ABSTRACT
Elevated osteoclast (OC) activity is a major contributor to inflammatory bone loss (IBL) during chronic inflammatory diseases. However, the specific OC precursors (OCPs) responding to inflammatory cues and the underlying mechanisms leading to IBL are poorly understood. We identified two distinct OCP subsets: Ly6ChiCD11bhi inflammatory OCPs (iOCPs) induced during chronic inflammation, and homeostatic Ly6ChiCD11blo OCPs (hOCPs) which remained unchanged. Functional and proteomic characterization revealed that while iOCPs were rare and displayed low osteoclastogenic potential under normal conditions, they expanded during chronic inflammation and generated OCs with enhanced activity. In contrast, hOCPs were abundant and manifested high osteoclastogenic potential under normal conditions but generated OCs with low activity and were unresponsive to the inflammatory environment. Osteoclasts derived from iOCPs expressed higher levels of resorptive and metabolic proteins than those generated from hOCPs, highlighting that different osteoclast populations are formed by distinct precursors. We further identified the TNF-α and S100A8/A9 proteins as key regulators that control the iOCP response during chronic inflammation. Furthermore, we demonstrated that the response of iOCPs but not that of hOCPs was abrogated in tnf-α-/- mice, in correlation with attenuated IBL. Our findings suggest a central role for iOCPs in IBL induction. iOCPs can serve as potential biomarkers for IBL detection and possibly as new therapeutic targets to combat IBL in a wide range of inflammatory conditions.
ABSTRACT
OBJECTIVE: Clinical success of atrial fibrillation (AF) ablation depends on persistent block of electrical conduction across the ablation lines. The fate of ablations performed with temperature-controlled bipolar radiofrequency (RF) is unknown. The purpose of this study was to validate the electrophysiological (EP) efficacy of these lesions, recording pulmonary vein isolation (PVI) after open chest ablation, in the human being. METHODS: Ten consecutive mitral patients (mean age: 53 ± 12 years) with concomitant AF were treated with the Cobra Revolution (Estech, San Ramon, CA, USA) bipolar RF device were enrolled for EP assessment. During surgery, pairs of additional temporary wires were positioned on the right PVs (RPV) and on the roof of the left atrium (RLA), before ablation. Pacing thresholds (PTs) were assessed before, after a single encircling ablation and at chest's closure. EP study was repeated before discharge and at 3 weeks. RLA wires served as control. RESULTS: Baseline PTs were 0.83 ± 0.81 mA (range 0.2-3 mA) from RPV and 1.13 ± 0.78 mA (range 0.3-3 mA) from RLA. PVI was reached in all patients acutely, and was maintained at 1 week. At 3 weeks, the PTs were 14.3 ± 4.3 mA from RPV (range 7-20 mA) and 3.1 ± 1.3 mA (range 1.5-7 mA) from RLA. All patients were discharged in sinus rhythm. CONCLUSIONS: Cobra Revolution temperature-controlled bipolar RF provides complete PVI after a single ablation up to 1 week. This notwithstanding, only 30% of patients were completely isolated (exit block validation) at 3 weeks.
