Zebrafish and medaka as models for biomedical research of bone diseases

Lleras-Forero, Laura; Winkler, Christoph; Schulte‐Merker, S.

doi:10.1016/j.ydbio.2019.07.009

Cited by 56 publications

(43 citation statements)

References 222 publications

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“…Small teleost fish, such as zebrafish and medaka, are widely used to model human bone diseases given their unique experimental advantages, as well as genetic and cellular similarities of medaka and human bone. ( 42 ) In the present study, we used live imaging to demonstrate that in medaka, similar to mammals, ( 3 ) osteoclasts are derived from the monocyte/macrophage lineage in RANKL‐induced conditions. Our macrophage depletion data suggest that in medaka no alternative cellular sources exist for osteoclasts, and that the formation of osteoclasts requires a high integrity of the macrophage population.…”

Section: Discussionmentioning

confidence: 96%

“…Small teleost fish, such as zebrafish and medaka, are widely used to model human bone diseases given their unique experimental advantages, as well as genetic and cellular similarities of medaka and human bone. (42) In the present study, we used live imaging Macrophage recruitment and differentiation are impaired in tnfa mutants. (A) WT siblings, heterozygous and homozygous tnfa mutants with rankl:HSE:cfp/ mpeg1:mCherry-F/ctsk:GFP transgenic background were heat-shocked at 9 days postfertilization (dpf) for 2 hours.…”

Section: Discussionmentioning

confidence: 99%

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Macrophages Switch to an Osteo‐Modulatory Profile Upon RANKL Induction in a Medaka (Oryzias latipes) Osteoporosis Model

et al. 2020

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In mammals, osteoclasts differentiate from macrophages in the monocyte lineage. Although many factors driving osteoclast formation are known, the detailed processes underlying precursor recruitment, differentiation, and interaction of macrophages with other cell types involved in bone remodeling are poorly understood. Using live imaging in a transgenic medaka osteoporosis model, where ectopic osteoclasts are induced by RANKL expression, we show that a subset of macrophages is recruited to bone matrix to physically interact with bone-forming osteoblast progenitors. These macrophages subsequently differentiate into cathepsin K-(ctsk-) positive osteoclasts. One day later, other macrophages are recruited to clear dying osteoclasts from resorbed bone by phagocytosis. To better understand the molecular changes underlying these dynamic processes, we performed transcriptome profiling of activated macrophages upon RANKL induction. This revealed an upregulation of several bone-related transcripts. Besides osteoclast markers, we unexpectedly also found expression of osteoblast-promoting signals in activated macrophages, suggesting a possible non-cell autonomous role in osteogenesis. Finally, we show that macrophage differentiation into osteoclasts is dependent on inflammatory signals. Medaka deficient for TNFα or treated with the TNFα-inhibitor pentoxifylline exhibited impaired macrophage recruitment and osteoclast differentiation. These results show the involvement of inflammatory signals and the dynamics of a distinct subset of macrophages during osteoclast formation.

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Section: Discussionmentioning

confidence: 96%

“…Small teleost fish, such as zebrafish and medaka, are widely used to model human bone diseases given their unique experimental advantages, as well as genetic and cellular similarities of medaka and human bone. (42) In the present study, we used live imaging Macrophage recruitment and differentiation are impaired in tnfa mutants. (A) WT siblings, heterozygous and homozygous tnfa mutants with rankl:HSE:cfp/ mpeg1:mCherry-F/ctsk:GFP transgenic background were heat-shocked at 9 days postfertilization (dpf) for 2 hours.…”

Section: Discussionmentioning

confidence: 99%

Macrophages Switch to an Osteo‐Modulatory Profile Upon RANKL Induction in a Medaka (Oryzias latipes) Osteoporosis Model

et al. 2020

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“…Zebrafish and medaka have become popular models for human skeletal disorders (10). Both species are amenable to advanced forward and reversed genetics and genome modification and uniquely suited for live bioimaging, which makes them ideal for bone research.…”

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confidence: 99%

Cxcl9l and Cxcr3.2 regulate recruitment of osteoclast progenitors to bone matrix in a medaka osteoporosis model

Phan

Tan

Liu

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Bone homeostasis requires continuous remodeling of bone matrix to maintain structural integrity. This involves extensive communication between bone-forming osteoblasts and bone-resorbing osteoclasts to orchestrate balanced progenitor cell recruitment and activation. Only a few mediators controlling progenitor activation are known to date and have been targeted for intervention of bone disorders such as osteoporosis. To identify druggable pathways, we generated a medaka (Oryzias latipes) osteoporosis model, where inducible expression of receptor-activator of nuclear factor kappa-Β ligand (Rankl) leads to ectopic formation of osteoclasts and excessive bone resorption, which can be assessed by live imaging. Here we show that upon Rankl induction, osteoblast progenitors up-regulate expression of the chemokine ligand Cxcl9l. Ectopic expression of Cxcl9l recruits mpeg1-positive macrophages to bone matrix and triggers their differentiation into osteoclasts. We also demonstrate that the chemokine receptor Cxcr3.2 is expressed in a distinct subset of macrophages in the aorta-gonad-mesonephros (AGM). Live imaging revealed that upon Rankl induction, Cxcr3.2-positive macrophages get activated, migrate to bone matrix, and differentiate into osteoclasts. Importantly, mutations in cxcr3.2 prevent macrophage recruitment and osteoclast differentiation. Furthermore, Cxcr3.2 inhibition by the chemical antagonists AMG487 and NBI-74330 also reduced osteoclast recruitment and protected bone integrity against osteoporotic insult. Our data identify a mechanism for progenitor recruitment to bone resorption sites and Cxcl9l and Cxcr3.2 as potential druggable regulators of bone homeostasis and osteoporosis.

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“…• Knockout of individual genes can disrupt the functions of neighboring genes (101) (127,128) and advantages over mouse models include acquiring data more rapidly. Zebrafish mutants have been described for several of the 441 genes in this review.…”

Section: Mouse Study Precautionsmentioning

confidence: 99%

High Fidelity of Mouse Models Mimicking Human Genetic Skeletal Disorders

Brommage

Ohlsson

2020

Front. Endocrinol.

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The 2019 International Skeletal Dysplasia Society nosology update lists 441 genes for which mutations result in rare human skeletal disorders. These genes code for enzymes (33%), scaffolding proteins (18%), signal transduction proteins (16%), transcription factors (14%), cilia proteins (8%), extracellular matrix proteins (5%), and membrane transporters (4%). Skeletal disorders include aggrecanopathies, channelopathies, ciliopathies, cohesinopathies, laminopathies, linkeropathies, lysosomal storage diseases, protein-folding and RNA splicing defects, and ribosomopathies. With the goal of evaluating the ability of mouse models to mimic these human genetic skeletal disorders, a PubMed literature search identified 260 genes for which mutant mice were examined for skeletal phenotypes. These mouse models included spontaneous and ENU-induced mutants, global and conditional gene knockouts, and transgenic mice with gene over-expression or specific base-pair substitutions. The human X-linked gene ARSE and small nuclear RNA U4ATAC, a component of the minor spliceosome, do not have mouse homologs. Mouse skeletal phenotypes mimicking human skeletal disorders were observed in 249 of the 260 genes (96%) for which comparisons are possible. A supplemental table in spreadsheet format provides PubMed weblinks to representative publications of mutant mouse skeletal phenotypes. Mutations in 11 mouse genes (Ccn6,

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Zebrafish and medaka as models for biomedical research of bone diseases

Cited by 56 publications

References 222 publications

Macrophages Switch to an Osteo‐Modulatory Profile Upon RANKL Induction in a Medaka (Oryzias latipes) Osteoporosis Model

Macrophages Switch to an Osteo‐Modulatory Profile Upon RANKL Induction in a Medaka (Oryzias latipes) Osteoporosis Model

Cxcl9l and Cxcr3.2 regulate recruitment of osteoclast progenitors to bone matrix in a medaka osteoporosis model

High Fidelity of Mouse Models Mimicking Human Genetic Skeletal Disorders

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