DOT1L safeguards cartilage homeostasis and protects against osteoarthritis

Monteagudo, S.; Cornelis, F.M.; Aznar-Lopez, Carolina; Yibmantasiri, Ploi; Guns, Laura-An; Carmeliet, Peter; Cailotto, F.; Lories, Rik

doi:10.1038/ncomms15889

Cited by 114 publications

(125 citation statements)

References 61 publications

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“…Previously reported cross of the conditional Dot1l KO line with the Col2‐Cre line was more successful in generating mice that survived Dot1l deletion, possibly because of decreased penetration of the deletion than in the present study; however, profound growth retardation at 1 month of age was reported. The previous study did not go into details on the number of pups born, but a different Col2‐Cre mouse line in B6SJL/F1 background was used, which possibly contributed to the difference in observed phenotype.…”

Section: Discussioncontrasting

confidence: 43%

“…(12,13) It has been shown that human Dot1l polymorphism rs12982744 is associated with increased risk of osteoarthritis in European and Chinese populations in genome-wide association studies. (14,15) Dot1l is expressed in the normal growth plate and articular cartilage of prenatal and skeletally mature mice, (16) and may preserve cartilage health by preventing the hyperactivation of Wnt signaling, (17) inhibiting osteoclastogenesis, (18) and preventing age-related and posttraumatic osteoarthritis. (19) This study further assesses the role of Dot1l in prenatal and postnatal chondrocytes and trabecular bone in vivo using conditional KO mouse models.…”

Section: Introductionmentioning

confidence: 99%

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The Role of Dot1l in Prenatal and Postnatal Murine Chondrocytes and Trabecular Bone

Domowicz

Henry

et al. 2019

JBMR Plus

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Osteoarthritis and osteoporosis are widely prevalent and have far‐reaching public health implications. There is increasing evidence that epigenetics, in particular, histone 3 lysine 79 methyltransferase DOT1L, plays an important role in the cartilage and bone biology. In this study, we evaluated the role of Dot1l in the articular cartilage, growth plate, and trabecular bone utilizing conditional KO mouse models. We generated chondrocyte‐specific constitutive and inducible conditional Dot1l KO mouse lines using Col2a1‐Cre and Acan‐CreER systems. Prenatal deletion of Dot1l in mouse chondrocytes led to perinatal mortality, accelerated ossification, and dysregulation of Col10a1 expression. Postnatal deletion of Dot1l in mouse chondrocytes resulted in trabecular bone loss decreased extracellular matrix production, and disruption of the growth plate. In addition, pharmacological inhibition of DOT1L in a progeria mouse model partially rescued the abnormal osseous phenotype. In conclusion, Dot1l is important in maintaining the growth plate, extracellular matrix production, and trabecular bone. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

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Section: Discussioncontrasting

confidence: 43%

Section: Introductionmentioning

confidence: 99%

The Role of Dot1l in Prenatal and Postnatal Murine Chondrocytes and Trabecular Bone

Domowicz

Henry

et al. 2019

JBMR Plus

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“…Processes that determine the transmission of heritable phenotypes in the absence of DNA sequence alterations are termed epigenetics . Recent studies focused on articular chondrocytes have uncovered a number of epigenetic alterations in OA disease, involving SIRT1, DOT1L and other histone modifiers . The miRNAs that are differentially expressed in OA can modulate the expression of genes that contribute to the pathology .…”

Section: Epigenetic Dysregulation Of Oa Chondrocytesmentioning

confidence: 99%

Phenotypic instability of chondrocytes in osteoarthritis: on a path to hypertrophy

Singh

Marcu

Goldring

et al. 2018

Annals of the New York Academy of Sciences

114

139

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Articular chondrocytes are quiescent, fully differentiated cells responsible for the homeostasis of adult articular cartilage by maintaining cellular survival functions and the fine-tuned balance between anabolic and catabolic functions. This balance requires phenotypic stability that is lost in osteoarthritis (OA), a disease that affects and involves all joint tissues and especially impacts articular cartilage structural integrity. In OA, articular chondrocytes respond to the accumulation of injurious biochemical and biomechanical insults by shifting toward a degradative and hypertrophy-like state, involving abnormal matrix production and increased aggrecanase and collagenase activities. Hypertrophy is a necessary, transient developmental stage in growth plate chondrocytes that culminates in bone formation; in OA, however, chondrocyte hypertrophy is catastrophic and it is believed to initiate and perpetuate a cascade of events that ultimately result in permanent cartilage damage. Emphasizing changes in DNA methylation status and alterations in NF-κB signaling in OA, this review summarizes the data from the literature highlighting the loss of phenotypic stability and the hypertrophic differentiation of OA chondrocytes as central contributing factors to OA pathogenesis.

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“…The mapping of risk loci for polygenic traits is now a relatively straightforward procedure, with the next major step in complex trait analysis being the transition from association signal to functional characterization 32 . For OA, considerable strides have been made in this regard in recent years 33–35 . Our interest is in the epigenetic dimension of OA genetic risk and especially the role of DNA methylation.…”

Section: Discussionmentioning

confidence: 99%

“…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

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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

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DOT1L safeguards cartilage homeostasis and protects against osteoarthritis

Cited by 114 publications

References 61 publications

The Role of Dot1l in Prenatal and Postnatal Murine Chondrocytes and Trabecular Bone

The Role of Dot1l in Prenatal and Postnatal Murine Chondrocytes and Trabecular Bone

Phenotypic instability of chondrocytes in osteoarthritis: on a path to hypertrophy

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

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