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Bou-Gharios Lab Connective tissue Research

Connective tissues are dynamic systems, which are continually undergoing change throughout development and adult life. Connective tissue homeostasis (the biosynthesis, deposition, degradation and turnover of extracellular matrix (ECM) molecules is controlled primarily by the major resident cell type and their response to stimuli such as specific cytokines, growth factors and surface receptors. The turnover of ECM is regulated by proteolytic enzymes including metzencin family of enzymes as well as others. We are using transgenic approaches to investigate the disregulation of the ECM synthesis and breakdown that lead to two opposing pathology aspects of connective tissue.

A PhD bumper year, great graduation day for three of my students: Kirsty, Amy and Stephanie.

PhDs are available

We are interested in understanding the normal physiology and pathologies of connective tissue diseases such as:

Lab members and collaborators

1. Fibrosis In fibrosis the repair process that include synthesis and deposition of new components is impaired for unknown reason. Accompanying these events is a fundamental genetic reprogramming of the resident cell, the fibroblast, resulting in differential expression of matrix modulating enzymes such as metalloproteinases (MMPs) and their inhibitors (TIMPs). We are investigating the effect of genes that influence that balance in gain and loss of function experiments to readdress the balance by using collagen type I specific enhancer to target cells that produce collagen in fibrotic conditions.

Lung (top) and Skin (bottom) sections from double transgenic mouse expressing inducible cre recombinase driven by fibroblast-specific col1a2 promoter (left, green) in dual florescent protein reporter mouse where red (right) is control

2. Osteoarthritis (OA) is the most common form of joint disease, characterized by the progressive destruction of articular cartilage matrix. We are taking a broad view at the whole synovial joints from synovium, ligaments, bone and articular cartilage to investigate what goes wrong in OA and way to ameliorate the disease.

Mohammad Al Hashmi, a PhD student with photomicrographs of in vivo bioluminescence of Acan expression in knee and hip corresponding to LacZ staining in the same joints

We identified several aggrecan (Acan) enhancers that express in different chondrocytes and at different time during development and adulthood ( Li et al Sci Rep. 2018 Jan 17;8(1):950). we are using these enhancers to understand how cartilage is made and what goes wrong in OA.

Contact details: Email ggharios@liverpool.ac.uk, Phone +447949061, Address Institute of Ageing and Chronic Disease, William Henry Duncan Building, 6 West Derby Street, Liverpool L7 8TX, UK

Time for celebration, Christmas 2019

Institute Collaboration We are fortunate to have great colleagues at the Institute who are happy to collaborate. We are using non-invasive loading technique to induce OA with Dr Blandine Poulet (Curr Rheumatol Rep (2016) 18: 40). We are taking advantage of the LRP1 uptake of degradative enzymes with Dr Kazu Yamamoto (Arthritis Rheumatol 69(6), 1246-1256, 2017) to ameliorate the disease progression. We are also collaborating with Professor Rob Van't Hof and Dr Anna Daroszewska on syndican in cartilage and bone. We are helping the National centre of Alkaptonuria in Liverpool (https://www.akusociety.org/aku-national-aku-centre.html) to generate new inducible mouse model to understand osteoarthritis-induced ochronosis (Ann Rheum Dis 2014; 73(1): 284-289). We are collaborating with Dr Simon Tew to investigate RNA stability in an in vivo models. Our most adventurous collaboration is with Dr Kris D' Aout using biplanar X-Ray based gait analysis for minimally invasive detection of knee osteoarthritis in mouse models. Last but not least. I am grateful to my clinical colleagues Lisa Spencer, Rob Moots and Sonya Craig for keeping my interest in pulmonary disease focused on the patients.

External Collaborators Checco Ramirez ( Mount Sinai, NY), Andy Pitsillides (Professor of Skeletal Dynamics, The Royal Veterinary College, UCL), Dr Sarah De Val (Ludwig Institute for Cancer Research, University of Oxford), David Abraham (Professor of Cell and Molecular Biology, UCL- Royal Free Campus), Professor David Young and Dr Louise Reynard (Newcastle University), Dr Andrew Leask and Dr Cheryle Seguin (University of Western Ontario, Canada). We recently obtained funding from the Sasakawa foundation to explore collaboration with colleagues in Japan and our first visit was to Kanazawa and Okayama where we had great talks about strengthening our ties (see photos below)

Collaborative visit to Kanazawa University Dec 2019
Visiting colleagues in Okayama University Dec 2019

Career progression of individuals from my lab: Ian M LI, my first student in Liverpool, finished his PhD and joined a post-doctoral training program at Harvard. Amy Horwell and Kirsty Johnston joined AstraZeneca, Caroline Cotton defended her PhD and became a registrar at Aintree Hospital, Stephanie Frost is a Post-doc at QMC, London. Ioannis Kanakis, a post-doc was scooped by my colleagues at the Institute. Dr Ooi went back to Japan to head a research group.

Recent Peer reviewed papers:

Hughes JH, Liu K, Plagge A, Wilson PJM, Sutherland H, Norman BP, Hughes AT, Keenan CM, Milan AM, Sakai T, Ranganath LR, Gallagher JA, Bou-Gharios G. Conditional targeting in mice reveals that hepatic homogentisate 1,2-dioxygenase activity is essential in reducing circulating homogentisic acid and for effective therapy in the genetic disease alkaptonuria. Hum Mol Genet. 2019 Oct 10. pii:ddz234.

Hughes JH, Wilson PJM, Sutherland H, Judd S, Hughes AT, Milan AM, Jarvis JC, Bou-Gharios G, Ranganath LR, Gallagher JA. Dietary restriction of tyrosine and phenylalanine lowers tyrosinaemia associated with nitisinone therapy of alkaptonuria. J Inherit Metab Dis. 2019 Sep 10. ahead of print] PubMed PMID: 31503358.

Scavenius C, Poulsen EC, Thøgersen IB, Roebuck M, Frostick S, Bou-Gharios G, Yamamoto K, Deleuran B, Enghild JJ. Matrix-degrading protease ADAMTS-5 cleaves inter-α-inhibitor and release active heavy chain 2 in synovial fluids from arthritic patients. J Biol Chem. 2019 Sep 4. pii: jbc.RA119.008844.

Davison AS, Strittmatter N, Sutherland H, Hughes AT, Hughes J, Bou-Gharios G, Milan AM, Goodwin RJA, Ranganath LR, Gallagher JA. Assessing the effect of nitisinone induced hypertyrosinaemia on monoamine neurotransmitters in brain tissue from a murine model of alkaptonuria using mass spectrometry imaging. Metabolomics. 2019 Apr 29;15(5):68.

Neal A, Nornes S, Payne S, Wallace MD, Fritzsche M, Louphrasitthiphol P, Wilkinson RN, Chouliaras KM, Liu K, Plant K, Sholapurkar R, Ratnayaka I, Herzog W, Bond G, Chico T, Bou-Gharios G, De Val S. Venous identity requires BMP signalling through ALK3. Nat Commun. 2019 Jan 28;10(1):453

Kanakis I, Liu K, Poulet B, Javaheri B, van 't Hof RJ, Pitsillides AA, Bou-Gharios G. Targeted Inhibition of Aggrecanases Prevents Articular Cartilage Degradation and Augments Bone Mass in the STR/Ort Mouse Model of Spontaneous Osteoarthritis. Arthritis Rheumatol. 2018 Oct 31. doi: 10.1002/art.40765.

Li IMH, Liu K, Neal A, Clegg PD, De Val S, Bou-Gharios G. Differential tissue specific, temporal and spatial expression patterns of the Aggrecan gene is modulated by independent enhancer elements. Sci Rep. 2018 Jan 17;8(1):950.

Frost SL, Liu K, Li IMH, Poulet B, Comerford E, De Val S, Bou-Gharios G. Multiple enhancer regions govern the transcription of CCN2 during embryonic development. J Cell Commun Signal. 2018 Mar;12(1):231-243

Chiang IK, Fritzsche M, Pichol-Thievend C, Neal A, Holmes K, Lagendijk A, Overman J, D'Angelo D, Omini A, Hermkens D, Lesieur E, Fossat N, Radziewic T, Liu K, Ratnayaka I, Corada M, Bou-Gharios G, Tam PPL, Carroll J, Dejana E, Schulte-Merker S, Hogan BM, Beltrame M, De Val S, Francois M. Correction: SoxF factors induce Notch1 expression via direct transcriptional regulation during early arterial development. Development doi: 10.1242/dev.146241. Development. 2017 Oct 15;144(20):3847-3848..

Li IMH, Horwell AL, Chu G, de Crombrugghe B, Bou-Gharios G. Characterization of Mesenchymal-Fibroblast Cells Using the Col1a2 Promoter/Enhancer. Methods Mol Biol. 2017;1627:139-161.

Miller B, Spevak L, Lukashova L, Javaheri B, Pitsillides AA, Boskey A, Bou-Gharios G, Carriero A. Altered Bone Mechanics, Architecture and Composition in the Skeleton of TIMP-3-Deficient Mice. Calcif Tissue Int. 2017 Jun;100(6):631-640. doi: 10.1007/s00223-017-0248-5.

Poulet B, Liu K, Plumb D, Vo P, Shah M, Staines K, Sampson A, Nakamura H, Nagase H, Carriero A, Shefelbine S, Pitsillides AA, Bou-Gharios G. Overexpression of TIMP-3 in Chondrocytes Produces Transient Reduction in Growth Plate Length but Permanently Reduces Adult Bone Quality and Quantity. PLoS One. 2016 Dec 21;11(12):e0167971.

Sacilotto N, Chouliaras KM, Nikitenko LL, Lu YW, Fritzsche M, Wallace MD, Nornes S, García-Moreno F, Payne S, Bridges E, Liu K, Biggs D, Ratnayaka I, Herbert SP, Molnár Z, Harris AL, Davies B, Bond GL, Bou-Gharios G, Schwarz JJ, De Val S. MEF2 transcription factors are key regulators of sprouting angiogenesis. Genes Dev. 2016 Oct 15;30(20):2297-2309.

Javaheri B, Hopkinson M, Poulet B, Pollard AS, Shefelbine SJ, Chang YM, Francis-West P, Bou-Gharios G, Pitsillides AA. Deficiency and Also Transgenic. Overexpression of Timp-3 Both Lead to Compromised Bone Mass and Architecture In Vivo. PLoS One. 2016 Aug 12;11(8):e0159657.

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skin showing fibroblasts in green