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Genetics and Epigenetics of Musculoskeletal Pathologies
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Genetics and Epigenetics of Musculoskeletal Pathologies

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (10 August 2023) | Viewed by 9515

Special Issue Editor

Dr. Stuart Raleigh

E-Mail Website
Guest Editor
Cardiovascular and Lifestyle Medicine Research Group, CSELS, Coventry University, Coventry CV1 5FB, UK
Interests: chronic diseases; musculoskeletal disorders; gene association studies; epigenetics; cognition and dementia

Special Issue Information

Dear Colleagues, 

This Special Issue will explore our current understanding of the genetics and epigenetics of musculoskeletal pathologies. We are interested exclusively in studies conducted in human cohorts and/or in studies where human tissue has been used.

The field of musculoskeletal genetics continues to grow  and many gene variants have been associated with distinct phenotypes. However, we still do not understand how these associated variants cause or contribute to pathology. It is likely that individual risk alleles interact with each other and/or the environment to predispose to musculoskeletal pathologies, but a detailed understanding of this mechanism has yet to be elucidated. Furthermore, it is also likely that epigenetic factors (such as DNA methylation, miRNA expression levels and histone modification) contribute significantly to these problems; however, to date, very few studies have focused on this.

Therefore, we invite researchers working within the field to contribute to this Special Issue and look forward to advancing our understanding of how genetic variability, epigenetic factors, and the interaction of both predispose to these disabling problems.

Dr. Stuart Raleigh
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Genes is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • musculoskeletal injuries
  • tendinoapthies
  • ligament ruptures
  • arthritis related pathologies
  • epigenetics
  • gene variants
  • molecular mechanisms
  • sarcopenia

Published Papers (6 papers)

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Research

21 pages, 4059 KiB  
Article
Differential Regulation of POC5 by ERα in Human Normal and Scoliotic Cells
by Amani Hassan, Edward T. Bagu, Shunmoogum A. Patten, Sirinart Molidperee, Stefan Parent, Soraya Barchi, Isabelle Villemure, André Tremblay and Florina Moldovan
Genes 2023, 14(5), 1111; https://doi.org/10.3390/genes14051111 - 19 May 2023
Viewed by 1304
Abstract
Adolescent idiopathic scoliosis (AIS) is a complex three-dimensional spinal deformity. The incidence of AIS in females is 8.4 times higher than in males. Several hypotheses on the role of estrogen have been postulated for the progression of AIS. Recently, Centriolar protein gene POC5 [...] Read more.
Adolescent idiopathic scoliosis (AIS) is a complex three-dimensional spinal deformity. The incidence of AIS in females is 8.4 times higher than in males. Several hypotheses on the role of estrogen have been postulated for the progression of AIS. Recently, Centriolar protein gene POC5 (POC5) was identified as a causative gene of AIS. POC5 is a centriolar protein that is important for cell cycle progression and centriole elongation. However, the hormonal regulation of POC5 remains to be determined. Here, we identify POC5 as an estrogen-responsive gene under the regulation of estrogen receptor ERα in normal osteoblasts (NOBs) and other ERα-positive cells. Using promoter activity, gene, and protein expression assays, we found that the POC5 gene was upregulated by the treatment of osteoblasts with estradiol (E2) through direct genomic signaling. We observed different effects of E2 in NOBs and mutant POC5A429V AIS osteoblasts. Using promoter assays, we identified an estrogen response element (ERE) in the proximal promoter of POC5, which conferred estrogen responsiveness through ERα. The recruitment of ERα to the ERE of the POC5 promoter was also potentiated by estrogen. Collectively, these findings suggest that estrogen is an etiological factor in scoliosis through the deregulation of POC5. Full article
(This article belongs to the Special Issue Genetics and Epigenetics of Musculoskeletal Pathologies)
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12 pages, 1368 KiB  
Article
Characterization of Histone Modifications in Late-Stage Rotator Cuff Tendinopathy
by Kayleigh J. A. Orchard, Moeed Akbar, Lindsay A. N. Crowe, John Cole, Neal L. Millar and Stuart M. Raleigh
Genes 2023, 14(2), 496; https://doi.org/10.3390/genes14020496 - 15 Feb 2023
Cited by 1 | Viewed by 1754
Abstract
The development and progression of rotator cuff tendinopathy (RCT) is multifactorial and likely to manifest through a combination of extrinsic, intrinsic, and environmental factors, including genetics and epigenetics. However, the role of epigenetics in RCT, including the role of histone modification, is not [...] Read more.
The development and progression of rotator cuff tendinopathy (RCT) is multifactorial and likely to manifest through a combination of extrinsic, intrinsic, and environmental factors, including genetics and epigenetics. However, the role of epigenetics in RCT, including the role of histone modification, is not well established. Using chromatin immunoprecipitation sequencing, differences in the trimethylation status of H3K4 and H3K27 histones in late-stage RCT compared to control were investigated in this study. For H3K4, 24 genomic loci were found to be significantly more trimethylated in RCT compared to control (p < 0.05), implicating genes such as DKK2, JAG2, and SMOC2 in RCT. For H3K27, 31 loci were shown to be more trimethylated (p < 0.05) in RCT compared to control, inferring a role for EPHA3, ROCK1, and DEFβ115. Furthermore, 14 loci were significantly less trimethylated (p < 0.05) in control compared to RCT, implicating EFNA5, GDF6, and GDF7. Finally, the TGFβ signaling, axon guidance, and regulation of focal adhesion assembly pathways were found to be enriched in RCT. These findings suggest that the development and progression of RCT is, at least in part, under epigenetic control, highlighting the influence of histone modifications in this disorder and paving the way to further understand the role of epigenome in RCT. Full article
(This article belongs to the Special Issue Genetics and Epigenetics of Musculoskeletal Pathologies)
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9 pages, 512 KiB  
Communication
Association between the rs820218 Variant within the SAP30BP Gene and Rotator Cuff Rupture in an Amazonian Population
by Rui Sergio Monteiro de Barros, Carla de Castro Sant’ Anna, Diego Di Felipe Ávila Alcantara, Karla Beatriz Cardias Cereja Pantoja, Marianne Rodrigues Fernandes, Lívia Guerreiro de Barros Bentes, Antônio Leonardo Jatahi Cavalcanti Pimentel, Rafael Silva Lemos, Nyara Rodrigues Conde de Almeida, Manuela Rodrigues Neiva Fernandes, Thiago Sequeira da Cruz, Atylla de Andrade Candido and Rommel Mario Rodriguez Burbano
Genes 2023, 14(2), 367; https://doi.org/10.3390/genes14020367 - 31 Jan 2023
Viewed by 1384
Abstract
Background: Rotator cuff disease is one of the leading causes of musculoskeletal pain and disability, and its etiology is most likely multifactorial but remains incompletely understood. Therefore, the objective of this research was to investigate the relationship of the single-nucleotide rs820218 polymorphism of [...] Read more.
Background: Rotator cuff disease is one of the leading causes of musculoskeletal pain and disability, and its etiology is most likely multifactorial but remains incompletely understood. Therefore, the objective of this research was to investigate the relationship of the single-nucleotide rs820218 polymorphism of the SAP30-binding protein (SAP30BP) gene with rotator cuff tears in the Amazonian population. Methods: The case group consisted of patients who were operated on due to rotator cuff tears in a hospital in the Amazon region between 2010 and 2021, and the control group was composed of individuals who were selected after negative physical examinations for rotator cuff tears. Genomic DNA was obtained from saliva samples. For the genotyping and allelic discrimination of the selected single nucleotide polymorphism (rs820218) in the SAP30BP gene, real-time PCR was performed. Results: The frequency of the A allele in the control group was four times as high as that in the case group (AA homozygotes); an association of the genetic variant rs820218 of the SAP30BP gene with rotator cuff tears was not established (p = 0.28 and 0.20), as the A allelic frequency is ordinarily low in the general population. Conclusions: The presence of the A allele indicates protection against rotator cuff tears. Full article
(This article belongs to the Special Issue Genetics and Epigenetics of Musculoskeletal Pathologies)
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16 pages, 1235 KiB  
Article
Polymorphisms in COMT and OPRM1 Collectively Contribute to Chronic Shoulder Pain and Disability in South African Breast Cancer Survivors’
by Firzana Firfirey, Delva Shamley and Alison V. September
Genes 2023, 14(1), 9; https://doi.org/10.3390/genes14010009 - 21 Dec 2022
Cited by 2 | Viewed by 1374
Abstract
Chronic shoulder pain and disability is a common adverse effect experienced by >40% of breast cancer survivors (BCS). Pain management protocols for acute and chronic pain include the use of opioids and opioid derivatives. Furthermore, pain-modulating genes, such as COMT and OPRM1, [...] Read more.
Chronic shoulder pain and disability is a common adverse effect experienced by >40% of breast cancer survivors (BCS). Pain management protocols for acute and chronic pain include the use of opioids and opioid derivatives. Furthermore, pain-modulating genes, such as COMT and OPRM1, have been linked to the aetiology of chronic pain. This study aimed to investigate the association between genetic variants of major pain modulator genes and chronic pain/disability in BCS. Assessment of pain, disability and combined (pain and disability) symptoms were determined using the Shoulder Pain and Disability Index (SPADI). Participants were grouped according to their scores such as no-low (<30%) and moderate-high (≥30%) groups of pain, disability and combined (pain and disability). Genotyping of the COMT rs6269 (A > G), rs4633 (C > T), rs4818 (C > G) and the functional rs4680(G > A) SNPs within the BCS (N = 252) cohort were conducted using TaqMan® SNP assays. Genotype, allele, haplotype, and allele–allele combination frequencies were evaluated. Statistical analysis was applied, with significance accepted at p < 0.05. The COMT rs4680:A/A genotype was significantly associated with moderate-high pain (p = 0.024, OR: 3.23, 95% CI: 1.33–7.81) and combined (pain and disability) (p = 0.015, OR: 3.81, 95% CI: 1.47–9.85). The rs4680:A allele was also significantly associated with moderate-high pain (p = 0.035, OR: 1.58, 95% CI: 1.03–2.43) and combined (pain and disability) (p = 0.017, OR: 1.71, 95% CI: 1.07–2.71). For the inferred COMT (rs6269 A > G-rs4680 G > A) haplotype analyses, the G-G (p = 0.026, OR: 0.67, 95% CI: 0.38–1.18) and A-A (p = 0.007, OR: 2.09, 95% CI: 0.89–4.88) haplotypes were significantly associated with reduced and increased likelihoods of reporting moderate-high pain, respectively. The inferred A-A (p = 0.003, OR: 2.18, 95% CI: 0.92–5.17) haplotype was also significantly associated with combined (pain and disability). Gene–gene interaction analyses further showed allele–allele combinations for COMT (rs4680 G > A)-OPRM1 (rs1799971 A > G) and COMT (rs4680 G > A)-OPRM1(rs540825 T > A) were associated with reporting pain and combined (pain and disability) symptoms, p < 0.05. The findings of this study suggest that COMT and OPRM1 SNPs play a role in the development of chronic shoulder pain/disability in BCS in a unique South African cohort from the Western Cape. Full article
(This article belongs to the Special Issue Genetics and Epigenetics of Musculoskeletal Pathologies)
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12 pages, 1041 KiB  
Article
The Association of Variants within Types V and XI Collagen Genes with Knee Joint Laxity Measurements
by Samantha Beckley, Roopam Dey, Shaun Stinton, Willem van der Merwe, Thomas Branch, Alison V. September, Mike Posthumus and Malcolm Collins
Genes 2022, 13(12), 2359; https://doi.org/10.3390/genes13122359 - 14 Dec 2022
Cited by 2 | Viewed by 1467
Abstract
Joint laxity is a multifactorial phenotype with a heritable component. Mutations or common polymorphisms within the α1(V) (COL5A1), α1(XI) (COL11A1) and α2(XI) (COL11A2) collagen genes have been reported or proposed to associate with joint hypermobility, range [...] Read more.
Joint laxity is a multifactorial phenotype with a heritable component. Mutations or common polymorphisms within the α1(V) (COL5A1), α1(XI) (COL11A1) and α2(XI) (COL11A2) collagen genes have been reported or proposed to associate with joint hypermobility, range of motion and/or genu recurvatum. The aim of this study was to investigate whether polymorphisms within these collagen-encoding genes are associated with measurements of knee joint laxity and computed ligament length changes within the non-dominant leg. One hundred and six healthy participants were assessed for genu recurvatum (knee hyperextension), anterior-posterior tibial translation, external-internal tibial rotation and ligament length changes during knee rotation of their non-dominant leg. Participants were genotyped for COL5A1 rs12722 (T/C), COL11A1 rs3753841 (C/T), COL11A1 rs1676486 (T/C) and COL11A2 rs1799907 (A/T). The genotype-genotype combination of any two or more of the four COL5A1 rs12722 CC, COL11A1 rs3753841 CC, COL11A1 rs1676486 TT and COL11A2 rs1799907 AA genotypes was associated with decreased active and passive knee hyperextension. These genotype-genotype combinations, including sex (male), increased age and decreased body mass collectively, also contributed to decreased passive knee hyperextension. These findings suggest that COL5A1, COL11A1 and COL11A2 gene-gene interactions are associated with knee hyperextension measurements of the non-dominant leg of healthy individuals. Full article
(This article belongs to the Special Issue Genetics and Epigenetics of Musculoskeletal Pathologies)
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17 pages, 1518 KiB  
Article
Short-Term Exposure to Ciprofloxacin Reduces Proteoglycan Loss in Tendon Explants
by Stuart James, John Daffy, Jill Cook and Tom Samiric
Genes 2022, 13(12), 2210; https://doi.org/10.3390/genes13122210 - 25 Nov 2022
Cited by 1 | Viewed by 1186
Abstract
Fluoroquinolone antibiotics are associated with increased risk of tendinopathy and tendon rupture, which can occur well after cessation of treatment. We have previously reported that the fluoroquinolone ciprofloxacin (CPX) reduced proteoglycan synthesis in equine tendon explants. This study aimed to determine the effects [...] Read more.
Fluoroquinolone antibiotics are associated with increased risk of tendinopathy and tendon rupture, which can occur well after cessation of treatment. We have previously reported that the fluoroquinolone ciprofloxacin (CPX) reduced proteoglycan synthesis in equine tendon explants. This study aimed to determine the effects of CPX on proteoglycan catabolism and whether any observed effects are reversible. Equine superficial digital flexor tendon explant cultures were treated for 4 days with 1, 10, 100 or 300 µg/mL CPX followed by 8 days without CPX. The loss of [35S]-labelled proteoglycans and chemical pool of aggrecan and versican was studied as well as the gene expression levels of matrix-degrading enzymes responsible for proteoglycan catabolism. CPX suppressed [35S]-labelled proteoglycan and total aggrecan loss from the explants, although not in a dose-dependent manner, which coincided with downregulation of mRNA expression of MMP-9, -13, ADAMTS-4, -5. The suppressed loss of proteoglycans was reversed upon removal of the fluoroquinolone with concurrent recovery of MMP and ADAMTS mRNA expression, and downregulated TIMP-2 and upregulated TIMP-1 expression. No changes in MMP-3 expression by CPX was observed at any stage. These findings suggest that CPX suppresses proteoglycan catabolism in tendon, and this is partially attributable to downregulation of matrix-degrading enzymes. Full article
(This article belongs to the Special Issue Genetics and Epigenetics of Musculoskeletal Pathologies)
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