Translating osteoarthritis genetics research: challenging times ahead

Loughlin, John

doi:10.1016/j.molmed.2021.12.007

Cited by 10 publications

(7 citation statements)

References 75 publications

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“…Whilst decades of research have been dedicated to understanding the genetic aetiology of OA, the clinical exploitation of OA genetic discoveries is still out of reach ( 51 ). In this report, we undertook a detailed molecular genetic analysis of well-characterized OA risk loci, using primary human musculoskeletal fetal tissues for the first time.…”

Section: Discussionmentioning

confidence: 99%

Genetic risk of osteoarthritis operates during human skeletogenesis

Rice

Brumwell

Falk

et al. 2022

Human Molecular Genetics

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Osteoarthritis (OA) is a polygenic disease of older people resulting in the breakdown of cartilage within articular joints. Although a leading cause of disability, there are no disease-modifying therapies. Evidence is emerging to support the origins of OA in skeletogenesis. Whilst methylation QTLs (mQTLs) co-localizing with OA GWAS signals have been identified in aged human cartilage and used to identify effector genes and variants, such analyses have never been conducted during human development. Here, for the first time, we have investigated the developmental origins of OA genetic risk at seven well-characterized OA risk loci, comprising 39 OA-mQTL CpGs, in human foetal limb (FL) and cartilage (FC) tissues using a range of molecular genetic techniques. We compared our results to aged cartilage samples (AC) and identified significant OA-mQTLs at 14 CpGs and 29 CpGs in FL and FC tissues, respectively. Differential methylation was observed at 26 sites between foetal and aged cartilage, with the majority becoming actively hypermethylated in old age. Notably, 6/9 OA effector genes showed allelic expression imbalances during foetal development. Finally, we conducted ATAC-sequencing in cartilage from the developing and aged hip and knee to identify accessible chromatin regions, and found enrichment for transcription factor binding motifs including SOX9 and FOS/JUN. For the first time, we have demonstrated the activity of OA-mQTLs and expression imbalance of OA effector genes during skeletogenesis. We show striking differences in the spatiotemporal function of these loci, contributing to our understanding of OA aetiology, with implications for the timing and strategy of pharmacological interventions.

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Section: Discussionmentioning

confidence: 99%

Genetic risk of osteoarthritis operates during human skeletogenesis

Rice

Brumwell

Falk

et al. 2022

Human Molecular Genetics

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“…We did not however observe meQTLs for TSEN15, and the epigenetic modulation of cg15204595 and cg21606956 did not significantly alter TSEN15 expression. Furthermore, our in silico analyses of the TSEN15 missense variants did not indicate impact of the changes Clinical exploitation of OA genetic discoveries will require an understanding of the molecular mechanism by which risk-conferring alleles impact their target genes (1,46,47). In this report, we undertook a detailed analysis of the OA locus marked by rs1046934, highlighting its effect on the expression of COLGALT2 via two distal enhancers that are epigenetically regulated.…”

Section: Discussionmentioning

confidence: 94%

“…Although OA is a disease of older people, OA susceptibility has been reported to have developmental origins, with many OA SNPs associating with joint shape phenotypes ( 38 , 39 , 40 , 41 , 42 , 43 ). This implies that a proportion of OA genetic risk is functionally active during skeletogenesis and early postnatal life and manifests with aging ( 44 , 45 , 46 ). We previously investigated this by assessing AEI and mQTLs at OA risk loci in fetal cartilage samples ( 24 ).…”

Section: Discussionmentioning

confidence: 99%

Mediation of the Same Epigenetic and Transcriptional Effect by Independent Osteoarthritis Risk–Conferring Alleles on a Shared Target Gene, COLGALT2

Kehayova

Wilkinson

Rice

et al. 2023

Arthritis & Rheumatology

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Objective. Over 100 DNA variants have been associated with osteoarthritis (OA), including rs1046934, located within a linkage disequilibrium block encompassing part of COLGALT2 and TSEN15. Here, we used human foetal cartilage, cartilage from arthroplasty patients, and a chondrocyte cell model to determine the target gene(s) at the locus and the mechanism of action. Methods. Genotyping and methylation array data of cartilage DNA (n=87) were used to determine if rs1046934 genotype associated with differential DNA methylation at proximal CpGs. Results were replicated in arthroplasty (n=132) and foetal (n=77) cartilage DNA using pyrosequencing. Allelic expression imbalance (AEI) measured effect of genotype upon COLGALT2 and TSEN15 expression. Reporter gene assays and epigenetic editing determined the functional role of regions harbouring differentially methylated CpGs. In silico analyses complemented these experiments.Results. Three differentially methylated CpGs residing within regulatory regions were detected, two of which replicated. AEI was detected for COLGALT2 and TSEN15, with associations between expression and methylation for COLGALT2. Reporter assays confirmed that the CpGs are in chondrocyte enhancers with epigenetic editing directly linking methylation with COLGALT2 expression. Conclusion.COLGALT2 is a target of this OA locus. We previously characterised another OA locus, marked by rs11583641, that independently targets COLGALT2. rs1046934, like rs11583641, mediates its effect by modulating expression of COLGALT2 via methylation changes to CpGs located in enhancers. The SNPs, CpGs and enhancers are distinct between the loci but the effect on COLGALT2 is the same. COLGALT2 is the target of independent OA risk loci sharing a common mechanism of action.

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“…The current work explored the relationship between iron hemostasis and OA and its mechanism. The pathophysiology of OA is complicated and involves several elements including validation, mechanical signaling, inter‐organ connections, cell death, and oxidative stress (Cicuttini & Wluka, 2014 ; Goldring & Goldring, 2016 ; Grandi & Bhutani, 2020 ; Guan et al, 2020 ; Guan, Luo, et al, 2022 ; Loughlin, 2022 ; Wen & Lohmander, 2014 ). Since the role of iron homeostasis in OA cannot be fully simulated using animal or cellular models, we first examined the effect of iron homeostasis on OA using clinical data and discovered iron overload in osteoarthritic patients, which was validated by the LASSO prediction model.…”

Section: Discussionmentioning

confidence: 99%

The gut microbiota metabolite capsiate regulate SLC2A1 expression by targeting HIF‐1α to inhibit knee osteoarthritis‐induced ferroptosis

et al. 2023

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Ferroptosis is an iron‐dependent cell death that has been found to aggravate the progression of osteoarthritis (OA) and gut microbiota‐ OA axis refers to the bidirectional information network between the gut microbiota and OA, which may provide a new way to protect the OA. However, the role of gut microbiota‐derived metabolites in ferroptosis‐relative osteoarthritis remains unclear. The objective of this study was to analyze the protective effect of gut microbiota and its metabolite capsiate (CAT) on ferroptosis‐relative osteoarthritis in vivo and in vitro experiments. From June 2021 to February 2022, 78 patients were evaluated retrospectively and divided into two groups: The health group (n = 39) and the OA group (n = 40). Iron and oxidative stress indicators were determined in peripheral blood samples. And then in vivo and in vitro experiments, a surgically destabilized medial meniscus (DMM) mice model was established and treated with CAT or Ferric Inhibitor‐1 (Fer‐1). Solute Carrier Family 2 Member 1 (SLC2A1) short hairpin RNA (shRNA) was utilized to inhibit SLC2A1 expression. Serum iron was increased significantly but total iron binding capacity was decreased significantly in OA patients than healthy people (p < 0.0001). The least absolute shrinkage and selection operator clinical prediction model suggested that serum iron, total iron binding capacity, transferrin, and superoxide dismutase were all independent predictors of OA (p < 0.001). Bioinformatics results suggested that SLC2A1, Metastasis‐Associated Lung Adenocarcinoma Transcript 1 (MALAT1), and HIF‐1α (Hypoxia Inducible Factor 1 Alpha)‐related oxidative stress signaling pathways play an important role in iron homeostasis and OA. In addition, gut microbiota 16s RNA sequencing and untargeted metabolomics were used to find that gut microbiota metabolites CAT in mice with osteoarthritis were negatively correlated with Osteoarthritis Research Society International (OARSI) scores for chondrogenic degeneration (p = 0.0017). Moreover, CAT reduced ferroptosis‐dependent osteoarthritis in vivo and in vitro. However, the protective effect of CAT against ferroptosis‐dependent osteoarthritis could be eliminated by silencing SLC2A1. SLC2A1 was upregulated but reduced the SLC2A1 and HIF‐1α levels in the DMM group. HIF‐1α, MALAT1, and apoptosis levels were increased after SLC2A1 knockout in chondrocyte cells (p = 0.0017). Finally, downregulation of SLC2A1 expression by Adeno‐associated Virus (AAV) ‐SLC2A1 shRNA improves osteoarthritis in vivo. Our findings indicated that CAT inhibited HIF‐1a expression and reduced ferroptosis‐relative osteoarthritis progression by activating SLC2A1.

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Translating osteoarthritis genetics research: challenging times ahead

Cited by 10 publications

References 75 publications

Genetic risk of osteoarthritis operates during human skeletogenesis

Genetic risk of osteoarthritis operates during human skeletogenesis

Mediation of the Same Epigenetic and Transcriptional Effect by Independent Osteoarthritis Risk–Conferring Alleles on a Shared Target Gene, COLGALT2

The gut microbiota metabolite capsiate regulate SLC2A1 expression by targeting HIF‐1α to inhibit knee osteoarthritis‐induced ferroptosis

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