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Your search keyword '"Clark, Matthew J."' showing total 3 results
Start Over Author "Clark, Matthew J." Topic transcription factors
3 results on '"Clark, Matthew J."'

1. The Kinesin Gene KIF26B Modulates the Severity of Post-Traumatic Heterotopic Ossification.

Author

Pickering, George A. E., Felix-Ilemhenbhio, Favour, Clark, Matthew J., Kocsy, Klaudia, Simpson, Jonathan, Bellantuono, Ilaria, Gartland, Alison, Wilkinson, Jeremy Mark, Hatzikotoulas, Konstantinos, and Kiss-Toth, Endre

Subjects
HETEROTOPIC ossification, HUMAN stem cells, KINESIN, MESENCHYMAL stem cells, MITOGEN-activated protein kinases, OSTEOCALCIN, PLURIPOTENT stem cells, TRANSCRIPTION factors
Abstract

The formation of pathological bone deposits within soft tissues, termed heterotopic ossification (HO), is common after trauma. However, the severity of HO formation varies substantially between individuals, from relatively isolated small bone islands through to extensive soft tissue replacement by bone giving rise to debilitating symptoms. The aim of this study was to identify novel candidate therapeutic molecular targets for severe HO. We conducted a genome-wide scan in men and women with HO of varying severity following hip replacement for osteoarthritis. HO severity was dichotomized as mild or severe, and association analysis was performed with adjustment for age and sex. We next confirmed expression of the gene encoded by the lead signal in human bone and in primary human mesenchymal stem cells. We then examined the effect of gene knockout in a murine model of osseous trans-differentiation, and finally we explored transcription factor phosphorylation in key pathways perturbed by the gene. Ten independent signals were suggestively associated with HO severity, with KIF26B as the lead. We subsequently confirmed KIF26B expression in human bone and upregulation upon BMP2-induced osteogenic differentiation in primary human mesenchymal stem cells, and also in a rat tendo-Achilles model of post-traumatic HO. CRISPR-Cas9 mediated knockout of Kif26b inhibited BMP2-induced Runx2, Sp7/Osterix, Col1A1, Alp, and Bglap/Osteocalcin expression and mineralized nodule formation in a murine myocyte model of osteogenic trans-differentiation. Finally, KIF26B deficiency inhibited ERK MAP kinase activation during osteogenesis, whilst augmenting p38 and SMAD 1/5/8 phosphorylation. Taken together, these data suggest a role for KIF26B in modulating the severity of post-traumatic HO and provide a potential novel avenue for therapeutic translation. [ABSTRACT FROM AUTHOR]

Published
2022
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2. A molecular quantitative trait locus map for osteoarthritis

Author

Steinberg, Julia, Southam, Lorraine, Roumeliotis, Theodoros I, Clark, Matthew J, Jayasuriya, Raveen L, Swift, Diane, Shah, Karan M, Butterfield, Natalie C, Brooks, Roger A, McCaskie, Andrew W, Bassett, JH Duncan, Williams, Graham R, Choudhary, Jyoti S, Wilkinson, J Mark, and Zeggini, Eleftheria

Subjects
Phenotype, Gene Expression Regulation, Gene Expression Profiling, Osteoarthritis, Quantitative Trait Loci, Humans, Genetic Predisposition to Disease, Transcriptome, 3. Good health, Genome-Wide Association Study, Transcription Factors
Abstract

Osteoarthritis causes pain and functional disability for over 500 million people worldwide. To develop disease-stratifying tools and modifying therapies, we need a better understanding of the molecular basis of the disease in relevant tissue and cell types. Here, we study primary cartilage and synovium from 115 patients with osteoarthritis to construct a deep molecular signature map of the disease. By integrating genetics with transcriptomics and proteomics, we discover molecular trait loci in each tissue type and omics level, identify likely effector genes for osteoarthritis-associated genetic signals and highlight high-value targets for drug development and repurposing. These findings provide insights into disease aetiopathology, and offer translational opportunities in response to the global clinical challenge of osteoarthritis.

3. A molecular quantitative trait locus map for osteoarthritis

Author

Raveen L Jayasuriya, D Swift, Karan M. Shah, Jyoti S. Choudhary, Lorraine Southam, Graham R. Williams, Eleftheria Zeggini, Andrew McCaskie, Theodoros I. Roumeliotis, Julia Steinberg, J. H. Duncan Bassett, Roger A. Brooks, M.J. Clark, J. Mark Wilkinson, Natalie C. Butterfield, Steinberg, Julia [0000-0002-0585-2312], Clark, Matthew J [0000-0003-2152-2257], Shah, Karan M [0000-0001-9909-6409], Butterfield, Natalie C [0000-0002-5209-7508], Bassett, JH Duncan [0000-0003-0817-0082], Williams, Graham R [0000-0002-8555-8219], Choudhary, Jyoti S [0000-0003-0881-5477], Wilkinson, J Mark [0000-0001-5577-3674], Zeggini, Eleftheria [0000-0003-4238-659X], Apollo - University of Cambridge Repository, Clark, Matthew J. [0000-0003-2152-2257], Shah, Karan M. [0000-0001-9909-6409], Butterfield, Natalie C. [0000-0002-5209-7508], Bassett, J. H. Duncan [0000-0003-0817-0082], Williams, Graham R. [0000-0002-8555-8219], Choudhary, Jyoti S. [0000-0003-0881-5477], and Wilkinson, J. Mark [0000-0001-5577-3674]

Subjects
0301 basic medicine, Article, Gene expression profiling, Gene regulation, Genome-wide association studies, Transcriptomics, Science, Quantitative Trait Loci, 631/208/205/2138, General Physics and Astronomy, Genome-wide association study, Computational biology, Osteoarthritis, Disease, Biology, Quantitative trait locus, Proteomics, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 0302 clinical medicine, 631/208/200, medicine, Humans, Genetic Predisposition to Disease, Repurposing, 45/91, 030203 arthritis & rheumatology, Science & Technology, Multidisciplinary, 45, 631/208/212/2019, Gene Expression Profiling, General Chemistry, Omics, medicine.disease, ddc, 3. Good health, Multidisciplinary Sciences, 030104 developmental biology, Phenotype, Drug development, Gene Expression Regulation, Science & Technology - Other Topics, 631/208/191/2018, Transcriptome, Genome-Wide Association Study, Transcription Factors
Abstract

Osteoarthritis causes pain and functional disability for over 500 million people worldwide. To develop disease-stratifying tools and modifying therapies, we need a better understanding of the molecular basis of the disease in relevant tissue and cell types. Here, we study primary cartilage and synovium from 115 patients with osteoarthritis to construct a deep molecular signature map of the disease. By integrating genetics with transcriptomics and proteomics, we discover molecular trait loci in each tissue type and omics level, identify likely effector genes for osteoarthritis-associated genetic signals and highlight high-value targets for drug development and repurposing. These findings provide insights into disease aetiopathology, and offer translational opportunities in response to the global clinical challenge of osteoarthritis., Understanding the molecular effects of disease variants in relevant tissues is essential to understanding and treating disease. Here, the authors discover expression and protein quantitative trait loci in cartilage and synovium from 115 osteoarthritis patients to pinpoint genes of action and potential drug treatments.

Published
2021
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