Dataset Information

Association of Acroosteolysis With Enhanced Osteoclastogenesis and Higher Blood Levels of Vascular Endothelial Growth Factor in Systemic Sclerosis.

ABSTRACT: Bone resorption of distal phalanges, or acroosteolysis (AO), can develop in patients with systemic sclerosis (SSc), causing pain and functional limitation. This study was undertaken to investigate whether AO may be associated with abnormal osteoclastogenesis in SSc patients and whether hypoxia may be involved in this process.Peripheral blood mononuclear cells (PBMCs) obtained from 26 SSc patients (11 with AO and 15 without AO) and 14 healthy controls were cultured in the presence of RANKL and macrophage colony-stimulating factor for 9 days. Tartrate-resistant acid phosphatase-positive multinucleated giant cells (MGCs) containing 3 or more nuclei were counted as osteoclasts. Plasma levels and effects of vascular endothelial growth factor (VEGF) on osteoclast formation were evaluated.SSc patients with AO formed significantly more osteoclasts after 9 days than did patients without AO (mean?±?SD 142.4?±?67.0 versus 27.2?±?17.6 MGCs/well; P < 0.001) or healthy controls (mean?±?SD 18.7?± 27.0 MGCs/well; P < 0.001). No significant difference in osteoclast formation was noted between the patients without AO and healthy controls. Plasma levels of VEGF were higher in SSc patients with AO compared to those without (mean?±?SD 142.4?±?69.6 pg/ml versus 88.1?±?38.2 pg/ml; P < 0.005) or healthy controls (54.2?± 24.6 pg/ml; P?=?0.018). Priming with VEGF-A for 24 hours significantly increased osteoclast generation by 5.3?±?1.9 fold (P?=?0.0018). The radiographic extent of AO was associated with increased osteoclast formation (Spearman's ??=?0.741, P?=?0.01).Our findings indicate that increased osteoclast formation and higher VEGF levels may contribute to AO in SSc patients. Further studies are needed to elucidate whether targeting osteoclastogenesis may provide a specific therapeutic option for SSc-associated AO.

SUBMITTER: Park JK

PROVIDER: S-EPMC4690758 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Association of Acroosteolysis With Enhanced Osteoclastogenesis and Higher Blood Levels of Vascular Endothelial Growth Factor in Systemic Sclerosis.

Park Jin Kyun JK Fava Andrea A Carrino John J Del Grande Filippo F Rosen Antony A Boin Francesco F

Arthritis & rheumatology (Hoboken, N.J.) 20160101 1

<h4>Objective</h4>Bone resorption of distal phalanges, or acroosteolysis (AO), can develop in patients with systemic sclerosis (SSc), causing pain and functional limitation. This study was undertaken to investigate whether AO may be associated with abnormal osteoclastogenesis in SSc patients and whether hypoxia may be involved in this process.<h4>Methods</h4>Peripheral blood mononuclear cells (PBMCs) obtained from 26 SSc patients (11 with AO and 15 without AO) and 14 healthy controls were cultur ...[more]

PMID: 26361270

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Project description:AimsGut microbiota and their generated metabolites impact the host vascular phenotype. The metaorganismal metabolite trimethylamine N-oxide (TMAO) is both associated with adverse clinical thromboembolic events, and enhances platelet responsiveness in subjects. The impact of TMAO on vascular Tissue Factor (TF) in vivo is unknown. Here, we explore whether TMAO-enhanced thrombosis potential extends beyond TMAO effects on platelets, and is linked to TF. We also further explore the links between gut microbiota and vascular endothelial TF expression in vivo.Methods and resultsIn initial exploratory clinical studies, we observed that among sequential stable subjects (n = 2989) on anti-platelet therapy undergoing elective diagnostic cardiovascular evaluation at a single-site referral centre, TMAO levels were associated with an increased incident (3 years) risk for major adverse cardiovascular events (MACE) (myocardial infarction, stroke, or death) [4th quartile (Q4) vs. Q1 adjusted hazard ratio (HR) 95% confidence interval (95% CI), 1.73 (1.25-2.38)]. Similar results were observed within subjects on aspirin mono-therapy during follow-up [adjusted HR (95% CI) 1.75 (1.25-2.44), n = 2793]. Leveraging access to a second higher risk cohort with previously reported TMAO data and monitoring of anti-platelet medication use, we also observed a strong association between TMAO and incident (1 year) MACE risk in the multi-site Swiss Acute Coronary Syndromes Cohort, focusing on the subset (n = 1469) on chronic dual anti-platelet therapy during follow-up [adjusted HR (95% CI) 1.70 (1.08-2.69)]. These collective clinical data suggest that the thrombosis-associated effects of TMAO may be mediated by cells/factors that are not inhibited by anti-platelet therapy. To test this, we first observed in human microvascular endothelial cells that TMAO dose-dependently induced expression of TF and vascular cell adhesion molecule (VCAM)1. In mouse studies, we observed that TMAO-enhanced aortic TF and VCAM1 mRNA and protein expression, which upon immunolocalization studies, was shown to co-localize with vascular endothelial cells. Finally, in arterial injury mouse models, TMAO-dependent enhancement of in vivo TF expression and thrombogenicity were abrogated by either a TF-inhibitory antibody or a mechanism-based microbial choline TMA-lyase inhibitor (fluoromethylcholine).ConclusionEndothelial TF contributes to TMAO-related arterial thrombosis potential, and can be specifically blocked by targeted non-lethal inhibition of gut microbial choline TMA-lyase.

Dataset Information

Association of Acroosteolysis With Enhanced Osteoclastogenesis and Higher Blood Levels of Vascular Endothelial Growth Factor in Systemic Sclerosis.

Publications

Association of Acroosteolysis With Enhanced Osteoclastogenesis and Higher Blood Levels of Vascular Endothelial Growth Factor in Systemic Sclerosis.

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