Genome-wide association and functional studies identify a role for<i>IGFBP3</i>in hip osteoarthritis

Evans, Daniel S.; Cailotto, F.; Parimi, Neeta; Valdes, Ana M.; Castaño-Betancourt, Martha C.; Liu, Youfang; Kaplan, Robert C.; Bidlingmaier, Martin; Vasan, Ramachandran S.; Teumer, Alexander; Tranah, Gregory J.; Nevitt, Michael C.; Cummings, Steven R.; Orwoll, Eric S.; Barrett‐Connor, Elizabeth; Renner, Jordan B.; Jordan, Joanne M.; Doherty, Michael; Doherty, Sally; Uitterlinden, André G.; Meurs, Joyce B. J. van; Spector, Tim D.; Lories, Rik; Lane, Nancy E.

doi:10.1136/annrheumdis-2013-205020

Cited by 49 publications

(29 citation statements)

References 49 publications

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“…Some of these genes are involved in well‐described IGF regulatory or signaling pathways (such as IGFBP3 and IGFALS ) (Deal et al ., 2001; Gu et al ., 2010; Schumacher et al ., 2010) and are believed to influence traits that are also associated with concentrations or bioactivity of IGFs (e.g., FOXO3 locus associated with longevity (Willcox et al ., 2008) and IGFBP3 locus associated with hip osteoarthritis (Evans et al ., 2015)). To identify additional genetic variants with smaller effect sizes and enable sex specific analyses, we expanded our GWAS meta‐analysis to include up to a total of 30 884 individuals of European ancestry from 21 studies with measured circulating concentrations of IGF‐I and IGFBP‐3.…”

Section: Introductionmentioning

confidence: 99%

Genomewide meta‐analysis identifies loci associated with IGF ‐I and IGFBP ‐3 levels with impact on age‐related traits

Teumer¹,

Qi²,

Nethander³

et al. 2016

Aging Cell

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SummaryThe growth hormone/insulin‐like growth factor (IGF) axis can be manipulated in animal models to promote longevity, and IGF‐related proteins including IGF‐I and IGF‐binding protein‐3 (IGFBP‐3) have also been implicated in risk of human diseases including cardiovascular diseases, diabetes, and cancer. Through genomewide association study of up to 30 884 adults of European ancestry from 21 studies, we confirmed and extended the list of previously identified loci associated with circulating IGF‐I and IGFBP‐3 concentrations (IGF1, IGFBP3,GCKR,TNS3, GHSR, FOXO3, ASXL2, NUBP2/IGFALS, SORCS2, and CELSR2). Significant sex interactions, which were characterized by different genotype–phenotype associations between men and women, were found only for associations of IGFBP‐3 concentrations with SNPs at the loci IGFBP3 and SORCS2. Analyses of SNPs, gene expression, and protein levels suggested that interplay between IGFBP3 and genes within the NUBP2 locus (IGFALS and HAGH) may affect circulating IGF‐I and IGFBP‐3 concentrations. The IGF‐I‐decreasing allele of SNP rs934073, which is an eQTL of ASXL2, was associated with lower adiposity and higher likelihood of survival beyond 90 years. The known longevity‐associated variant rs2153960 (FOXO3) was observed to be a genomewide significant SNP for IGF‐I concentrations. Bioinformatics analysis suggested enrichment of putative regulatory elements among these IGF‐I‐ and IGFBP‐3‐associated loci, particularly of rs646776 at CELSR2. In conclusion, this study identified several loci associated with circulating IGF‐I and IGFBP‐3 concentrations and provides clues to the potential role of the IGF axis in mediating effects of known (FOXO3) and novel (ASXL2) longevity‐associated loci.

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Section: Introductionmentioning

confidence: 99%

Genomewide meta‐analysis identifies loci associated with IGF ‐I and IGFBP ‐3 levels with impact on age‐related traits

Teumer¹,

Qi²,

Nethander³

et al. 2016

Aging Cell

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“…By combining reported genetic OA signals with AI SNPs that alter transcription of articular cartilage genes in ‐ cis , we also had the opportunity to address functionality of OA risk alleles. For example, the A allele of rs788748, located upstream of IGFBP3 , is associated with lower odds of hip OA . Given that this SNP is not located in an exon, we assessed its potential revelance to AI through rs6670 double heterozygotes, which revealed that the protective rs788748 A allele marks lower expression of IGFBP3 compared to the G allele.…”

Section: Discussionmentioning

confidence: 99%

Annotating Transcriptional Effects of Genetic Variants in Disease‐Relevant Tissue: Transcriptome‐Wide Allelic Imbalance in Osteoarthritic Cartilage

Hollander

Pulyakhina

Boer

et al. 2019

Arthritis & Rheumatology

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Objective Multiple single‐nucleotide polymorphisms ( SNP s) conferring susceptibility to osteoarthritis ( OA ) mark imbalanced expression of positional genes in articular cartilage, reflected by unequally expressed alleles among heterozygotes (allelic imbalance [ AI ]). We undertook this study to explore the articular cartilage transcriptome from OA patients for AI events to identify putative disease‐driving genetic variation. Methods AI was assessed in 42 preserved and 5 lesioned OA cartilage samples (from the Research Arthritis and Articular Cartilage study) for which RNA sequencing data were available. The count fraction of the alternative alleles among the alternative and reference alleles together ( φ ) was determined for heterozygous individuals. A meta‐analysis was performed to generate a meta‐ φ and P value for each SNP with a false discovery rate ( FDR ) correction for multiple comparisons. To further validate AI events, we explored them as a function of multiple additional OA features. Results We observed a total of 2,070 SNP s that consistently marked AI of 1,031 unique genes in articular cartilage. Of these genes, 49 were found to be significantly differentially expressed (fold change <0.5 or >2, FDR <0.05) between preserved and paired lesioned cartilage, and 18 had previously been reported to confer susceptibility to OA and/or related phenotypes. Moreover, we identified notable highly significant AI SNP s in the CRLF 1 , WWP 2 , and RPS 3 genes that were related to multiple OA features. Conclusion We present a framework and resulting data set for researchers in the OA research field to probe for disease‐relevant genetic variation that affects gene expression in pivotal disease‐affected tissue. This likely includes putative novel compelling OA risk genes such as CRLF 1 , WWP 2 , and RPS 3 .

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“…Of note, IGFBP3‐induced hBMSC migration coincided with the activation of CCR2 and CCR2 inhibitors completely blocked the IGFBP3‐induced MSC migration, indicating that IGFBP3 promoted hBMSC migration through a CCR2‐dependent mechanism (Figures and ). On the other hand, genome‐wide association and functional studies have shown that IGFBP3 overexpression induced cartilage catabolism and osteogenic differentiation in hip osteoarthritis (Evans et al, ). Transcriptome analysis of homing cells showed that the hUCMSC‐ECM significantly increased the expressions of 7 promigratory genes, including TβRI and CCR2 in vivo (Figure a).…”

Section: Discussionmentioning

confidence: 99%

IGFBP3 deposited in the human umbilical cord mesenchymal stem cell‐secreted extracellular matrix promotes bone formation

Deng

Luo

Hou

et al. 2018

Journal Cellular Physiology

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The extracellular matrix (ECM) contains rich biological cues for cell recruitment, proliferationm, and even differentiation. The osteoinductive potential of scaffolds could be enhanced through human bone marrow mesenchymal stem cell (hBMSC) directly depositing ECM on surface of scaffolds. However, the role and mechanism of human umbilical cord mesenchymal stem cells (hUCMSC)‐secreted ECM in bone formation remain unknown. We tested the osteoinductive properties of a hUCMSC‐secreted ECM construct (hUCMSC‐ECM) in a large femur defect of a severe combined immunodeficiency (SCID) mouse model. The hUCMSC‐ECM improved the colonization of endogenous MSCs and bone regeneration, similar to the hUCMSC‐seeded scaffold and superior to the scaffold substrate. Besides, the hUCMSC‐ECM enhanced the promigratory molecular expressions of the homing cells, including CCR2 and TβRI. Furthermore, the hUCMSC‐ECM increased the number of migrated MSCs by nearly 3.3 ± 0.1‐fold, relative to the scaffold substrate. As the most abundant cytokine deposited in the hUCMSC‐ECM, insulin‐like growth factor binding protein 3 (IGFBP3) promoted hBMSC migration in the TβRI/II‐ and CCR2‐dependent mechanisms. The hUCMSC‐ECM integrating shRNA‐mediated silencing of Igfbp3 that down‐regulated IGFBP3 expression by approximately 60%, reduced the number of migrated hBMSCs by 47%. In vivo, the hUCMSC‐ECM recruited 10‐fold more endogenous MSCs to initiate bone formation compared to the scaffold substrate. The knock‐down of Igfbp3 in the hUCMSC‐ECM inhibited nearly 60% of MSC homing and bone regeneration capacity. This research demonstrates that IGFBP3 is an important MSC homing molecule and the therapeutic potential of hUCMSC‐ECM in bone regeneration is enhanced by improving MSC homing in an IGFBP3‐dependent mechanism.

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Genome-wide association and functional studies identify a role forIGFBP3in hip osteoarthritis

Cited by 49 publications

References 49 publications

Genomewide meta‐analysis identifies loci associated with IGF ‐I and IGFBP ‐3 levels with impact on age‐related traits

Genomewide meta‐analysis identifies loci associated with IGF ‐I and IGFBP ‐3 levels with impact on age‐related traits

Annotating Transcriptional Effects of Genetic Variants in Disease‐Relevant Tissue: Transcriptome‐Wide Allelic Imbalance in Osteoarthritic Cartilage

IGFBP3 deposited in the human umbilical cord mesenchymal stem cell‐secreted extracellular matrix promotes bone formation

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