Erika Kague Research Group

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Research in a Nutshell

Osteocytes are the most abundant cells in our skeleton and wield their job as the true maestros of bone remodelling. In the field of Bone Research, they are the superstars in the spotlight. Osteocytes are star-like cells, that resemble neurons, and live buried in the hard bone matrix, dwelling in an environment of challenging access. The elusive nature of their habitat has left us with only a partial understanding of their function. Despite their pivotal role, we still don’t fully understand how osteocytes influence bone diseases. Our research aims to bridge this knowledge gap, shedding light on osteocyte development and function and the molecular mechanisms that govern their role in both bone health and disease.

We are particularly interested on understanding how changes in osteocytes, often regarded as the bone’s mechanostat, could drive the onset of osteoarthritis. This degenerative disease heavily hinges on mechanical loading as a central factor. Osteoarthritis is a chronic condition, without effective treatment, that afflicts 70% of the ageing global population, causing pain. Therefore, our ultimate goal is to translate our findings about osteocytes into viable therapeutic strategies for combating osteoarthritis.

To functionally study osteocytes in bone health and disease, we use zebrafish and osteocyte cell culture. Zebrafish are aquatic model organisms that have osteocytes and develop osteoarthritis in their life course. Zebrafish share about 80% of disease-causing genes with humans, and these genes can be easily mutated using CRISPR. Moreover, they are transparent during a long period of their development allowing to dynamically study how cells are formed and how they interact with other cell types in a living organism.

Our approach to identifying molecular mechanisms of osteocyte function involves the utilization of genomic data from GWAS and transcriptomic data. Currently, our research is centred on exploring the roles of neuronal genes expressed in osteocytes throughout the progression of osteoarthritis. Leveraging the unique advantages of zebrafish, we can untangle the complexities of neuronal innervation in relation to bone and osteocyte function, with spin offs to understand pain in osteoarthritis.

People

Contact

ekague@ed.ac.uk

Key Publications

Medina-Gomez C, Mullin BH, Chesi A, Prijatelj V, Kemp JP, Shochat-Carvalho C, Trajanoska K, Wang C, Joro R, Evans TE, Schraut KE, Li-Gao R, Ahluwalia TS, Zillikens MC, Zhu K, Mook-Kanamori DO, Evans DS, Nethander M, Knol MJ, Thorleifsson G, Prokic I, Zemel B, Broer L, McGuigan FE, van Schoor NM, Reppe S, Pawlak MA, Ralston SH, van der Velde N, Lorentzon M, Stefansson K, Adams HHH, Wilson SG, Ikram MA, Walsh JP, Lakka TA, Gautvik KM, Wilson JF, Orwoll ES, van Duijn CM, Bønnelykke K, Uitterlinden AG, Styrkársdóttir U, Akesson KE, Spector TD, Tobias JH, Ohlsson C, Felix JF, Bisgaard H, Grant SFA, Richards JB, Evans DM, van der Eerden B, van de Peppel J, Ackert-Bicknell C, Karasik D, Kague E*, Rivadeneira F*. Bone mineral density loci specific to the skull portray potential pleiotropic effects on craniosynostosis. Commun Biol. 2023 Jul 4;6(1):691. doi: 10.1038/s42003-023-04869-0. PMID: 37402774; PMCID: PMC10319806. (*co-senior authors)

Kague E, Turci F, Newman E, Yang Y, Brown KR, Aglan MS, Otaify GA, Temtamy SA, Ruiz-Perez VL, Cross S, Royall CP, Witten PE, Hammond CL. 3D assessment of intervertebral disc degeneration in zebrafish identifies changes in bone density that prime disc disease. Bone Res. 2021 Aug 31;9(1):39. doi: 10.1038/s41413-021-00156-y. PMID: 34465741; PMCID: PMC8408153.  

López-Cuevas P, Deane L, Yang Y, Hammond CL, Kague E. Transformed notochordal cells trigger chronic wounds in zebrafish, destabilizing the vertebral column and bone homeostasis. Dis Model Mech. 2021 Mar 1;14(3):dmm047001. doi: 10.1242/dmm.047001. Epub 2021 Mar 19. PMID: 33579726; PMCID: PMC7988777.

Salazar-Silva R, Dantas VLG, Alves LU, Batissoco AC, Oiticica J, Lawrence EA, Kawafi A, Yang Y, Nicastro FS, Novaes BC, Hammond C, Kague E*, Mingroni-Netto RC*. NCOA3 identified as a new candidate to explain autosomal dominant progressive hearing loss. Hum Mol Genet. 2021 Jan 21;29(22):3691-3705. doi: 10.1093/hmg/ddaa240. Erratum in: Hum Mol Genet. 2021 Dec 17;31(1):156. PMID: 33326993; PMCID: PMC7823111. (*co-senior authors)

Lawrence EA*, Kague E*, Aggleton JA, Harniman RL, Roddy KA, Hammond CL. The mechanical impact of col11a2 loss on joints; col11a2 mutant zebrafish show changes to joint development and function, which leads to early-onset osteoarthritis. Philos Trans R Soc Lond B Biol Sci. 2018 Sep 24;373(1759):20170335. doi: 10.1098/rstb.2017.0335. PMID: 30249781; PMCID: PMC6158203. (*co-first authors)

Collaborations

• Professor Stuart Ralston, University of Edinburgh
• Dr David Karasik, Bar Llan University and Harvard
• Professor Fernando Rivadeneira, Erasmus University, Rotterdam
• Dr Carolina Medina-Gomez, Erasmus University, Rotterdam
• Professor Eleftheria Zeggini, Helmholtz, Munich
• Dr John Kemp, University of Queensland
• Professor Eckhard Witten, Gent University
• Dr Stefaan Verbruggen, Queen Mary
• Dr Himadri Goupta, Queen Mary
• Dr Elis Newman, Queen Mary
• Dr Kathleen Curran, University College Dublin
• Dr Stephen Cross, University of Bristol
• Dr Francesco Turci, University of Bristol

Partners and Funders

Versus Arthritis (Career Development Award)