Cushioning the cartilage: a canonical Wnt restricting matter

Monteagudo, S.; Lories, Rik

doi:10.1038/nrrheum.2017.171

Cited by 55 publications

(50 citation statements)

References 103 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Sh3bp4 thus represents a new osteoarthritis susceptibility gene, the deletion of which accelerates joint damage. Its role in disease pathogenesis may involve the key TfR, FGFR, mTOR and Wnt signalling pathways, which regulate bone and cartilage homeostasis and tissue repair [47][48][49][50] .…”

Section: Early Onset Osteoarthritis In Bhlhe40 -/And Sh3pb4 -/Mutant mentioning

confidence: 99%

Accelerating functional gene discovery in osteoarthritis

Butterfield

Curry

Steinberg

et al. 2019

Preprint

View full text Add to dashboard Cite

Osteoarthritis causes debilitating pain and disability, resulting in a huge socioeconomic burden, yet no drugs are available that prevent disease onset or progression. Here, we develop, validate and use rapid-throughput imaging techniques to identify abnormal joint phenotypes in unselected mutant mice generated by the International Knockout Mouse Consortium. We identify 14 genes with functional involvement in osteoarthritis pathogenesis, including the homeobox gene Pitx1, and functionally characterize 6 candidate human osteoarthritis genes in mouse models. We demonstrate sensitivity of the methods by identifying age-related degenerative joint damage in wild-type mice. Finally, we generate mutant mice with an osteoarthritis-associated polymorphism in the Dio2 gene by Crispr/Cas9 genome editing and demonstrate a protective role in disease onset with public health implications. This expanding resource of unselected mutant mice will transform the field by accelerating functional gene discovery in osteoarthritis and offering unanticipated drug discovery opportunities for this common and incapacitating chronic disease.

show abstract

Section: Early Onset Osteoarthritis In Bhlhe40 -/And Sh3pb4 -/Mutant mentioning

confidence: 99%

Accelerating functional gene discovery in osteoarthritis

Butterfield

Curry

Steinberg

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…Mechanistically, DOT1L's protective role is accomplished via limiting Wnt signalling, a pathway that when hyper-activated leads to joint disease 13e15 . The Wnt cascade has been strongly linked to joint homeostasis and disease pathogenesis 13,16 , but mechanisms controlling the level of Wnt activation are not fully understood.…”

Section: Introductionmentioning

confidence: 99%

Increased susceptibility to develop spontaneous and post-traumatic osteoarthritis in Dot1l-deficient mice

Cornelis

Storms

et al. 2019

Osteoarthritis and Cartilage

View full text Add to dashboard Cite

Objective: We earlier identified that the histone methyltransferase Disruptor of telomeric silencing 1-like (DOT1L) is as a master protector of cartilage health via limiting excessive activation of the Wnt pathway. However, cartilage-specific homozygous Dot1l knockout mice exhibited a severe growth phenotype and perinatal death, which hampered their use in induced or ageing models of osteoarthritis (OA). The aim of this study was to generate and examine haploinsufficient and inducible conditional Dot1l-deficient mouse models to evaluate the importance of DOT1L during post-traumatic or ageing-associated OA onset and progression. Method: We used cartilage-specific heterozygous and postnatal tamoxifen-inducible Dot1l knockout mice and performed destabilization of the medial meniscus (DMM) and ageing as OA models. Mice were examined histologically using X-rays and micro-computed tomography (mCT), and cartilage damage and osteophyte formation were assessed based on OARSI guidelines. Immunohistochemistry of DOT1L, H3K79me2, TCF1 and COLX was performed. Results: Both Dot1l-deficient strains exhibit a phenotype characterized by joint remodeling with extensive osteophyte formation and ectopic ossification upon ageing, indicating accelerated development of spontaneous osteoarthritis. In the DMM-induced OA mouse model, absence of Dot1l resulted in increased cartilage damage. Wnt signalling hyper-activation and ectopic chondrocyte hypertrophy were observed in the articular cartilage of both Dot1l-deficient mice. Conclusions: This study demonstrated the functional relevance of DOT1L in vivo during the development of OA using genetically modified mice. Thus, maintaining or enhancing DOT1L activity during ageing or after trauma might prevent OA onset and progression.

show abstract

“…Of particular note, both the innate and the acquired immune response showed an upregulation, an effect that has been reported on previously in OA for both cartilage and synovium 38–39 . Downregulation of Wnt signalling was also of interest, as this pathway is critical to cartilage homeostasis 33,40 . Furthermore, there is growing evidence of an interplay between Wnt signalling and inflammation in joint tissues 41 .…”

Section: Discussionmentioning

confidence: 99%

Multi-tissue epigenetic analysis of the osteoarthritis susceptibility locus mapping to the plectin gene PLEC

Sorial

Hofer

Tselepi

et al. 2020

Preprint

View full text Add to dashboard Cite

Running headline: Epigenetic analysis of the PLEC OA risk locusObjective 1 Osteoarthritis (OA) associated single nucleotide polymorphism (SNP) rs11780978 correlates 2 with differential expression of PLEC, and methylation quantitative trait loci (mQTLs) at PLEC 3 CpGs in cartilage. This implies that methylation links chondrocyte genotype and phenotype, 4 thus driving the functional effect. PLEC encodes plectin, a cytoskeletal protein that enables 5 tissues to respond to mechanical forces. We sought to assess whether PLEC functional effects 6 were cartilage specific. 7 8 Method 9Cartilage, fat pad, synovium and peripheral blood were collected from patients undergoing 10 arthroplasty. PLEC CpGs were analysed for mQTLs and allelic expression imbalance (AEI) 11 was performed. We focussed on previously reported mQTL clusters neighbouring cg19405177 12 and cg14598846. Plectin was knocked down in a mesenchymal stem cell (MSC) line using 13 CRISPR/Cas9 and cells phenotyped by RNA-sequencing. 14 15Results 16 Novel mQTLs were discovered in fat pad, synovium and peripheral blood at both clusters. The 17 genotype-methylation effect of rs11780978 was stronger in cg14598846 than in cg19405177 18 and stronger in joint tissues than in peripheral blood. We observed AEI in synovium in the 19 same direction as for cartilage. Knocking-down plectin impacted on pathways reported to have 20 a role in OA, including Wnt signalling, glycosaminoglycan biosynthesis and immune 21 regulation. 22 23 Conclusions 24Synovium is also a target of the rs11780978 OA association functionally operating on PLEC. 25In fat pad, mQTLs were identified but these did not correlate with PLEC expression, suggesting 26 the functional effect is not joint-wide. Our study highlights interplay between genetic risk, 27 DNA methylation and gene expression in OA, and reveals clear differences between tissues 28 from the same diseased joint. 29 30

show abstract

Cushioning the cartilage: a canonical Wnt restricting matter

Cited by 55 publications

References 103 publications

Accelerating functional gene discovery in osteoarthritis

Accelerating functional gene discovery in osteoarthritis

Increased susceptibility to develop spontaneous and post-traumatic osteoarthritis in Dot1l-deficient mice

Multi-tissue epigenetic analysis of the osteoarthritis susceptibility locus mapping to the plectin gene PLEC

Contact Info

Product

Resources

About