João M.A. Santos (1), Vincent Laizé (1), Paulo J. Gavaia (1,2), Natércia Conceição (1,2), M. Leonor Cancela (1,2)
Affiliation(s):
1. Centre Of Marine Sciences, University Of Algarve, 8005-139 Faro, Portugal;
2. Faculty of Medicine and Biomedical Sciences, University of Algarve, 8005-139 Faro, Portugal
Ectopic calcification refers to the pathological accumulation of calcium ions in soft tissues and is often the result of a dysregulated action or disrupted function of proteins involved in extracellular matrix mineralization. Animal models of ectopic calcification are critical to better understand disease pathophysiology and allow the screening of novel therapeutics. While the mouse has been so far the model of choice to investigate the mechanisms of ectopic calcification and has greatly contributed to the better understanding of calcium-associated pathologies, it as some issues that have prevented further advances in this field. In this regard, loss-of-function mouse models often show exacerbated phenotypes and die prematurely, limiting our understanding of the pathological mechanisms.
The zebrafish (Danio rerio) has recently emerged as a valuable model to gain new insights into the mechanisms underlying the development of human diseases as it brings intrinsic advantages over mammalian models. In this work, we aimed at providing evidences that zebrafish is a relevant model to study pathologies associated with ectopical tissue calcification and outlined the current tools, techniques, and zebrafish mutants available to study the mechanisms of ectopic calcification and calcium-associated pathologies. We found that the major mechanisms underlying calcium metabolism are conserved from fish to human and gathered information on zebrafish mutants that share phenotypic similarities with human mineralization disorders. We also provide a list of zebrafish mutants – whose phenotype has yet to be described in the literature – that could be established as new models of ectopic mineralization.
Beside the large provision of mutant lines and the possibility to easily create new models through reverse genetic-based approaches, transgenic lines and water-soluble calcium specific dyes have accelerated the use of zebrafish for in vivo real-time detection of calcium deposition, and drugs that can induce and rescue pathological calcifications disorders have been successfully studied/discovered in zebrafish. As for mammalian systems, zebrafish ectopic calcification models develop calcium deposits in most soft tissues, and the detection of sites of ectopic calcification could be detected early during development (as soon as 2 dpf, the period at which zebrafish larvae hatch).
This study was funded by the European Joint Programme on Rare Diseases (EJP-RD) and the Portuguese Foundation for Science and Technology (FCT) through project PhysPath-KS (grant EJPRD/0004/2020) and by FCT through founds (grants UIDB/04326/2020, UIDP/04326/2020 and LA/P/0101/2020).