation of the bone-forming cells, the osteoblasts, is complex. Many signaling pathways converge on the master regulator of osteoblast differentiation Runx2. The role of molecules that integrate several signaling pathways such as the Rho GTPases need to be better understood. We, therefore, asked at which stage Rac1, one of the Rho GTPase, is needed for osteoblast differentiation and whether it is involved in two pathways, the anabolic response to parathyroid hormone and the stimulatory effect of fibronectin isoforms on integrins. Genetic deletion of Rac1 in preosteoblasts using the osterix promoter diminished osteoblast differentiation in vitro. This effect was however similar to the presence of the promoter by itself. We, therefore, applied a Rac1 inhibitor and confirmed a decrease in differentiation. In vivo, Rac1 deletion using the osterix promoter decreased bone mineral density as well as histomorphometric measures of osteoblast function. In contrast, deleting Rac1 in differentiating osteoblasts using the collagen α1(I) promoter had no effects. We then evaluated whether intermittent parathyroid hormone (PTH) was able to affect bone mineral density in the absence of Rac1 in preosteoblasts. The increase in bone mineral density was similar in control animals and in mice in which Rac1 was deleted using the osterix promoter. Furthermore, stimulation of integrin by integrin isoforms was able to enhance osteoblast differentiation, despite the deletion of Rac1. In summary, Rac1 in preosteoblasts is required for normal osteoblast function and bone density, but it is neither needed for PTH-mediated anabolic effects nor for integrin-mediated enhancement of differentiation.

In Vitro and in Vivo Spiral CT to Determine Bone Mineral Density: Initial Experience in Patients at Risk for Osteoporosis

Radiology ◽  
2004 ◽  
Vol 231 (3) ◽  
pp. 805-811 ◽  
Author(s):  
Thomas M. Link ◽  
Boris B. Koppers ◽  
Thomas Licht ◽  
Jan Bauer ◽  
Ying Lu ◽  
...  
Keyword(s):  
Bone Mineral Density ◽  
At Risk ◽  
Bone Mineral ◽  
Spiral Ct ◽  
Initial Experience ◽  
Mineral Density ◽  
Patients At Risk

scholarly journals The Non-Erythropoietic EPO Analogue Cibinetide Inhibits Osteoclastogenesis In Vitro and Increases Bone Mineral Density in Mice

2021 ◽  
Vol 23 (1) ◽  
pp. 55
Author(s):  
Zamzam Awida ◽  
Almog Bachar ◽  
Hussam Saed ◽  
Anton Gorodov ◽  
Nathalie Ben-Califa ◽  
...  
Keyword(s):  
Bone Mineral Density ◽  
Bone Loss ◽  
Bone Mineral ◽  
Molecular Mechanisms ◽  
Mineral Density ◽  
Female Mice ◽  
Epo Receptor

The two erythropoietin (EPO) receptor forms mediate different cellular responses to erythropoietin. While hematopoiesis is mediated via the homodimeric EPO receptor (EPOR), tissue protection is conferred via a heteromer composed of EPOR and CD131. In the skeletal system, EPO stimulates osteoclast precursors and induces bone loss. However, the underlying molecular mechanisms are still elusive. Here, we evaluated the role of the heteromeric complex in bone metabolism in vivo and in vitro by using Cibinetide (CIB), a non-erythropoietic EPO analogue that exclusively binds the heteromeric receptor. CIB is administered either alone or in combination with EPO. One month of CIB treatment significantly increased the cortical (~5.8%) and trabecular (~5.2%) bone mineral density in C57BL/6J WT female mice. Similarly, administration of CIB for five consecutive days to female mice that concurrently received EPO on days one and four, reduced the number of osteoclast progenitors, defined by flow cytometry as Lin−CD11b−Ly6Chi CD115+, by 42.8% compared to treatment with EPO alone. In addition, CIB alone or in combination with EPO inhibited osteoclastogenesis in vitro. Our findings introduce CIB either as a stand-alone treatment, or in combination with EPO, as an appealing candidate for the treatment of the bone loss that accompanies EPO treatment.

scholarly journals Bone mineral density (BMD) and computer tomographic measurements of the equine proximal phalanx in correlation with breaking strength

2013 ◽  
Vol 16 (1) ◽  
pp. 3-8 ◽  
Author(s):  
P. Tóth ◽  
C. Horváth ◽  
V. Ferencz ◽  
B. Tóth ◽  
A. Váradi ◽  
...  
Keyword(s):  
Bone Mineral Density ◽  
Fracture Risk ◽  
Bone Mineral ◽  
Risk Model ◽  
Breaking Strength ◽  
Proximal Phalanx ◽  
Ct Images ◽  
Mineral Density

Abstract Despite the fact that bone mineral density (BMD) is an important fracture risk predictor in human medicine, studies in equine orthopedic research are still lacking. We hypothesized that BMD correlates with bone failure and fatigue fractures of this bone. Thus, the objectives of this study were to measure the structural and mechanical properties of the proximal phalanx with dual energy X-ray absorptiometry (DXA), to correlate the data obtained from DXA and computer tomography (CT) measurements to those obtained by loading pressure examination and to establish representative region of interest (ROI) for in vitro BMD measurements of the equine proximal phalanx for predicting bone failure force. DXA was used to measure the whole bone BMD and additional three ROI sites in 14 equine proximal phalanges. Following evaluation of the bone density, whole bone, cortical width and area in the mid-diaphyseal plane were measured on CT images. Bones were broken using a manually controlled universal bone crusher to measure bone failure force and reevaluated for the site of fractures on follow-up CT images. Compressive load was applied at a constant displacement rate of 2 mm/min until failure, defined as the first clear drop in the load measurement. The lowest BMD was measured at the trabecular region (mean ± SD: 1.52 ± 0.12 g/cm2; median: 1.48 g/cm2; range: 1.38-1.83 g/cm2). There was a significant positive linear correlation between trabelcular BMD and the breaking strength (P=0.023, r=0.62). The trabecular region of the proximal phalanx appears to be the only significant indicator of failure of strength in vitro. This finding should be reassessed to further reveal the prognostic value of trabecular BMD in an in vivo fracture risk model.

Erk1 Plays Critical Role in Macrophage Development

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 517-517 ◽  
Author(s):  
Yongzheng He ◽  
Karl Staser ◽  
Steven D Rhodes ◽  
Xiaohua Wu ◽  
Ping Zhang ◽  
...  
Keyword(s):  
Bone Mineral Density ◽  
Bone Marrow ◽  
Bone Mineral ◽  
Type I ◽  
Mineral Density ◽  
Macrophage Differentiation ◽  
Fold Reduction ◽  
The Impact

Abstract Abstract 517 Extracellular signal-regulated kinase (ERK 1 and 2) are widely expressed and are involved in the regulation of meiosis, mitosis, and postmitotic functions in multiple cell lineages, including T cells, B cells and osteoblasts. Macrophages are capable of differentiating into osteoclasts, which resorb bone. Abnormal osteoclast development and functions underlie certain diseases, especially skeletal defects. Altered ERK1/2 signaling has been found in several genetic diseases with skeletal phenotypes, including Noonan syndrome, polycystic kidney disease and serious developmental disorders such as cardio-facio-cutaneous syndrome. These clinical findings suggest the importance of the ERK MAPK pathway in human skeletal development. In the present study, we examined the consequence of Erk1 and Erk2 disruption in modulating macrophage development in the murine system. We found that deletion of Erk1 reduced macrophage progenitor numbers. Erk1−/− bone marrow mononuclear cells (BMMNCs) had significant reduction in osteoclast formation as compared to wildtype BMMNCs. In addition, Erk1−/− macrophages; the osteoclast progenitors, had a two-three fold reduction in migration and a two-fold reduction in αv ß3 mediated adhesion as compared to WT macrophages as evaluated by transwell and adhesion assay, respectively. These in vitro data demonstrate that Erk1 positively regulates macrophage differentiation into osteoclasts. To evaluate the impact of deficiency of Erk1 in vivo, we examined bone mineral density and trabecular microarchitecture in the distal femoral metaphysis by dual-energy X-ray absorptiometry (DEXA) with a Lunar Piximus densitometer and a high-resolution desktop microcomputed tomography imaging system (μCT-20; Scanco Medical AG, Basserdorf, Switzerland), respectively. Erk1−/− mice displayed elevated bone mineral density and increased trabecular bone formation as compared to WT mice. Histomorphometric analysis indicated that the Erk1−/− femur had significant reduction in osteoclast numbers as determined by tartrate resistant acid phosphatase staining, an osteoclast specific staining, as compared to femur of wildtype and Erk2−/− mice. Most importantly, Erk1−/− plasma had reduced C-terminal telopeptide of type I collagen, indicating less bone resorption in vivo. These data suggest that the impaired macrophage differentiation and osteoclast bone resorptive activity play an important role in increased bone mass in Erk1−/− mice. Finally, to verify that the macrophage-osteoclast lineage is a key cell lineage for the phenotypic changes in vivo in Erk1−/− mice, we performed bone marrow transplantation. WT mice reconstituted long-term with Erk1−/− hematopoietic stem cells demonstrated increased bone mineral density as compared to WT and Erk2−/− stem cell recipients, implicating marrow autonomous, Erk1-dependent macrophage differentiation and osteoclast bioactivity in vivo. Collectively, our in vitro and in vivo data demonstrate isoform-specific Erk function in macrophage while providing rationale for the development of a specific inhibitor for Erk1 that might be used for the treatment of dysplastic and erosive bone diseases. Disclosures: No relevant conflicts of interest to declare.

Europium-Doped Gd2O3 Nanotubes Increase Bone Mineral Density in Vivo and Promote Mineralization in Vitro

2017 ◽  
Vol 9 (7) ◽  
pp. 5784-5792 ◽  
Author(s):  
Huifang Liu ◽  
Yi Jin ◽  
Kun Ge ◽  
Guang Jia ◽  
Zhenhua Li ◽  
...  
Keyword(s):  
Bone Mineral Density ◽  
Bone Mineral ◽  
Mineral Density ◽  
Increase Bone Mineral Density

scholarly journals Repeated in vivo determinations of bone mineral density during parathyroid hormone treatment in ovariectomized mice

2001 ◽  
Vol 170 (3) ◽  
pp. 529-537 ◽  
Author(s):  
N Andersson ◽  
MK Lindberg ◽  
C Ohlsson ◽  
K Andersson ◽  
B Ryberg
Keyword(s):  
Bone Mineral Density ◽  
Parathyroid Hormone ◽  
Bone Mineral ◽  
Growth And Development ◽  
Drug Evaluation ◽  
Mineral Density ◽  
Ovariectomized Mice ◽  
Volumetric Bmd ◽  
Total Body

The recent development of different genetically modified mice with potentially interesting bone phenotypes has increased the demand for effective non-invasive methods to evaluate effects on bone of mice during growth and development, and for drug evaluation. In the present study, the skeleton was analyzed by repeated in vivo scans using dual energy X-ray absorptiometry (DXA) and peripheral quantitative computed tomography (pQCT). Ovariectomized (ovx) mice treated with parathyroid hormone (PTH) were used as an animal model to evaluate these two techniques at different times after the onset of treatment. Female mice (6 weeks of age) were allocated randomly to four groups: (1) sham-operated+vehicle; (2) ovx+vehicle; (3) sham-operated+PTH(1-84) 150 microg/kg per day; (4) ovx+PTH. Six weeks after ovariectomy the drug treatment began and was continued for 8 weeks. The total body bone mineral content (BMC) and total body areal bone mineral density (BMD) were measured by DXA. Ovariectomy reduced total body BMC and total body areal BMD by 6.2+/-1.7% and 2.6+/-0.9% respectively. No effect of PTH on total body BMC was seen during the treatment period. The trabecular volumetric BMD was measured by pQCT. Ovariectomy reduced the trabecular volumetric BMD by 52+/-6.7%. The pQCT technique detected a clear effect on trabecular volumetric BMD after 2 weeks of PTH treatment (ovx 94+/-29% and sham-operated 46+/-10% more than vehicle-treated). The cortical bone was measured in a mid-diaphyseal pQCT scan of the tibia. Ovariectomy reduced the cortical BMC by 9+/-2%. PTH treatment for 8 weeks increased cortical BMC in ovx mice. In conclusion, the pQCT technique is more sensitive than the DXA technique in the detection of bone loss after ovariectomy and increased bone mass after PTH treatment in mice. Notably, the pQCT, but not the DXA, technique detected a dramatic effect as early as after 2 weeks of PTH treatment. Dynamic pQCT measurements will be useful for monitoring skeletal changes during growth and development, and for drug evaluation in mice.

scholarly journals P114 Effect of vitamin D on parathyroid hormone, serum calcium and bone mineral density in patients with primary hyperparathyroidism being managed conservatively

Rheumatology ◽  
2021 ◽  
Vol 60 (Supplement_1) ◽  
Author(s):  
Mahrukh Khalid ◽  
Vismay Deshani ◽  
Khalid Jadoon
Keyword(s):  
Bone Mineral Density ◽  
Vitamin D ◽  
Parathyroid Hormone ◽  
Primary Hyperparathyroidism ◽  
Bone Mineral ◽  
Serum Calcium ◽  
Mineral Density ◽  
Neck Of Femur ◽  
Vitamin D Levels ◽  
Significant Difference

Abstract Background/Aims  Vitamin D deficiency is associated with more severe presentation of primary hyperparathyroidism (PTHP) with high parathyroid hormone (PTH) levels and reduced bone mineral density (BMD). We analyzed data to determine if vitamin D levels had any impact on PTH, serum calcium and BMD at diagnosis and 3 years, in patients being managed conservatively. Methods  Retrospective analysis of patients presenting with PHPT. Based on vitamin D level at diagnosis, patients were divided into two groups; vitamin D sufficient (≥ 50 nmol/L) and vitamin D insufficient (≤ 50 nmol/L). The two groups were compared for age, serum calcium and PTH levels at diagnosis and after mean follow up of 3 years. BMD at forearm and neck of femur (NOF) was only analyzed in the two groups at diagnosis, due to lack of 3 year’s data. Results  There were a total of 93 patients, 17 males, mean age 70; range 38-90. Mean vitamin D level was 73.39 nmol/L in sufficient group (n = 42) and 34.48 nmol/L in insufficient group (n = 40), (difference between means -38.91, 95% confidence interval -45.49 to -32.33, p < 0.0001). There was no significant difference in age, serum calcium and PTH at the time of diagnosis. After three years, there was no significant difference in vitamin D levels between the two groups (mean vitamin D 72.17 nmol/L in sufficient group and 61.48 nmol/L in insufficient group). Despite rise in vitamin D level in insufficient group, no significant change was observed in this group in PTH and serum calcium levels. BMD was lower at both sites in vitamin D sufficient group and difference was statistically significant at NOF. Data were analyzed using unpaired t test and presented as mean ± SEM. Conclusion  50% of patients presenting with PHPT were vitamin D insufficient at diagnosis. Vitamin D was adequately replaced so that at 3 years there was no significant difference in vitamin D status in the two groups. Serum calcium and PTH were no different in the two groups at diagnosis and at three years, despite rise in vitamin D levels in the insufficient group. Interestingly, BMD was lower at forearm and neck of femur in those with sufficient vitamin D levels and the difference was statistically significant at neck of femur. Our data show that vitamin D insufficiency does not have any significant impact on PTH and calcium levels and that vitamin D replacement is safe in PHPT and does not impact serum calcium and PTH levels in the short term. Lower BMD in those with adequate vitamin D levels is difficult to explain and needs further research. Disclosure  M. Khalid: None. V. Deshani: None. K. Jadoon: None.

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