: Medicine Articles
Letter: Brain-type creatine kinase has a crucial role in osteoclast-mediated bone resorptionOsteoclasts differentiate from precursor cells of the monocyte-macrophage lineage and subsequently become activated to be competent for bone resorption through programs primarily governed by receptor activator of nuclear factor-κB ligand in cooperation with macrophage colony–stimulating factor. Proteins prominently expressed at late phases of osteoclastogenesis and with a supportive role in osteoclast function are potential therapeutic targets for bone-remodeling disorders. In this study, we used a proteomics approach to show that abundance of the brain-type cytoplasmic creatine kinase (Ckb) is greatly increased during osteoclastogenesis. Decreasing Ckb abundance by RNA interference or blocking its enzymatic activity with a pharmacological inhibitor, cyclocreatine, suppressed the bone-resorbing activity of osteoclasts grown in vitro via combined effects on actin ring formation, RhoA GTPase activity and vacuolar ATPase function. Activities of osteoclasts derived from Ckb−/− mice were similarly affected. In vivo studies showed that Ckb−/− mice were better protected against bone loss induced by ovariectomy, lipopolysaccharide challenge or interleukin-1 treatment than wild-type controls. Furthermore, administration of cyclocreatine or adenoviruses harboring Ckb small hairpin RNA attenuated bone loss in rat and mouse models. Our findings establish an important role for Ckb in the bone-resorbing function of osteoclasts and underscore its potential as a new molecular target for antiresorptive drug development. Nature Medicine, vol. 14 #9, pp966-972 |
Letter: PlGF–MMP-9–expressing cells restore microcirculation and efficacy of cell therapy in aged dystrophic muscleSclerosis and reduced microvessel density characterize advanced stages of muscular dystrophy and hamper cell or gene delivery, precluding treatment of most individuals with Duchenne muscular dystrophy. Modified tendon fibroblasts expressing an angiogenic factor (placenta growth factor, PlGF) and a metalloproteinase (matrix metalloproteinase-9, MMP-9) are able to restore a vascular network and reduce collagen deposition, allowing efficient cell therapy in aged dystrophic mice. These data open the possibility of extending new therapies to currently untreatable individuals. Nature Medicine, vol. 14 #9, pp973-978 |
Letter: Attenuated Plasmodium yoelii lacking purine nucleoside phosphorylase confer protective immunityMalaria continues to devastate sub-Saharan Africa owing to the emergence of drug resistance to established antimalarials and to the lack of an efficacious vaccine. Plasmodium species have a unique streamlined purine pathway in which the dual specificity enzyme purine nucleoside phosphorylase (PNP) functions in both purine recycling and purine salvage. To evaluate the importance of PNP in an in vivo model of malaria, we disrupted PyPNP, the gene encoding PNP in the lethal Plasmodium yoelii YM strain. P. yoelii parasites lacking PNP were attenuated and cleared in mice. Although able to form gametocytes, PNP-deficient parasites did not form oocysts in mosquito midguts and were not transmitted from mosquitoes to mice. Mice given PNP-deficient parasites were immune to subsequent challenge to a lethal inoculum of P. yoelii YM and to challenge from P. yoelii 17XNL, another strain. These in vivo studies with PNP-deficient parasites support purine salvage as a target for antimalarials. They also suggest a strategy for the development of attenuated nontransmissible metabolic mutants as blood-stage malaria vaccine strains. Nature Medicine, vol. 14 #9, pp954-958 |
Letter: Catapult-like release of mitochondrial DNA by eosinophils contributes to antibacterial defenseAlthough eosinophils are considered useful in defense mechanisms against parasites, their exact function in innate immunity remains unclear. The aim of this study is to better understand the role of eosinophils within the gastrointestinal immune system. We show here that lipopolysaccharide from Gram-negative bacteria activates interleukin-5 (IL-5)- or interferon-γ–primed eosinophils to release mitochondrial DNA in a reactive oxygen species–dependent manner, but independent of eosinophil death. Notably, the process of DNA release occurs rapidly in a catapult-like manner—in less than one second. In the extracellular space, the mitochondrial DNA and the granule proteins form extracellular structures able to bind and kill bacteria both in vitro and under inflammatory conditions in vivo. Moreover, after cecal ligation and puncture, Il5-transgenic but not wild-type mice show intestinal eosinophil infiltration and extracellular DNA deposition in association with protection against microbial sepsis. These data suggest a previously undescribed mechanism of eosinophil-mediated innate immune responses that might be crucial for maintaining the intestinal barrier function after inflammation-associated epithelial cell damage, preventing the host from uncontrolled invasion of bacteria. Nature Medicine, vol. 14 #9, pp949-953 |
Letter: Restoration of chaperone-mediated autophagy in aging liver improves cellular maintenance and hepatic functionChaperone-mediated autophagy (CMA), a selective mechanism for degradation of cytosolic proteins in lysosomes, contributes to the removal of altered proteins as part of the cellular quality-control systems. We have previously found that CMA activity declines in aged organisms and have proposed that this failure in cellular clearance could contribute to the accumulation of altered proteins, the abnormal cellular homeostasis and, eventually, the functional loss characteristic of aged organisms. To determine whether these negative features of aging can be prevented by maintaining efficient autophagic activity until late in life, in this work we have corrected the CMA defect in aged rodents. We have generated a double transgenic mouse model in which the amount of the lysosomal receptor for CMA, previously shown to decrease in abundance with age, can be modulated. We have analyzed in this model the consequences of preventing the age-dependent decrease in receptor abundance in aged rodents at the cellular and organ levels. We show here that CMA activity is maintained until advanced ages if the decrease in the receptor abundance is prevented and that preservation of autophagic activity is associated with lower intracellular accumulation of damaged proteins, better ability to handle protein damage and improved organ function. Nature Medicine, vol. 14 #9, pp959-965 |
News and Views: Disarming the malaria parasiteInvestigation of a genetically attenuated malaria parasite—which infects but does not kill its host—provides insight into how to develop a malaria vaccine (pages 954–958). Nature Medicine, vol. 14 #9, pp912-913 |
News and Views: Cell-free DNA resuscitated for tumor testingExtracellular DNA floating around in blood plasma provides an accessible template for detecting mutations associated with tumors. A new technique is able to quantify such mutated DNA and predict relapse in individuals with colorectal cancer. The technique complements other approaches, such as the analysis of tumor cells in the plasma (pages 985–990). Nature Medicine, vol. 14 #9, pp914-915 |
News and Views: Mitochondrial missile defenseA relatively obscure immune cell, the eosinophil, has a dramatic way of defending against pathogens. It rapidly ejects mitochondrial DNA, ensnaring bacteria and hastening their demise (pages 949–953). Nature Medicine, vol. 14 #9, pp910-912 |
News and Views: Live longer with LAMP-2Upregulation of a protein involved in lysosomal degradation of proteins helps stave off some of the cellular decline observed with aging. The findings could lead to new approaches to fend off age-related disease or even extend lifespan (pages 959–965). Nature Medicine, vol. 14 #9, pp909-910 |