Stk11 (Lkb1) deletion in the osteoblast lineage leads to high bone turnover, increased trabecular bone density and cortical porosity

Background: Genetic alterations in the osteoprogenitor cells has been shown to induce acute myeloid leukemia (AML) in several mouse models. Moreover, we have recently reported that AML cells induce osteogenic differentiation in mesenchymal stromal cells (MSC) to gain growth advantage in the bone marrow (BM; Battula et al., JCI Insight, 2017). However, the effect of AML cells on bone homeostasis/turnover and its impact on AML progression is unknown. Here, we hypothesize that AML cells expand osteoprogenitor cells and alter the balance between bone formation and resorption. Methods: To investigate the effect of AML cells on osteoprogenitor cells and mature osteoblasts, we used triple transgenic reporter mice with the genotype Osx-CreERt2;Ocn-GFP;ROSA-tdTomato. Murine AML cells with MLL-ENL translocation were implanted into these transgenic mice, and Osteoprogenitor (Osx+) cells and mature osteoblasts (Ocn+) in femurs were measured by confocal microscopy. To investigate the effect of human AML cells on bone composition, patient-derived xenograft (PDX) cells were implanted into non-obese diabetic scid interleukin-2Rγnull (NSG) mice and bone histomorphometry was performed using H&E and Goldner's trichrome staining. Computed tomography (micro-CT) was used to measure bone volume (BV) and mineral density (BMD) in mice. Tartrate-resistant acidic phosphatase (TRAP) staining was performed to measure osteoclast number/activation. Finally, bone density on the vertebral bone (T12) was measured in 263 de-novo AML patients and 23 normal individuals by CT imaging. Results: In transgenic mice implanted with syngenic AML cells, we found a 3-4 fold increase in Osterix+, but not Osteocalcin+ cells, suggesting AML cells expand osteoprogenitor cells in the BM during short term exposure (2-3 weeks). To investigate the effects of AML on bone during a long term exposure, we implanted 10 different AML-PDX models in NSG mice (3 mice per model) and analyzed femurs by micro-CT and bone histomorphometry analysis. Interestingly, we observed a dramatic increase in new web-like medullary bone formation in 5/10 of the PDX models tested. Moreover, higher bone volume is associated with less aggressive PDX models (which takes 4-6 months to reach 90% circulating leukemia), but not aggressive PDX models (only 4-8 weeks to reach 90% circulating cells). These findings were also confirmed by micro-CT of mouse femurs. Interestingly, in some PDX models, CT images revealed large cavities in cortical bones close to epiphysis and metaphysis areas in the femur and tibia of mice with AML suggesting bone resorption. To validate bone resorption, we performed TRAP staining and found a significant increase in osteoclast activity on the endosteal surface and massive bone resorption in AML bone compared to normal bone. These data indicate high bone turnover in mice with AML compared to control mice. Next, we measured bone densities in AML patients and normal individuals by chest CT imaging. We found bone densities were gradually decrease with age in both healthy individuals and AML patients. However, compared to healthy individuals, bone densities are significantly higher in majority of AML patients (~70%) (p<0.01). Interestingly, survival analysis revealed that higher bone density is associated with good prognosis in AML patients (p<0.01), suggesting high bone turnover alters patient outcomes. Conclusion: Our data suggest that AML cells expand osteoprogenitor-rich niche and alter BM microenvironment by high bone turnover. New bone induction by less aggressive AML-PDX models coupled with AML patient CT data suggests that high bone density and volume are associated with favorable prognostic factors in AML. Mechanisms underlying this observation are under investigation. Disclosures Andreeff: Amgen: Research Funding; Daiichi-Sankyo; Jazz Pharmaceuticals; Celgene; Amgen; AstraZeneca; 6 Dimensions Capital: Consultancy; Daiichi-Sankyo; Breast Cancer Research Foundation; CPRIT; NIH/NCI; Amgen; AstraZeneca: Research Funding; Centre for Drug Research & Development; Cancer UK; NCI-CTEP; German Research Council; Leukemia Lymphoma Foundation (LLS); NCI-RDCRN (Rare Disease Clin Network); CLL Founcdation; BioLineRx; SentiBio; Aptose Biosciences, Inc: Membership on an entity's Board of Directors or advisory committees. Konopleva:Ablynx: Research Funding; AstraZeneca: Research Funding; Kisoji: Consultancy; Ascentage: Research Funding; Stemline Therapeutics: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Reata Pharmaceutical Inc.;: Patents & Royalties: patents and royalties with patent US 7,795,305 B2 on CDDO-compounds and combination therapies, licensed to Reata Pharmaceutical; Rafael Pharmaceutical: Research Funding; Amgen: Consultancy; Agios: Research Funding; Sanofi: Research Funding; Cellectis: Research Funding; Calithera: Research Funding; Forty-Seven: Consultancy, Research Funding; Eli Lilly: Research Funding; Genentech: Consultancy, Research Funding; F. Hoffmann La-Roche: Consultancy, Research Funding. Battula:Leukemia Lymphoma Society: Research Funding; Tolero Pharmaceuticals: Research Funding; Golfers Against Cancer: Research Funding.

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Cessation of ambulation results in a dramatic loss of trabecular bone density in boys with Duchenne muscular dystrophy

Bone Abstracts ◽

10.1530/boneabs.2.p134 ◽

2013 ◽

Author(s):

Crabtree Nicola ◽

Bebbington Natalie ◽

Roper Helen ◽

McMurchie Heather ◽

Shaw Nicholas

Keyword(s):

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Bone Density ◽

Trabecular Bone ◽

Trabecular Bone Density

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High bone turnover markers and disturbances of bone mineral density in children with hypophosphataemic rickets

Bone Abstracts ◽

10.1530/boneabs.6.p074 ◽

2017 ◽

Author(s):

Agnieszka Rusinska ◽

Izabela Michalus ◽

Izabela Woch ◽

Paulina Adamiecka ◽

Danuta Chlebna-Sokol

Keyword(s):

Bone Mineral Density ◽

Bone Turnover ◽

Bone Mineral ◽

Bone Turnover Markers ◽

Mineral Density ◽

Hypophosphataemic Rickets ◽

High Bone Turnover ◽

High Bone ◽

Turnover Markers

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Faculty Opinions recommendation of Whole-exome sequencing reveals a heterozygous LRP5 mutation in a 6-year-old boy with vertebral compression fractures and low trabecular bone density.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718048076.793481338 ◽

2013 ◽

Author(s):

Wim van Hul

Keyword(s):

Bone Density ◽

Trabecular Bone ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Vertebral Compression Fractures ◽

Trabecular Bone Density ◽

Compression Fractures ◽

Whole Exome

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The effect of deer antler from East Kalimantan to increase trabecular bone density and calcium levels in serum on osteoporotic mice

Journal of Basic and Clinical Physiology and Pharmacology ◽

10.1515/jbcpp-2020-0140 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Retno Widyowati ◽

Suciati Suciati ◽

Dewi Melani Haryadi ◽

Hsin-I Chang ◽

IPG Ngurah Suryawan ◽

...

Keyword(s):

Bone Density ◽

Trabecular Bone ◽

Aqueous Extract ◽

Dependent Manner ◽

Aqueous Extracts ◽

Trabecular Bone Density ◽

Male Mice ◽

Deer Antler ◽

East Kalimantan ◽

Dose Dependent

Abstract Objectives Glucocorticoid-induced osteoporosis (dexamethasone) is a primary cause of secondary osteoporosis by the decreasing formation and increasing resorption activities. Previously, the in vitro study showed that 70% ethanol and aqueous extract of deer antler have increased alkaline phosphatase in osteoblast cell that known as marker of bone formation. The mind of this study is to analyze the effect of deer antlers in increasing the bone trabecular density of osteoporosis-induced male mice. Methods This study used a post-test control group design. A total of 54 healthy male mice were randomly divided to nine groups, i.e., healthy control, osteoporotic, positive control, 70% ethanol (4, 8, and 12 mg/kg BW), and aqueous extracts (4, 8, and 12 mg/kg BW) of deer antler groups. All of the interventions were given 1 mL of test sample for 4 weeks orally. The bone densities were determined using histomorphometry by Image J and Adobe Photoshop. The statistical data were performed using SPSS 23 and statistical significance was set at p<0.05. Results The results showed that alendronate group, 70% ethanol, and aqueous extract groups increased bone density and calcium levels in serum (p<0.05) compared to osteoporotic group in dose dependent manner. It indicated that 70% ethanol and aqueous extract of deer antler stimulating bone turnover and aqueous extract showed the highest. Conclusions Dexamethasone induction for 4 weeks caused osteoporotic mice and the administration of 70% ethanol and aqueous extracts of deer antler from East Kalimantan increased trabecular bone density and calcium levels in dose dependent manner.

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POS1092 SUBCHONDRAL BONE NORMALIZATION AFTER KNEE JOINT DISTRACTION TREATMENT AS MEASURED WITH CT

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-eular.1329 ◽

2021 ◽

Vol 80 (Suppl 1) ◽

pp. 825.2-826

Author(s):

M. Jansen ◽

A. Ooms ◽

T. D. Turmezei ◽

J. W. Mackay ◽

S. Mastbergen ◽

...

Keyword(s):

Bone Density ◽

Trabecular Bone ◽

Cortical Bone ◽

Subchondral Bone ◽

Trabecular Bone Density ◽

Bone Thickness ◽

Cortical Bone Thickness ◽

Bone Changes ◽

One Year ◽

Shape Changes

Background:In addition to cartilage degeneration, knee osteoarthritis (OA) causes bone changes, including cortical bone thickening, subchondral bone density decrease, and bone shape changes as a result of widening and flattening condyles and osteophyte formation. Knee joint distraction (KJD) is a joint-preserving treatment for younger (<65 years) knee OA patients that has been shown to reverse OA cartilage degradation. On radiographs, KJD showed a decrease in subchondral bone density and an increase in osteophyte formation. However, these bone changes have never been evaluated with a 3D imaging technique.Objectives:To evaluate cortical bone thickness, subchondral trabecular bone density, and bone shape on CT scans before and one year after KJD treatment.Methods:19 KJD patients were included in an extended imaging protocol, undergoing a CT scan before and one year after treatment. Stradview v6.0 was used for semi-automatic tibia and femur segmentation from axial thin-slice (0.45mm) CT scans. Cortical bone thickness (mm) and trabecular bone density (Hounsfield units, HU) were measured with an automated algorithm. Osteophytes were excluded. Afterwards, wxRegSurf v18 was used for surface registration. Registration data was used for bone shape measurements. MATLAB R2020a and the SurfStat MATLAB package were used for data analysis and visualization. Two-tailed F-tests were used to calculate changes over time. Two separate linear regression models were used to show the influence of baseline Kellgren-Lawrence grade and sex on the changes over time. Statistical significance was calculated with statistical parametric mapping; a p-value <0.05 was considered statistically significant. Bone shape changes were explored visually using vertex by vertex displacements between baseline and follow-up. Patients were separated into two groups based on whether their most affected compartment (MAC) was medial or lateral. Only patients with axial CT scans at both time points available for analysis were included for evaluation.Results:3 Patients did not have complete CTs and in 1 patient the imaged femur was too short, leaving 16 patients for tibial analyses and 15 patients for femoral analyses. The MAC was predominantly the medial side (medial MAC n=14; lateral n=2). Before treatment, the MAC cortical bone was compared to the rest of the joint (Figure 1). One year after treatment, MAC cortical thickness decreased, although this decrease of up to approximately 0.25 mm was not statistically significant. The trabecular bone density was also higher before treatment in the MAC, and a decrease was seen throughout the entire joint, although statistically significant only for small areas on mostly the MAC where this decrease was up to approximately 80 HU (Figure 1). Female patients and patients with a higher Kellgren-Lawrence grade showed a somewhat larger decrease in cortical bone thickness. Trabecular density decreased less for patients with a higher Kellgren-Lawrence grade, and female patients showed a higher density decrease interiorly while male patients showed a higher decrease exteriorly. None of this was statistically significant. The central areas of both compartments showed an outward shape change, while the outer ring showed inward changes.Conclusion:MAC cortical bone thickness shows a partial decrease after KJD. Trabecular bone density decreased on both sides of the joint, likely as a direct result of the bicompartmental unloading. For both subchondral bone parameters, MAC values became more similar to the LAC, indicating (partial) subchondral bone normalization in the most affected parts of the joint. The bone shape changes may indicate a reversal of typical OA changes, although the inward difference that was seen on the outer edges may be a result of osteophyte-related changes that might have affected the bone segmentation. In conclusion, KJD treatment shows subchondral bone normalization in the first year after treatment, and longer follow-up might show whether these changes are a temporary result of joint unloading or indicate more prolonged bone changes.Disclosure of Interests:None declared.

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