Rescuing mitochondrial dysfunction in macrophages prevents osteonecrosis of the jaw in anti-resorptive therapy
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE306512 | GEO | 2026/03/04
REPOSITORIES: GEO
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Project description:Objectives: Osteonecrosis of the jaw (ONJ), a necrotic bone disease unique to the craniofacial region, is often observed among cancer patients treated with bisphosphonate (BP)-based chemotherapy and becomes a costly and debilitating source of pain and reduced quality of life. Elucidation of clinicopathological mechanism and biomarkers of ONJ that can indicate probable disease course would allow for better assessment of treatment strategies for individual patients. To address our overall goal of identifying novel diagnostic and prognostic strategies for ONJ, this study specifically aims to understand the alendronate (ALN) treatment-induced perturbation of bone proteome and microenvironmental pathophysiology of ONJ using targeted molecular analyses and computational approaches based on an in vitro cell culture system. This study also focuses on identifying proteome perturbation and potential molecular biomarkers during ONJ development. Methods: To understand the molecular mechanisms underlying ONJ, an unbiased and global proteomics approach combined with big data analysis using bioinformatics was applied. Biochemical and functional analyses were followed to tease out the mechanisms regulated by ALN treatment. Results: The current findings from our global proteomics study and biochemical analyses suggested that the RIPK3/Wnt/GSK3/β-catenin signaling pathway is significantly perturbed upon alendronate treatment, resulting in abnormal angiogenesis/inflammation/bone anabolism/remodeling/bone mineralization in the in vitro cell culture system. Conclusion: This investigation on potential key signaling mechanisms underlying ONJ will provide a rational basis for suppressing BP-induced ONJ and novel therapeutic strategies against ONJ.
2021-09-10 | PXD024585 | Pride
Project description:BACKGROUND:; Osteonecrosis of the jaw (ONJ) has been reported in patients with a history of aminobisphosphonate use. METHODS:; In order to define ONJ and gain insights into its pathophysiology, clinical, radiographic, biochemical, and microarray profiling studies were conducted in 11 patients with multiple myeloma (MM) and ONJ. RESULTS:; Eleven patients between the ages of 57 and 81 yrs were treated with either pamidronate (n=3), zoledronate (n=4), or both agents sequentially (n=4) for a mean of 38.7 months. Radiographic studies demonstrated radiolucency and sclerosis on plain films. Functional imaging with positron emission tomography (PET) demonstrated a visual increase in glucose metabolism and mineralization at sites of ONJ, using fluorodeoxyglucose (FDG) and sodium fluoride (NaF), respectively. Quantitative regional analysis confirmed an increased standardized uptake value (SUVmax) in areas of ONJ. The target to background ratio of SUVmax was significantly greater for NaF-PET than FDG-PET scans, suggesting that NaF-PET may provide superior image quality for identifying ONJ. Transcriptional profiling of peripheral blood mononuclear cells (PBMCs) using the Affymetrix U133Plus 2.0 gene chip in all 11 MM patients compared with 10 age matched MM controls and 5 healthy volunteers demonstrated that genes involved in osteoblast and osteoclast signaling cascades were significantly downregulated in patients with ONJ, as were proteins confirmed by ELISA. CONCLUSIONS:; ONJ is seen in patients with a history of aminobisphosphonate use. Functional imaging with NaF PET confirms the diagnosis of ONJ. Gene and protein studies are consistent with altered bone remodeling, evidenced by suppression of both bone resorption and formation. Experiment Overall Design: Transcriptional profiling of peripheral blood mononuclear cells (PBMCs) was performed using the Affymetrix U133Plus 2.0 Gene Chip (Affymetrix, Santa Clara, CA, USA) in 11 patients with osteonecrosis of the jaw and multiple myeloma and compared with the profiles of the 10 myeloma patients on bisphosphonate therapy without osteonecrosis of the jaw and 5 healthy volunteers.
2008-06-15 | E-GEOD-7116 | biostudies-arrayexpress
Project description:We have explored the potential role of genetics in the development of osteonecrosis of the jaw (ONJ) in multiple myeloma (MM) patients under bisphosphonate therapy. A genome wide association study was performed using 500.568 single nucleotide polymorphisms (SNPs) in two series of homogeneously treated MM patients: one with ONJ (22 MM cases) and another without ONJ (65 matched MM controls). Four SNPs (rs1934951, rs1934980, rs1341162 and rs17110453) mapped within the Cytochrome P450-2C gene (CYP2C8) showed a different distribution between cases and controls with statistically significant differences (p=1.07x10-6, p=4.231x10-6, p=6.22x10-6 and p=2.15x10-5, respectively). SNP rs1934951 was significantly associated with a higher risk of ONJ development even after Bonferroni correction (P corrected value=0.02). Genotyping results displayed an overrepresentation of the T allele in cases as compared with controls (48% vs. 12%). Thus, individuals homozygous for the T allele had an increased likelihood of developing ONJ (Odds ratio 12.75, 95% confidence interval 3.7 to 43.5).
2008-09-25 | GSE11948 | GEO
Project description:We have explored the potential role of genetics in the development of osteonecrosis of the jaw (ONJ) in multiple myeloma (MM) patients under bisphosphonate therapy. A genome wide association study was performed using 500.568 single nucleotide polymorphisms (SNPs) in two series of homogeneously treated MM patients: one with ONJ (22 MM cases) and another without ONJ (65 matched MM controls). Four SNPs (rs1934951, rs1934980, rs1341162 and rs17110453) mapped within the Cytochrome P450-2C gene (CYP2C8) showed a different distribution between cases and controls with statistically significant differences (p=1.07x10-6, p=4.231x10-6, p=6.22x10-6 and p=2.15x10-5, respectively). SNP rs1934951 was significantly associated with a higher risk of ONJ development even after Bonferroni correction (P corrected value=0.02). Genotyping results displayed an overrepresentation of the T allele in cases as compared with controls (48% vs. 12%). Thus, individuals homozygous for the T allele had an increased likelihood of developing ONJ (Odds ratio 12.75, 95% confidence interval 3.7 to 43.5). We studied 22 cases (MM with ONJ) and 65 controls (MM without ONJ), matched for age, gender and ethnicity (note: all of the cases and controls are Caucasian). All patients were enrolled in the GEM-00 protocol, which consists on polychemotherapy and autologous transplantation. All received BPs therapy, either Pamidronate (16 cases, 57 controls) or Zoledronic Acid (6 cases, 8 controls) planned for 2 years (median 22 months, range 9-24 months). Clinical characteristics were similar between controls and cases. Study protocols were approved by the ethics committee and written informed consent was obtained from all participants. Each patient was genotyped using the Affymetrix GeneChip Mapping 500K set of microarrays (Affymetrix, Santa Clara, CA) according to the manufacturer’s recommendations. Genotypes were determined using the BRLMM algorithm with cases and controls undergoing joint cluster analysis, after ensuring a robust association test through quality filtering tests. Based on stringent quality control criteria a total of 339.972 SNPs were selected for subsequent analyses. Criteria for exclusion were: 1) call rate<90%, 2) minor allele frequency <5% and 3) deviations from Hardy-Weinberg equilibrium with a p<0.00001. Sexual chromosomes were excluded for analysis. To test for allelic associations between SNPs and ONJ, we constructed 2x2 contingency tables and compared using the two-sided Fisher’s exact or Chisquare tests through SPSS software (SPSS 14.0, Inc. Chicago, IL, USA). P-values were corrected (Pc) using the Bonferroni correction. The strength of association was estimated by the odds ratio (OR), and their 95% confidence intervals (CI) were calculated by Cornfield methods. Linkage disequilibrium between SNPs was analyzed using the Arlequin Software (http://anthro.unige.ch/arlequin).
2008-09-25 | E-GEOD-11948 | biostudies-arrayexpress
Project description:The presence of disseminated tumor cells in patient bone marrow (BM) aspirates predicts decreased recurrence-free survival, yet little is known about whether hematopoietic BM cells impact bone metastases. Here, we report that the BM can be rendered metastasis-suppressive by the bone-targeting bisphosphonate, zoledronic acid (ZA). In particular, ZA modulates hematopoietic myeloid/osteoclast progenitor cell (M/OCP) lineage potential to render them metastasis-suppressive. Granulocyte-colony stimulating factor (G-CSF) promotes resistance to ZA by re-directing M/OCP differentiation. We identified BM transcriptional programs that associate with metastasis suppression and resistance to ZA. Analysis of patient blood samples taken at randomization revealed that women with plasma G-CSF levels >23 pg/mL experienced significantly worse outcome with adjuvant ZA than those on ZA who had lower plasma G-CSF levels. Our findings establish that hematopoietic cells and M/OCP lineage potential profoundly impact bone metastasis and support the discovery of biomarkers that stratify therapeutic responses in patients at risk of recurrence.
2021-02-25 | GSE108250 | GEO
Project description:Medication-related osteonecrosis of the jaw (MRONJ) is a rare but serious complication of anti-resorptive agents used for osteoporosis and bone metastasis. As the global population ages, the number of patients with MRONJ continues to rise. Resorptive osteoclasts firmly attached to bone surfaces cannot be detected using single-cell RNA-Seq (scRNA-Seq); however, we hypothesized that multinucleated giant and detached osteoclasts (DetOCs) can be detected by this method. scRNA-Seq was performed on granulation tissues surrounding sequestra from four patients with MRONJ and radicular cysts, a common odontogenic infectious disease with normal bone metabolism. Our results show that DetOCs were detected exclusively in the granulation tissues of MRONJ. These DetOCs expressed well-known osteoclast markers as well as COL27A1. Subcluster analysis revealed that SPP1+ TREM2+ macrophages differentiated into DetOCs and expressed several types of collagens. Immunostaining confirmed the expression of COL27A1 in DetOCs in MRONJ, as well as in osteoclasts in mandibular cancer. Overall, we successfully identified DetOCs in the granulation tissues surrounding sequestra in MRONJ, and our scRNA-Seq analysis suggests the potential to classify osteoclast subtypes based on the expression of collagen types.
2025-11-27 | GSE303003 | GEO
Project description:Single-cell gene expression of control mandibular bone marrow cells and mandibular bone marrow cells under bisphosphonate-related osteonecrosis of the jaw (BRONJ)
| PRJNA1253544 | ENA
Project description:Purpose: The goal of this study was to characterize the gingival oral barrier immunity of bisphosphonate-related osteonecrosis of the jaw (BRONJ) and HMDP-treated BRONJ mouse maxilla. Method: Mouse BRONJ was induced by Zoledronate IV injection and maxillary left first molar extraction. HMDP-DNV was topically applied to the BRONJ lesion 2 times. Mouse palatal gingiva was harvested 2 weeks after tooth extraction. Gingival cells were harvested and subjected to 10X Genomix scRNA-seq. Cell Ranger processed data were analysed.
2022-01-08 | GSE193110 | GEO
Project description:Detached osteoclasts in the granulation tissue surrounding sequestra in medication-related osteonecrosis of the jaw
| PRJNA1293341 | ENA
Project description:BACKGROUND: Osteonecrosis of the jaw (ONJ) has been reported in patients with a history of aminobisphosphonate use. METHODS: In order to define ONJ and gain insights into its pathophysiology, clinical, radiographic, biochemical, and microarray profiling studies were conducted in 11 patients with multiple myeloma (MM) and ONJ. RESULTS: Eleven patients between the ages of 57 and 81 yrs were treated with either pamidronate (n=3), zoledronate (n=4), or both agents sequentially (n=4) for a mean of 38.7 months. Radiographic studies demonstrated radiolucency and sclerosis on plain films. Functional imaging with positron emission tomography (PET) demonstrated a visual increase in glucose metabolism and mineralization at sites of ONJ, using fluorodeoxyglucose (FDG) and sodium fluoride (NaF), respectively. Quantitative regional analysis confirmed an increased standardized uptake value (SUVmax) in areas of ONJ. The target to background ratio of SUVmax was significantly greater for NaF-PET than FDG-PET scans, suggesting that NaF-PET may provide superior image quality for identifying ONJ. Transcriptional profiling of peripheral blood mononuclear cells (PBMCs) using the Affymetrix U133Plus 2.0 gene chip in all 11 MM patients compared with 10 age matched MM controls and 5 healthy volunteers demonstrated that genes involved in osteoblast and osteoclast signaling cascades were significantly downregulated in patients with ONJ, as were proteins confirmed by ELISA. CONCLUSIONS: ONJ is seen in patients with a history of aminobisphosphonate use. Functional imaging with NaF PET confirms the diagnosis of ONJ. Gene and protein studies are consistent with altered bone remodeling, evidenced by suppression of both bone resorption and formation. Keywords: Therapy complication analysis
2007-11-29 | GSE7116 | GEO