Abstract:
:Understanding the mechanisms of osteoclastogenesis is crucial for developing new drugs to treat diseases associated with bone loss, such as osteoporosis. Here we report that the C-C chemokine receptor-2 (CCR2) is crucially involved in balancing bone mass. CCR2-knockout mice have high bone mass owing to a decrease in number, size and function of osteoclasts. In normal mice, activation of CCR2 in osteoclast progenitor cells results in both nuclear factor-kappaB (NF-kappaB) and extracellular signal-related kinase 1 and 2 (ERK1/2) signaling but not that of p38 mitogen-activated protein kinase or c-Jun N-terminal kinase. The induction of NF-kappaB and ERK1/2 signaling in turn leads to increased surface expression of receptor activator of NF-kappaB (RANK, encoded by Tnfrsf11a), making the progenitor cells more susceptible to RANK ligand-induced osteoclastogenesis. In ovariectomized mice, a model of postmenopausal osteoporosis, CCR2 is upregulated on wild-type preosteoclasts, thus increasing the surface expression of RANK on these cells and their osteoclastogenic potential, whereas CCR2-knockout mice are resistant to ovariectomy-induced bone loss. These data reveal a previously undescribed pathway by which RANK, osteoclasts and bone homeostasis are regulated in health and disease.
journal_name
Nat Medjournal_title
Nature medicineauthors
Binder NB,Niederreiter B,Hoffmann O,Stange R,Pap T,Stulnig TM,Mack M,Erben RG,Smolen JS,Redlich Kdoi
10.1038/nm.1945subject
Has Abstractpub_date
2009-04-01 00:00:00pages
417-24issue
4eissn
1078-8956issn
1546-170Xpii
nm.1945journal_volume
15pub_type
杂志文章相关文献
NATURE MEDICINE文献大全abstract::Preservation of the chemical architecture of a cell or of an organism under changing and perhaps stressful conditions is termed homeostasis. An integral feature of homeostasis is the rapid expression of genes whose products are specifically dedicated to protect cellular functions against stress. One of the best known ...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm1097-1150
更新日期:1997-10-01 00:00:00
abstract::Natural killer (NK) cells play an essential role in antiviral immunity, but knowledge of their function in secondary lymphoid organs is incomplete. Lymph node follicles constitute a major viral reservoir during infections with HIV-1 and simian immunodeficiency virus of macaques (SIVmac). In contrast, during nonpathoge...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm.4421
更新日期:2017-11-01 00:00:00
abstract::In many areas of oncology, we lack sensitive tools to track low-burden disease. Although cell-free DNA (cfDNA) shows promise in detecting cancer mutations, we found that the combination of low tumor fraction (TF) and limited number of DNA fragments restricts low-disease-burden monitoring through the prevailing deep ta...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/s41591-020-0915-3
更新日期:2020-07-01 00:00:00
abstract::LIGHT was recently described as a member of the tumor necrosis factor (TNF) 'superfamily'. We have isolated a mouse homolog of human LIGHT and investigated its immunoregulatory functions in vitro and in vivo. LIGHT has potent, CD28-independent co-stimulatory activity leading to T-cell growth and secretion of gamma int...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/73136
更新日期:2000-03-01 00:00:00
abstract::Viral replication and microbial translocation from the gut to the blood during HIV infection lead to hyperimmune activation, which contributes to the decline in CD4+ T cell numbers during HIV infection. Programmed death-1 (PD-1) and interleukin-10 (IL-10) are both upregulated during HIV infection. Blocking interaction...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm.2106
更新日期:2010-04-01 00:00:00
abstract::The recent development of tissue microarrays-composed of hundreds of tissue sections from different tumors arrayed on a single glass slide-facilitates rapid evaluation of large-scale outcome studies. Realization of this potential depends on the ability to rapidly and precisely quantify the protein expression within ea...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm791
更新日期:2002-11-01 00:00:00
abstract::Here we show that ischemia induces sustained contraction of pericytes on microvessels in the intact mouse brain. Pericytes remain contracted despite successful reopening of the middle cerebral artery after 2 h of ischemia. Pericyte contraction causes capillary constriction and obstructs erythrocyte flow. Suppression o...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm.2022
更新日期:2009-09-01 00:00:00
abstract::In the version of this article originally published, Dimitry G. Sayenko's affiliations were not correct. The following affiliation for this author was missing: Department of Neurosurgery, Center for Neuroregeneration, Houston Methodist Research Institute, Houston, TX, USA. This affiliation has been added for the autho...
journal_title:Nature medicine
pub_type: 已发布勘误
doi:10.1038/s41591-018-0248-7
更新日期:2018-12-01 00:00:00
abstract::Period (Per) genes are involved in regulation of the circadian clock and are thought to modulate several brain functions. We demonstrate that Per2(Brdm1) mutant mice, which have a deletion in the PAS domain of the Per2 protein, show alterations in the glutamatergic system. Lowered expression of the glutamate transport...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm1163
更新日期:2005-01-01 00:00:00
abstract::Pulmonary hypertension (PH) is characterized by increased proliferation and apoptosis resistance of pulmonary artery smooth muscle cells (PASMCs). Forkhead box O (FoxO) transcription factors are key regulators of cellular proliferation. Here we show that in pulmonary vessels and PASMCs of human and experimental PH lun...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm.3695
更新日期:2014-11-01 00:00:00
abstract::Mice carrying mutations in both the dystrophin and utrophin genes die prematurely as a consequence of severe muscular dystrophy. Here, we show that intravascular administration of recombinant adeno-associated viral (rAAV) vectors carrying a microdystrophin gene restores expression of dystrophin in the respiratory, car...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm1439
更新日期:2006-07-01 00:00:00
abstract::Parasites of the Leishmania genus are the causative agents of leishmaniasis in humans, a disease that affects more than 12 million people worldwide. These parasites replicate intracellularly in macrophages, and the primary mechanisms underlying host resistance involve the production of nitric oxide (NO). In this study...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm.3221
更新日期:2013-07-01 00:00:00
abstract::Lung cancer is the leading cause of death from cancer in the US and the world. The high mortality rate (80-85% within 5 years) results, in part, from a lack of effective tools to diagnose the disease at an early stage. Given that cigarette smoke creates a field of injury throughout the airway, we sought to determine i...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm1556
更新日期:2007-03-01 00:00:00
abstract::Idiopathic voiding disorders affect up to 10-15% of men and women. We describe bladder abnormalities in mice with targeted deletion of the gene for neuronal nitric oxide synthase which model the clinical disorders. The mice possess hypertrophic dilated bladders and dysfunctional urinary outlets which do not relax in r...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm0597-571
更新日期:1997-05-01 00:00:00
abstract::CD4-unhelped CD8(+) T cells are functionally defective T cells primed in the absence of CD4(+) T cell help. Given the co-stimulatory role of natural-killer group 2, member D protein (NKG2D) on CD8(+) T cells, we investigated its ability to rescue these immunologically impotent cells. We demonstrate that augmented co-s...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm.2683
更新日期:2012-02-26 00:00:00
abstract::The concentration of human immunodeficiency virus type 1 (HIV-1) particles in blood plasma is very predictive of the subsequent disease course in an infected individual; its measurement has become one of the most important parameters for monitoring clinical status. Steady-state virus levels in plasma reflect a balance...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/5576
更新日期:1999-02-01 00:00:00
abstract::The revolution in cancer research can be summed up in a single sentence: cancer is, in essence, a genetic disease. In the last decade, many important genes responsible for the genesis of various cancers have been discovered, their mutations precisely identified, and the pathways through which they act characterized. T...
journal_title:Nature medicine
pub_type: 杂志文章,评审
doi:10.1038/nm1087
更新日期:2004-08-01 00:00:00
abstract::Conceptual and practical advances in molecular medicine are changing our understanding of cancer pathogenesis. In time this should provide the opportunity to alter the natural history of many cancers. ...
journal_title:Nature medicine
pub_type: 杂志文章,评审
doi:10.1038/nm0495-309
更新日期:1995-04-01 00:00:00
abstract::Cystic fibrosis (CF) is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) that compromise its chloride channel activity. The most common mutation, p.Phe508del, results in the production of a misfolded CFTR protein, which has residual channel activity but is prematu...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm.4305
更新日期:2017-05-01 00:00:00
abstract::Transforming growth factor beta 1 (TGF-beta 1) is a platelet-derived cytokine involved in both normal wound healing and scarring. We show that human platelets contain two pools of latent TGF-beta 1, which constitute more than 95% of the total TGF-beta assayed in whole platelets. During clotting, one pool, the large la...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm0995-932
更新日期:1995-09-01 00:00:00
abstract::Oral administration of protein can induce antigen-specific immune hyporesponsiveness. However, the utility of oral tolerance to autoantigens in the treatment of autoimmune diseases may be limited when candidate autoantigens cannot be produced by conventional systems in quantities sufficient for clinical studies. Plant...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm0797-793
更新日期:1997-07-01 00:00:00
abstract::The neural tube defects (NTDs) spina bifida and anencephaly are widely prevalent severe birth defects. The mouse mutant curly tail (ct/ct) has served as a model of NTDs for 50 years, even though the responsible genetic defect remained unrecognized. Here we show by gene targeting, mapping and genetic complementation st...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm961
更新日期:2003-12-01 00:00:00
abstract::Insulin receptor substrate (IRS)-1 and IRS-2 have dominant roles in the action of insulin, but other substrates of the insulin receptor kinase, such as Gab1, c-Cbl, SH2-B and APS, are also of physiological relevance. Although the protein downstream of tyrosine kinases-1 (Dok1) is known to function as a multisite adapt...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm1706
更新日期:2008-02-01 00:00:00
abstract::The penumbra is an area of brain tissue that is damaged but not yet dead after focal ischemia. The existence of a penumbra implies that therapeutic salvage is theoretically possible after stroke. The first decade of penumbral science investigated the ischemic regulation of electrophysiology, cerebral blood flow and me...
journal_title:Nature medicine
pub_type: 杂志文章,评审
doi:10.1038/nm1735
更新日期:2008-05-01 00:00:00
abstract::Azoospermia or oligozoospermia due to disruption of spermatogenesis are common causes of human male infertility. We used the technique of spermatogonial transplantation in two infertile mouse strains, Steel (Sl) and dominant white spotting (W), to determine if stem cells from an infertile male were capable of generati...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/71496
更新日期:2000-01-01 00:00:00
abstract::Preoperative immunotherapy with anti-PD1 plus anti-CTLA4 antibodies has shown remarkable pathological responses in melanoma1 and colorectal cancer2. In NABUCCO (ClinicalTrials.gov: NCT03387761 ), a single-arm feasibility trial, 24 patients with stage III urothelial cancer (UC) received two doses of ipilimumab and two ...
journal_title:Nature medicine
pub_type: 杂志文章,多中心研究
doi:10.1038/s41591-020-1085-z
更新日期:2020-12-01 00:00:00
abstract::Human liver cancer research currently lacks in vitro models that can faithfully recapitulate the pathophysiology of the original tumor. We recently described a novel, near-physiological organoid culture system, wherein primary human healthy liver cells form long-term expanding organoids that retain liver tissue functi...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm.4438
更新日期:2017-12-01 00:00:00
abstract::Cytochrome P450 3A4 is an important mediator of drug catabolism that can be regulated by the steroid and xenobiotic receptor (SXR). We show here that SXR also regulates drug efflux by activating expression of the gene MDR1, which encodes the protein P-glycoprotein (ABCB1). Paclitaxel (Taxol), a commonly used chemother...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/87912
更新日期:2001-05-01 00:00:00
abstract::Foxp3(+) regulatory T (T(reg)) cells suppress different types of immune responses to help maintain homeostasis in the body. How T(reg) cells regulate humoral immunity, including germinal center reactions, is unclear. Here we identify a subset of T(reg) cells expressing CXCR5 and Bcl-6 that localize to the germinal cen...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm.2426
更新日期:2011-07-24 00:00:00
abstract::Rapid and accurate measurement of biomarkers in tissue and fluid samples is a major challenge in medicine. Here we report the development of a new, miniaturized diagnostic magnetic resonance (DMR) system for multiplexed, quantitative and rapid analysis. By using magnetic particles as a proximity sensor to amplify mole...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm.1711
更新日期:2008-08-01 00:00:00