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1.  Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture 
Zheng, Hou-Feng | Forgetta, Vincenzo | Hsu, Yi-Hsiang | Estrada, Karol | Rosello-Diez, Alberto | Leo, Paul J | Dahia, Chitra L | Park-Min, Kyung Hyun | Tobias, Jonathan H | Kooperberg, Charles | Kleinman, Aaron | Styrkarsdottir, Unnur | Liu, Ching-Ti | Uggla, Charlotta | Evans, Daniel S | Nielson, Carrie M | Walter, Klaudia | Pettersson-Kymmer, Ulrika | McCarthy, Shane | Eriksson, Joel | Kwan, Tony | Jhamai, Mila | Trajanoska, Katerina | Memari, Yasin | Min, Josine | Huang, Jie | Danecek, Petr | Wilmot, Beth | Li, Rui | Chou, Wen-Chi | Mokry, Lauren E | Moayyeri, Alireza | Claussnitzer, Melina | Cheng, Chia-Ho | Cheung, Warren | Medina-Gómez, Carolina | Ge, Bing | Chen, Shu-Huang | Choi, Kwangbom | Oei, Ling | Fraser, James | Kraaij, Robert | Hibbs, Matthew A | Gregson, Celia L | Paquette, Denis | Hofman, Albert | Wibom, Carl | Tranah, Gregory J | Marshall, Mhairi | Gardiner, Brooke B | Cremin, Katie | Auer, Paul | Hsu, Li | Ring, Sue | Tung, Joyce Y | Thorleifsson, Gudmar | Enneman, Anke W | van Schoor, Natasja M | de Groot, Lisette C.P.G.M. | van der Velde, Nathalie | Melin, Beatrice | Kemp, John P | Christiansen, Claus | Sayers, Adrian | Zhou, Yanhua | Calderari, Sophie | van Rooij, Jeroen | Carlson, Chris | Peters, Ulrike | Berlivet, Soizik | Dostie, Josée | Uitterlinden, Andre G | Williams, Stephen R. | Farber, Charles | Grinberg, Daniel | LaCroix, Andrea Z | Haessler, Jeff | Chasman, Daniel I | Giulianini, Franco | Rose, Lynda M | Ridker, Paul M | Eisman, John A | Nguyen, Tuan V | Center, Jacqueline R | Nogues, Xavier | Garcia-Giralt, Natalia | Launer, Lenore L | Gudnason, Vilmunder | Mellström, Dan | Vandenput, Liesbeth | Karlsson, Magnus K | Ljunggren, Östen | Svensson, Olle | Hallmans, Göran | Rousseau, François | Giroux, Sylvie | Bussière, Johanne | Arp, Pascal P | Koromani, Fjorda | Prince, Richard L | Lewis, Joshua R | Langdahl, Bente L | Hermann, A Pernille | Jensen, Jens-Erik B | Kaptoge, Stephen | Khaw, Kay-Tee | Reeve, Jonathan | Formosa, Melissa M | Xuereb-Anastasi, Angela | Åkesson, Kristina | McGuigan, Fiona E | Garg, Gaurav | Olmos, Jose M | Zarrabeitia, Maria T | Riancho, Jose A | Ralston, Stuart H | Alonso, Nerea | Jiang, Xi | Goltzman, David | Pastinen, Tomi | Grundberg, Elin | Gauguier, Dominique | Orwoll, Eric S | Karasik, David | Davey-Smith, George | Smith, Albert V | Siggeirsdottir, Kristin | Harris, Tamara B | Zillikens, M Carola | van Meurs, Joyce BJ | Thorsteinsdottir, Unnur | Maurano, Matthew T | Timpson, Nicholas J | Soranzo, Nicole | Durbin, Richard | Wilson, Scott G | Ntzani, Evangelia E | Brown, Matthew A | Stefansson, Kari | Hinds, David A | Spector, Tim | Cupples, L Adrienne | Ohlsson, Claes | Greenwood, Celia MT | Jackson, Rebecca D | Rowe, David W | Loomis, Cynthia A | Evans, David M | Ackert-Bicknell, Cheryl L | Joyner, Alexandra L | Duncan, Emma L | Kiel, Douglas P | Rivadeneira, Fernando | Richards, J Brent
Nature  2015;526(7571):112-117.
The extent to which low-frequency (minor allele frequency [MAF] between 1–5%) and rare (MAF ≤ 1%) variants contribute to complex traits and disease in the general population is largely unknown. Bone mineral density (BMD) is highly heritable, is a major predictor of osteoporotic fractures and has been previously associated with common genetic variants1–8, and rare, population-specific, coding variants9. Here we identify novel non-coding genetic variants with large effects on BMD (ntotal = 53,236) and fracture (ntotal = 508,253) in individuals of European ancestry from the general population. Associations for BMD were derived from whole-genome sequencing (n=2,882 from UK10K), whole-exome sequencing (n= 3,549), deep imputation of genotyped samples using a combined UK10K/1000Genomes reference panel (n=26,534), and de-novo replication genotyping (n= 20,271). We identified a low-frequency non-coding variant near a novel locus, EN1, with an effect size 4-fold larger than the mean of previously reported common variants for lumbar spine BMD8 (rs11692564[T], MAF = 1.7%, replication effect size = +0.20 standard deviations [SD], Pmeta = 2×10−14), which was also associated with a decreased risk of fracture (OR = 0.85; P = 2×10−11; ncases = 98,742 and ncontrols = 409,511). Using an En1Cre/flox mouse model, we observed that conditional loss of En1 results in low bone mass, likely as a consequence of high bone turn-over. We also identified a novel low-frequency non-coding variant with large effects on BMD near WNT16 (rs148771817[T], MAF = 1.1%, replication effect size = +0.39 SD, Pmeta = 1×10−11). In general, there was an excess of association signals arising from deleterious coding and conserved non-coding variants. These findings provide evidence that low-frequency non-coding variants have large effects on BMD and fracture, thereby providing rationale for whole-genome sequencing and improved imputation reference panels to study the genetic architecture of complex traits and disease in the general population.
PMCID: PMC4755714  PMID: 26367794 CAMSID: cams5439
2.  Expression and Function of Semaphorin 3A and Its Receptors in Human Monocyte-derived Macrophages 
Human immunology  2009;70(4):211-217.
Semaphorins are a large family of secreted and membrane-bound proteins. Recently, several roles of semaphorins in the immune system have emerged. Several semaphorins and their receptors are expressed in a variety of lymphoid and myeloid cells and affect immune cell functions, including cell proliferation, differentiation, chemotaxis, and cytokine production. However, the roles of class 3 semaphorins in human myeloid cells are not well known. Here we examined the regulation of expression of class 3 semaphorins and their receptors by inflammatory stimuli and their function in human macrophages. We show that the expression of Sema3A receptors (neuropilin-1 (NRP-1), NRP-2, plexin A1, plexin A2 and plexin A3) significantly increased during M-CSF-mediated differentiation of monocytes into macrophages under conditions that promote an M2 alternatively activated macrophage phenotype. Consistent with increased NRP-1 expression, cell surface binding of Sema3A increased during M2 differentiation. IFN-γ and LPS that promote classical M1 macrophage activation affected expression of NRP-1, NRP-2 and plexin A1. IFN-γ decreased NRP-1 expression and LPS suppressed NRP-2 and plexin A1 expression. Furthermore we show that Sema3A induced apoptosis in monocyte-derived macrophages, and cooperated with anti-Fas CH11 antibody to augment apoptosis. Our results suggest Sema3A plays a role in induction of apoptosis in monocyte-derived macrophages that are resistant to Fas-induced apoptosis and that its function can be modulated in inflammatory conditions.
PMCID: PMC4811352  PMID: 19480842
Semaphorin; Neuropilin; Plexin; Macrophages
3.  Physical, cognitive, social and mental health in near-centenarians and centenarians living in New York City: findings from the Fordham Centenarian Study 
BMC Geriatrics  2016;16:1.
Despite their strong increase, the population of the very old, including near-centenarians and centenarians, represent an unstudied and underserved population. Available studies mostly concentrate on predictors of exceptional longevity, but rarely extend their focus to other areas of functioning. Also, little is known about what contributes to experiencing a quality life in very old age. The present population-based study aims at providing a comprehensive picture of key domain of functioning, including physical, cognitive, social and mental function in very old individuals and to determine predictors of mental health indicators.
A total of 119 individuals aged 95 to 107 living in private dwellings and residential care facilities were recruited based on the New York City Voters Registry. Participants answered questions regarding their health and activities of daily living. Their cognitive functioning was determined using the Mini-Mental State Examination and the Global Deterioration Scale. Social resources were measured with number of children and the Lubben Scale. Mental health was assessed with the Geriatric Depression Scale and the Satisfaction with Life Scale.
An unexpectedly large proportion of the sample lived in the community. On average, cognitive functioning was high. Although five diseases were reported on average, participants reported good health. Functional status was reduced. Most participants had at least one person for communication/social support. On average, depression was below cut-off, and most participants reported high life satisfaction. Regression analyses indicated that individual differences in depression were associated with subjective health, IADL and relatives support. For life satisfaction, subjective health, ADL and number of children were most important. Demographic characteristics, number of illnesses or cognitive status were not significant.
Despite reduced levels of physical functioning and social resources, very old participants were in good mental health suggesting high resilience and ability to adapt to age-associated challenges. That a large proportion of them lived in the community further highlights their desire for leading an autonomous life, which may have been facilitated by New York service culture. More research is necessary to provide guidance for the development of well-suited services for this very old population.
PMCID: PMC4700778  PMID: 26729190
Centenarians; Health and well-being; Cognition; Social resources; Depression; Community and public health
4.  Inhibition of Osteoclastogenesis and Inflammatory Bone Resorption by Targeting BET Proteins and Epigenetic Regulation 
Nature communications  2014;5:5418.
Emerging evidence suggests that RANKL-induced changes in chromatin state are important for osteoclastogenesis, but these epigenetic mechanisms are not well understood and have not been therapeutically targeted. In this study we find that the small molecule I-BET151 that targets bromo and extra-terminal (BET) proteins that “read” chromatin states by binding to acetylated histones strongly suppresses osteoclastogenesis. I-BET151 suppresses pathologic bone loss in TNF-induced inflammatory osteolysis, inflammatory arthritis, and post-ovariectomy models. Transcriptome analysis identifies a MYC-NFAT axis important for osteoclastogenesis. Mechanistically, I-BET151 inhibits expression of the master osteoclast regulator NFATC1 by suppressing expression and recruitment of its newly identified upstream regulator MYC. MYC is elevated in rheumatoid arthritis and its induction by RANKL is important for osteoclastogenesis and TNF-induced bone resorption. These findings highlight the importance of an I-BET151-inhibited MYC-NFAT axis in osteoclastogenesis, and suggest targeting epigenetic chromatin regulators holds promise for treatment of inflammatory and estrogen deficiency-mediated pathologic bone resorption.
PMCID: PMC4249944  PMID: 25391636
5.  TNFα induces sustained signaling and a prolonged and unremitting inflammatory response in synovial fibroblasts 
Arthritis and rheumatism  2013;65(4):928-938.
The non resolving character of synovial inflammation in rheumatoid arthritis (RA) is a conundrum. To identify the contribution of fibroblast-like synoviocytes (FLS) to the perpetuation of synovitis, we investigated the molecular mechanisms that govern the TNFα-driven inflammatory program in human FLS.
FLS obtained from synovial tissues of patients with RA or osteoarthritis were stimulated with TNFα and assayed for gene expression and cytokine production by qPCR and ELISA. NF-κB signaling was evaluated using Western blotting. Histone acetylation, chromatin accessibility, and NF-κB p65 and RNA polymerase II (Pol II) occupancy at the IL6 promoter were measured by chromatin immunoprecipitation and restriction enzyme accessibility assays.
In FLS, TNFα induced prolonged transcription of IL6 and progressive accumulation of IL-6 protein over four days. Similarly, induction of CXCL8/IL-8, CCL5/RANTES, MMP1 and MMP3 mRNA after TNFα stimulation was sustained for several days. This contrasted with the macrophage response to TNFα, which characteristically involved a transient increase in the expression of pro-inflammatory genes. In FLS, TNFα induced prolonged activation of NF-κB signaling and sustained transcriptional activity indicated by increased histone acetylation, chromatin accessibility, and p65 and Pol II occupancy at the IL6 promoter. Furthermore, FLS expressed low levels of the feedback inhibitors ABIN3, IRAK-M, SOCS3 and ATF3 that terminate inflammatory responses in macrophages.
TNFα signaling is not effectively terminated in FLS, leading to an uncontrolled inflammatory response. The results suggest that prolonged and sustained inflammatory responses by FLS, in response to synovial TNFα, contribute to the persistence of synovial inflammation in RA.
PMCID: PMC3618592  PMID: 23335080
fibroblast-like synoviocytes; rheumatoid arthritis; signal transduction; TNFα; chromatin
6.  Negative Regulation of Osteoclast Precursor Differentiation by CD11b and β2 Integrin-BCL6 Signaling 
Negative regulation of osteoclastogenesis is important for bone homeostasis and prevention of excessive bone resorption in inflammatory and other diseases. Mechanisms that directly suppress osteoclastogenesis are not well understood. In this study we investigated regulation of osteoclast differentiation by the β2 integrin CD11b/CD18 that is expressed on myeloid lineage osteoclast precursors. CD11b-deficient mice exhibited decreased bone mass that was associated with increased osteoclast numbers and decreased bone formation. Accordingly, CD11b and β2 integrin signaling suppressed osteoclast differentiation by preventing RANKL-induced induction of the master regulator of osteoclastogenesis NFATc1 and of downstream osteoclast-related NFATc1 target genes. CD11b suppressed induction of NFATc1 by the complementary mechanisms of downregulation of RANK expression and induction of recruitment of the transcriptional repressor BCL6 to the NFATC1 gene. These findings identify CD11b as a negative regulator of the earliest stages of osteoclast differentiation, and provide an inducible mechanism by which environmental cues suppress osteoclastogenesis by activating a transcriptional repressor that makes genes refractory to osteoclastogenic signaling.
PMCID: PMC3522783  PMID: 22893614
osteoclast; signaling; integrin; CD11b; BCL6
7.  Lactobacillus plantarum DK119 as a Probiotic Confers Protection against Influenza Virus by Modulating Innate Immunity 
PLoS ONE  2013;8(10):e75368.
Lactobacillus plantarum DK119 (DK119) isolated from the fermented Korean cabbage food was used as a probiotic to determine its antiviral effects on influenza virus. DK119 intranasal or oral administration conferred 100% protection against subsequent lethal infection with influenza A viruses, prevented significant weight loss, and lowered lung viral loads in a mouse model. The antiviral protective efficacy was observed in a dose and route dependent manner of DK119 administration. Mice that were treated with DK119 showed high levels of cytokines IL-12 and IFN-γ in bronchoalveolar lavage fluids, and a low degree of inflammation upon infection with influenza virus. Depletion of alveolar macrophage cells in lungs and bronchoalveolar lavages completely abrogated the DK119-mediated protection. Modulating host innate immunity of dendritic and macrophage cells, and cytokine production pattern appeared to be possible mechanisms by which DK119 exhibited antiviral effects on influenza virus infection. These results indicate that DK119 can be developed as a beneficial antiviral probiotic microorganism.
PMCID: PMC3790790  PMID: 24124485
8.  Protective Effect of Korean Red Ginseng Extract on the Infections by H1N1 and H3N2 Influenza Viruses in Mice 
Journal of Medicinal Food  2012;15(10):855-862.
Ginseng has been used in humans for thousands of years and is known to have multiple biological and immunomodulatory effects. In this study, we investigated whether Korean red ginseng extract would have preventive and antiviral effects on influenza virus infection. Oral administration to mice of red ginseng extract prior to infection significantly increased survival after infection with the 2009 pandemic H1N1 virus. Daily oral treatment of vaccinated mice with red ginseng extract provided enhanced cross-protection against antigenically distinct H1N1 and H3N2 influenza viruses. Naive mice that were infected with virus mixed with red ginseng extract showed significantly enhanced protection, lower levels of lung viral titers and interleukin-6, but higher levels of interferon-γ compared with control mice having virus infections without red ginseng extract, indicating an antiviral effect of ginseng. In addition, ginseng extract exhibited inhibitory effects on the growth of influenza virus in vitro. This study provides evidence that intake of ginseng extract will have beneficial effects on preventing lethal infection with newly emerging influenza viruses.
PMCID: PMC3466917  PMID: 22856395
antioxidant activity; devil's claw extract; ginseng; immnunomodulation; mice
9.  ITAM-coupled receptors inhibit IFNAR signaling and alter macrophage responses to TLR4 and Listeria monocytogenes1 
Immunoreceptor tyrosine based activation motif (ITAM)-coupled receptors play an essential role in regulating macrophage activation and function by cross-regulating signaling from heterologous receptors. We investigated mechanisms by which ITAM-associated receptors inhibit type I interferon (IFN-α/β) signaling in primary human macrophages and tested the effects of simultaneous ligation of ITAM-associated receptors and TLR4 on TLR4-induced Jak-STAT signaling that is mediated by autocrine IFN-β. Preligation of ITAM-coupled β2 integrins and FcγRs inhibited proximal signaling by the type I IFN receptor IFNAR. Cross-inhibition of IFNAR signaling by β2 integrins resulted in decreased Jak1 activation and was mediated by partial downregulation of the IFNAR1 subunit and MAPK-dependent induction of USP18, which blocks the association of Jak1 with IFNAR2. Simultaneous engagement of ITAM-coupled β2 integrins or Dectin-1 with TLR4 did not affect TLR4-induced direct activation of inflammatory target genes such as TNF or IL6, but abrogated subsequent induction of IFN response genes that is mediated by autocrine IFN-β signaling. Type I IFNs promote macrophage death after infection by Listeria monocytogenes. Consequently, attenuation of IFN responses by β2 integrins protected primary human macrophages from Listeria monocytogenes induced apoptosis. These results provide a mechanism for cross-inhibition of type I IFN signaling by ITAM-coupledβ2 integrins and demonstrate that ITAM signaling qualitatively modulates macrophage responses to PAMPs and pathogens by selectively suppressing IFN responses.
PMCID: PMC3311708  PMID: 22368279
monocytes/macrophages; cytokines; inflammation; TLRs; signal transduction
10.  iRHOM2 is a critical pathogenic mediator of inflammatory arthritis 
iRHOM2, encoded by the gene Rhbdf2, regulates the maturation of the TNF-α convertase (TACE), which controls shedding of TNF-α and its biological activity in vivo. TACE is a potential target to treat TNF-α–dependent diseases, such as rheumatoid arthritis, but there are concerns about potential side effects, because TACE also protects the skin and intestinal barrier by activating EGFR signaling. Here we report that inactivation of Rhbdf2 allows tissue-specific regulation of TACE by selectively preventing its maturation in immune cells, without affecting its homeostatic functions in other tissues. The related iRHOM1, which is widely expressed, except in hematopoietic cells, supported TACE maturation and shedding of the EGFR ligand TGF-α in Rhbdf2-deficient cells. Remarkably, mice lacking Rhbdf2 were protected from K/BxN inflammatory arthritis to the same extent as mice lacking TACE in myeloid cells or Tnfa-deficient mice. In probing the underlying mechanism, we found that two main drivers of K/BxN arthritis, complement C5a and immune complexes, stimulated iRHOM2/TACE-dependent shedding of TNF-α in mouse and human cells. These data demonstrate that iRHOM2 and myeloid-expressed TACE play a critical role in inflammatory arthritis and indicate that iRHOM2 is a potential therapeutic target for selective inactivation of TACE in myeloid cells.
PMCID: PMC3561822  PMID: 23348744
11.  Feedback inhibition of osteoclastogenesis during inflammation by IL-10, M-CSF receptor shedding, and induction of IRF8 
Inflammation plays a key role in excessive bone loss in conditions such as rheumatoid arthritis and periodontitis. An important paradigm in immunology is that inflammatory factors activate feedback inhibition mechanisms to restrain inflammation and limit associated tissue damage. We hypothesized that inflammatory factors would activate similar feedback mechanisms to restrain bone loss in inflammatory settings. We have identified three mechanisms that inhibit osteoclastogenesis and are induced by inflammatory factors, such as toll-like receptor ligands and cytokines: downregulation of expression of costimulatory molecules such as TREM-2; induction of shedding and thereby inactivation of the M-CSF receptor c-Fms, leading to decreased RANK transcription; and induction of transcriptional repressors such as interferon regulatory factor 8. It is likely that these mechanisms work in a complementary and cooperative manner to fine tune the extent of osteoclastogenesis in inflammatory settings, and their augmentation may represent an alternative therapeutic approach to suppress bone resorption.
PMCID: PMC3263822  PMID: 22082370
inflammation; osteoclasts; toll-like receptors; M-CSF; c-Fms; IRF8
12.  TNF Induces Endotoxin Tolerance Mediated by GSK3 in Macrophages 
Nature Immunology  2011;12(7):607-615.
Endotoxin tolerance, a key mechanism for suppressing excessive inflammatory cytokine production and attendant toxicity, is induced by prior exposure of macrophages to TLR ligands. Induction of tolerance by endogenous cytokines has not been investigated. We show that prior exposure to TNF induces a tolerant state in macrophages, with diminished cytokine production on LPS challenge and protection from LPS-induced lethality. TNF-induced tolerization was mediated by coordinate action of two inhibitory mechanisms, suppression of LPS-induced signaling and chromatin remodeling. Mechanistically, TNF-induced tolerance was distinct from TLR-induced tolerance as it was dependent on GSK3, which suppressed chromatin accessibility and promoted rapid termination of NF-κB signaling by augmenting negative feedback by A20 and I-κBα. These results reveal an unexpected homeostatic function of TNF and provide a GSK3-mediated mechanism for preventing prolonged and excessive inflammation.
PMCID: PMC3258532  PMID: 21602809
13.  MyD88 Plays an Essential Role in Inducing B Cells Capable of Differentiating into Antibody-Secreting Cells after Vaccination ▿  
Journal of Virology  2011;85(21):11391-11400.
We investigated the roles of MyD88, an innate adaptor signaling molecule, in inducing protective humoral immunity after vaccination with influenza virus-like particles (VLPs). MyD88 knockout C57BL/6 mice (MyD88−/− mice) vaccinated with influenza VLPs showed significant defects in inducing IgG2a/c isotype antibodies and in generating splenic recall memory B cell responses and antibody-secreting plasma cells in the bone marrow. The protective efficacy of influenza VLP vaccination was lower in MyD88−/− mice than in the wild-type mice. Our findings indicate that MyD88-mediated innate signaling pathways are important for effectively inducing primary and boost immune responses, T helper type 1 isotype-switched antibodies, and gamma interferon (IFN-γ)-secreting T cell responses. In particular, the results in this study demonstrated for the first time that MyD88-mediated immune activation is likely an essential pathway for effective generation of long-lived antibody-secreting plasma cells and highly protective immunity after vaccination with influenza VLPs. This study provides insight into mechanisms by which recombinant viral vaccines induce protective immunity via the MyD88-mediated innate immune signaling pathway.
PMCID: PMC3194946  PMID: 21865389
14.  Protective Effect of Ginseng Polysaccharides on Influenza Viral Infection 
PLoS ONE  2012;7(3):e33678.
Ginseng polysaccharide has been known to have multiple immunomodulatory effects. In this study, we investigated whether Panax ginseng polysaccharide (GP) would have a preventive effect on influenza infection. Administration of mice with GP prior to infection was found to confer a survival benefit against infection with H1N1 (A/PR/8/34) and H3N2 (A/Philippines/82) influenza viruses. Mice infected with the 2009 H1N1 virus suspended in GP solution showed moderately enhanced survival rates and lower levels of lung viral titers and the inflammatory cytokine (IL-6). Daily treatment of vaccinated mice with GP improved their survival against heterosubtypic lethal challenge. This study demonstrates the first evidence that GP can be used as a remedy against influenza viral infection.
PMCID: PMC3307756  PMID: 22442708
15.  Dietary patterns are associated with physical growth among school girls aged 9-11 years 
Nutrition Research and Practice  2011;5(6):569-577.
The purpose of this study was to identify dietary patterns among Korean elementary school girls based on the change in body mass index (BMI), body fat, bone mineral density (BMD), and bone mineral content (BMC) during 22 months and to explore the characteristics of dietary patterns identified. Girls aged 9-11 years were recruited and 3-day dietary data were collected four times. Subjects with a diet record of 8 or more days and anthropometric data measured at baseline and 22 months later were included (n = 198). Reduced rank regression was utilized to derive dietary patterns using a change in BMI, body fat, and calcaneus BMD and BMC as response variables. Two dietary patterns were identified: the "Egg and Rice" dietary pattern and "Fruit, Nuts, Milk Beverage, Egg, Grain" (FNMBEG) dietary pattern. Subjects who had high score on the FNMBEG pattern consumed various food groups, including fruits, nuts and seeds, and dairy products, whereas subjects in the "Egg and Rice" dietary pattern group did not. Both dietary patterns showed a positive association with change in BMI and body fat. However, subjects who had a higher score on the "Egg and Rice" dietary pattern had less of a BMC increase, whereas subjects who had a higher score on the FMBEG dietary pattern had more increased BMC over 22 months after adjusting for age, body and bone mass, and Tanner stage at baseline. Our results provide evidence that a well-balanced diet contributes to lean body mass growth among young girls.
PMCID: PMC3259301  PMID: 22259683
Adolescent; physical growth; bone mass; dietary pattern; reduced rank regression
16.  Direct Inhibition of Human RANK+ Osteoclast Precursors Identifies a Homeostatic Function of IL-1β 
IL-1β is a key mediator of bone resorption in inflammatory settings, such as rheumatoid arthritis (RA). IL-1β promotes osteoclastogenesis by inducing RANKL expression on stromal cells and synergizing with RANKL to promote later stages of osteoclast differentiation. Because IL-1Rs share a cytosolic Toll–IL-1R domain and common intracellular signaling molecules with TLRs that can directly inhibit early steps of human osteoclast differentiation, we tested whether IL-1β also has suppressive properties on osteoclastogenesis in primary human peripheral blood monocytes and RA synovial macrophages. Early addition of IL-1β, prior to or together with RANKL, strongly inhibited human osteoclastogenesis as assessed by generation of TRAP+ multinucleated cells. IL-1β acted directly on human osteoclast precursors (OCPs) to strongly suppress expression of RANK, of the costimulatory triggering receptor expressed on myeloid cells 2 receptor, and of the B cell linker adaptor important for transmitting RANK-induced signals. Thus, IL-1β rendered early-stage human OCPs refractory to RANK stimulation. Similar inhibitory effects of IL-1β were observed using RA synovial macrophages. One mechanism of RANK inhibition was IL-1β–induced proteolytic shedding of the M-CSF receptor c-Fms that is required for RANK expression. These results identify a homeostatic function of IL-1β in suppressing early OCPs that contrasts with its well-established role in promoting later stages of osteoclast differentiation. Thus, the rate of IL-1–driven bone destruction in inflammatory diseases, such as RA, can be restrained by its direct inhibitory effects on early OCPs to limit the extent of inflammatory osteolysis.
PMCID: PMC3016227  PMID: 20935210
17.  IL-27 inhibits human osteoclastogenesis by abrogating RANKL-mediated induction of NFATc1 and suppressing proximal RANK signaling 
Arthritis and rheumatism  2010;62(2):402.
IL-27 has stimulatory and regulatory immune functions and is expressed in rheumatoid arthritis synovium. We investigated the effects of IL-27 on human osteoclastogenesis to determine whether IL-27 can stimulate or attenuate osteoclast-mediated bone resorption that is a hallmark of rheumatoid arthritis.
Osteoclasts were generated from blood-derived human CD14+ cells. The effects of IL-27 on osteoclast formation were evaluated by counting the number of TRAP+ multinucleated cells and measuring expression of osteoclast-related genes. The induction of NFATc1 and the activation of signaling pathways downstream of RANK were measured by immunoblotting. The expression of key molecules implicated in osteoclastogenesis (NFATc1, RANK, costimulatory receptors, ITAM-harboring adaptors) was measured by real time RT-PCR. Murine osteoclast precursors were obtained from bone marrow. Responsiveness to IL-27 of synovial fluid macrophages derived from RA patients was also tested.
IL-27 inhibited human osteoclastogenesis, suppressed the induction of NFATc1, downregulated expression of RANK and TREM-2, and inhibited RANKL-mediated activation of ERK, p38 and NF-κB in osteoclast precursors. Synovial fluid macrophages derived from RA patients were refractory to the effects of IL-27. In contrast to humans, IL-27 only moderately suppressed murine osteoclastogenesis, likely due to low expression of the IL-27 receptor subunit WSX-1 on murine osteoclast precursors.
IL-27 inhibits human osteoclastogenesis by a direct mechanism suppressing responses of osteoclast precursors to RANKL. Our findings suggest that in addition to its well-known anti-inflammatory effects, IL-27 plays a homeostatic role in restraining bone erosion. This homeostatic function is compromised under conditions of chronic inflammation such as RA synovitis.
PMCID: PMC2822027  PMID: 20112358
Osteoclastogenesis; Cytokines; Interleukins; RANKL; Rheumatoid Arthritis
18.  Inhibition of RANK Expression and Osteoclastogenesis by TLRs and IFN-γ in Human Osteoclast Precursors1 
TLRs have been implicated in promoting osteoclast-mediated bone resorption associated with inflammatory conditions. TLRs also activate homeostatic mechanisms that suppress osteoclastogenesis and can limit the extent of pathologic bone erosion associated with infection and inflammation. We investigated mechanisms by which TLRs suppress osteoclastogenesis. In human cell culture models, TLR ligands suppressed osteoclastogenesis by inhibiting expression of receptor activator of NF-κB (RANK), thereby making precursor cells refractory to the effects of RANKL. Similar but less robust inhibition of RANK expression was observed in murine cells. LPS suppressed generation of osteoclast precursors in mice in vivo, and adsorption of LPS onto bone surfaces resulted in diminished bone resorption. Mechanisms that inhibited RANK expression were down-regulation of RANK transcription, and inhibition of M-CSF signaling that is required for RANK expression. TLRs inhibited M-CSF signaling by rapidly down-regulating cell surface expression of the M-CSF receptor c-Fms by a matrix metalloprotease- and MAPK-dependent mechanism. Additionally, TLRs cooperated with IFN-γ to inhibit expression of RANK and of the CSF1R gene that encodes c-Fms, and to synergistically inhibit osteoclastogenesis. Our findings identify a new mechanism of homeostatic regulation of osteoclastogenesis that targets RANK expression and limits bone resorption during infection and inflammation.
PMCID: PMC2783334  PMID: 19890054
19.  IL-10 Suppresses Calcium-mediated Costimulation of RANK Signaling During Human Osteoclast Differentiation by Inhibiting TREM-2 Expression 
Induction of effective osteoclastogenesis by RANK requires costimulation by ITAM-coupled receptors. In humans, the TREM-2 ITAM-coupled receptor plays a key role in bone remodeling, as patients with TREM-2 mutations exhibit defective osteoclastogenesis and bone lesions. We have identified a new rapidly induced costimulatory pathway for RANK signaling that is dependent on TREM-2 and mediated by calcium signaling. TREM-2-dependent calcium signals are required for RANK-mediated activation of CaMKII and downstream MEK and ERK MAPKs that are important for osteoclastogenesis. IL-10 inhibited RANK-induced osteoclastogenesis and selectively inhibited calcium signaling downstream of RANK by inhibiting transcription of TREM-2. Downregulation of TREM-2 expression resulted in diminished RANKL-induced activation of the CaMK-MEK-ERK pathway and decreased expression of the master regulator of osteoclastogenesis NFATc1. These findings provide a new mechanism of inhibition of human osteoclast differentiation. The results also yield insights into crosstalk between ITAM-coupled receptors and heterologous receptors such as RANK, and identify a mechanism by which IL-10 can suppress cellular responses to TNFR family members.
PMCID: PMC2742169  PMID: 19625651
20.  Apoptotic cells inhibit LPS-induced cytokine and chemokine production and IFN responses in macrophages 
Human immunology  2007;68(3):156-164.
Apoptosis is a critical process in tissue homeostasis and results in immediate removal of the dying cell by professional phagocytes such as macrophages and dendritic cells. Phagocytosis of apoptotic cells actively suppresses production of pro-inflammatory growth factors and cytokines. Impaired phagocytosis of apoptotic cells has been implicated in the pathogenesis of chronic inflammatory and autoimmune diseases. In this study we found that, in addition to suppressing LPS-induced production of TNF-α and IL-6, phagocytosis of apoptotic cells by macrophages suppressed production of the chemokine CXCL10 that is activated by LPS-induced autocrine-acting type I IFNs. Inhibition of cytokine and chemokine production was not universally affected since LPS-induced production of IL-10 and IL-8 was not significantly affected. Apoptotic cells had minimal effects on LPS-induced activation of NF-κB and MAPKs, but induced expression of SOCS proteins and substantially suppressed induction of CXCL10 expression by IFN-α. In addition to suppressing LPS responses, apoptotic cells inhibited macrophage responses to another major macrophage activator IFN-γ by attenuating IFN-γ-induced STAT1 activation and downstream gene expression. These results identify suppressive effects of apoptotic cells on signal transduction, and extend our understanding of the anti-inflammatory effects of apoptotic cells to include suppression of Jak-STAT signaling.
PMCID: PMC2736914  PMID: 17349870
autoimmunity; inflammation; signaling; interferon; STAT
21.  Inhibition of Interleukin 10 Signaling after Fc Receptor Ligation and during Rheumatoid Arthritis 
The Journal of Experimental Medicine  2003;197(11):1573-1583.
Interleukin-10 (IL-10) is a potent deactivator of myeloid cells that limits the intensity and duration of immune and inflammatory responses. The activity of IL-10 can be suppressed during inflammation, infection, or after allogeneic tissue transplantation. We investigated whether inflammatory factors suppress IL-10 activity at the level of signal transduction. Out of many factors tested, only ligation of Fc receptors by immune complexes inhibited IL-10 activation of the Jak-Stat signaling pathway. IL-10 signaling was suppressed in rheumatoid arthritis joint macrophages that are exposed to immune complexes in vivo. Activation of macrophages with interferon-γ was required for Fc receptor–mediated suppression of IL-10 signaling, which resulted in diminished activation of IL-10–inducible genes and reversal of IL-10–dependent suppression of cytokine production. The mechanism of inhibition involved decreased cell surface IL-10 receptor expression and Jak1 activation and was dependent on protein kinase C delta. These results establish that IL-10 signaling is regulated during inflammation and identify Fc receptors and interferon-γ as important regulators of IL-10 activity. Generation of macrophages refractory to IL-10 can contribute to pathogenesis of inflammatory and infectious diseases characterized by production of interferon-γ and immune complexes.
PMCID: PMC2193912  PMID: 12782719
interleukin 10; Fc receptor; signal transduction; Jak-Stat; macrophage

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