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Osteoarthritis (OA) is the most common joint disease, and good therapeutic results are often difficult to obtain due to its complex pathogenesis and diverse causative factors. After decades of research and exploration of OA, it has been progressively found that subchondral bone is essential for its pathogenesis, and pathological changes in subchondral bone can be observed even before cartilage lesions develop. Osteoclasts, the main cells regulating bone resorption, play a crucial role in the pathogenesis of subchondral bone. Subchondral osteoclasts regulate the homeostasis of subchondral bone through the secretion of degradative enzymes, immunomodulation, and cell signaling pathways. In OA, osteoclasts are overactivated by autophagy, ncRNAs, and Rankl/Rank/OPG signaling pathways. Excessive bone resorption disrupts the balance of bone remodeling, leading to increased subchondral bone loss, decreased bone mineral density and consequent structural damage to articular cartilage and joint pain. With increased understanding of bone biology and targeted therapies, researchers have found that the activity and function of subchondral osteoclasts are affected by multiple pathways. In this review, we summarize the roles and mechanisms of subchondral osteoclasts in OA, enumerate the latest advances in subchondral osteoclast-targeted therapy for OA, and look forward to the future trends of subchondral osteoclast-targeted therapies in clinical applications to fill the gaps in the current knowledge of OA treatment and to develop new therapeutic strategies.

BackgroundIon cyclotron range of frequencies (ICRF) heating is one of the most widely used auxiliary heating methods in tokamaks. The HL-3 tokamak plans to equip a 6 MW ICRF heating system to conduct discharge experiments of high-performance plasma.PurposeThis study optimizes the parameters of ICRF using numerical simulations with the purpose of supporting the reactor-level plasma in HL-3 in future.MethodsOn the basis of NBI heating in the HL-3 device, ICRF heating was considered, and the TRANSP code was employed to explore the influence of ICRF frequency and power in HL-3 on the neutron emission rate, as well as the distribution of fast ions. The ICRF frequency range was between 25 MHz and 40 MHz, and the ICRF power range was between 1 MW and 6 MW. The neutron signals based on the concept of neutron camera diagnosis were also simulated.ResultsThe simulation results show that the ICRF frequency and power significantly influence the neutron emission rate. The neutron emission rate is directly proportional to the ICRF heating power at a fixed ICRF frequency whilst the increase in the neutron emission rate significantly depends on the ICRF frequency when the ICRF heating power is fixed. Among the investigated parameters, the ICRF with a frequency of 30 MHz yields the maximum increase in the neutron emission rate. The simulation results of fast ions demonstrate that the synergetic heating of neutral beam injection and ICRF can heat fast ions up to 1 MeV after considering ICRF heating, which effectively increases the neutron emission rate. The simulation results of neutron camera indicate that neutron camera can effectively measure the changes in neutron emission rate and distribution profile caused by ICRF heating.ConclusionsThe simulation results demonstrate that the appropriate selection of the ICRF frequency and power can effectively increase the neutron emission rate in HL-3 experiments, the optimal combination of ICRF frequency/power is 30 MHz/6 MW for the scenario analyzed in this study. The simulation of neutron camera for HL-3 provides a reference for designing future neutron camera systems and measuring neutron spatial distributions.

A European project was undertaken to improve the available SOL ICRF physics simulation tools and confront them with measurements. This paper first reviews code upgrades within the project. Using the multi-physics finite element solver COMSOL, the SSWICH code couples RF full-wave propagation with DC plasma biasing over “antenna-scale” 2D (toroidal/radial) domains, via non-linear RF and DC sheath boundary conditions (SBCs) applied at shaped plasma-facing boundaries. For the different modules and associated SBCs, more elaborate basic research in RF-sheath physics, SOL turbulent transport and applied mathematics, generally over smaller spatial scales, guides code improvement. The available simulation tools were applied to interpret experimental observations on various tokamaks. We focus on robust qualitative results common to several devices: the spatial distribution of RF-induced DC bias; left-right asymmetries over strap power unbalance; parametric dependence and antenna electrical tuning; DC SOL biasing far from the antennas, and RF-induced density modifications. From these results we try to identify the relevant physical ingredients necessary to reproduce the measurements, e.g. accurate radiated field maps from 3D antenna codes, spatial proximity effects from wave evanescence in the near RF field, or DC current transport. Pending issues towards quantitative predictions are also outlined.