C–C chemokine receptor 5 (CCR5) is a co-receptor of HIV. Epidemiological findings suggest that the functional loss of CCR5 is correlated with a lower incidence of bone-destructive diseases as well as of HIV transmission. However, it is not clear whether CCR5 is involved in regulation of the function of bone cells, in addition to that of immune cells. Here we show that blockade of CCR5 using specific antibodies impairs human osteoclast function in vitro. Ccr5-deficient (Ccr5 −/−) mice presented with dysfunctional osteoclasts and were resistant to osteoporosis induced by receptor activator of nuclear factor kappa-B ligand (RANKL), which triggers osteoporosis independently of inflammatory and immunomodulatory pathways. Furthermore, Ccr5 deficiency impairs the cellular locomotion and bone-resorption activity of osteoclasts, which is associated with the disarrangement of podosomes and adhesion complex molecules including Pyk2. Overall, the data provides evidence that CCR5 has an essential role in bone-destructive conditions through the functional regulation of osteoclasts.
clinical studies have reported that teriparatide (tptD), a human parathyroid hormone analog, reduces back pain in osteoporotic patients. However, the mechanistic insights of this pharmacological action remain elusive. This study investigated the antinociceptive effect of TPTD mainly on primary sensory neurons in ovariectomized (oVX) rats. the plantar test showed thermal hyperalgesia in the oVX rats, which was significantly, but not fully, recovered immediately after the initial TPTD administration. the von frey test also demonstrated reduced withdrawal threshold in the oVX rats. this was partially recovered by TPTD. Consistently, the number and size of spinal microglial cells were significantly increased in the OVX rats, while TPTD treatment significantly reduced the number but not size of these cells. RnA sequencing-based bioinformatics of the dorsal root ganglia (DRG) demonstrated that changes in neuro-protective and inflammatory genes were involved in the pharmacological effect of TPTD. Most neurons in the DRG expressed substantial levels of parathyroid hormone 1 receptor. TPTD treatment of the cultured DRG-derived neuronal cells reduced the cAMp level and augmented the intracellular calcium level as the concentration increased. These findings suggest that TPTD targets neuronal cells as well as bone cells to exert its pharmacological action.More than 80% of osteoporotic patients reportedly have low back pain, which leads to disability and progression of bone and muscle weakening, and eventually reduces quality of life 1,2 . This osteoporotic pain occurs in patients regardless of obvious bone fractures in the vertebrae and other sites. A possible causative mechanism of osteoporotic pain is chronic neuronal excitement in intraosseous sensory nerve systems by acids and inflammatory cytokines produced by the activation of osteoclasts, as well as monocytes and macrophages, due to estrogen deficiency 3,4 . This mechanism has been proposed to be involved in cancer-associated bone pain patients with bone metastases 5 . Osteoporotic patients may also experience pain originating from collapsed vertebral bodies, degenerated intervertebral disc and facet joints 6 . Chronification of osteoporotic pain involves hypoactivity of the descending inhibitory nerve system that modulates ascending pain-transmission in the spinal cord with the decreased expression of serotonin receptors 3,7 .Anti-osteoporotic agents have been reported to be clinically and experimentally effective against bone pain. Bisphosphonates (BPs) exerted pain-modulating effects by suppressing osteoclasts, monocytes, and macrophage activity to curb the production of acids and inflammatory cytokines 3,8 . It has also been reported that the BP drug www.nature.com/scientificreports www.nature.com/scientificreports/ minodronate exerts a pain-modulating effect by inhibiting the purinergic P2X2/3 receptor 9 . Calcitonin depresses bone resorption and osteoclast activity by acting on osteoclast surface receptors. It has also been reported that calcitonin exerts its pa...
Pediatric acute respiratory distress syndrome (PARDS), though both common and deadly in critically ill children, lacks targeted therapies. The development of effective pharmacotherapies has been limited, in part, by lack of clarity about the pathobiology of pediatric ARDS. Epithelial lung injury, vascular endothelial activation, and systemic immune activation are putative drivers of this complex disease process. Prior studies have used either hypothesis-driven (e.g., candidate genes and proteins, in vitro investigations) or unbiased (e.g., genome-wide association, transcriptomic, metabolomic) approaches to predict clinical outcomes and to define subphenotypes. Advances in multiple omics technologies, including genomics, transcriptomics, proteomics, and metabolomics, have permitted more comprehensive investigation of PARDS pathobiology. However, omics studies have been limited in children compared to adults, and analyses across multiple tissue types are lacking. Here, we synthesized existing literature on the molecular mechanism of PARDS, summarized our interrogation of publicly available genomic databases to determine the association of candidate genes with PARDS phenotypes across multiple tissues and cell types, and integrated recent studies that used single-cell RNA sequencing (scRNA-seq). We conclude that novel profiling methods such as scRNA-seq, which permits more comprehensive, unbiased evaluation of pathophysiological mechanisms across tissue and cell types, should be employed to investigate the molecular mechanisms of PRDS toward the goal of identifying targeted therapies.
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