FGFR3 is a positive regulator of osteoblast expansion and differentiation during zebrafish skull vault development

Dambroise, Emilie; Ktorza, Ivan; Brombin, Alessandro; Abdessalem, Ghaith; Edouard, Joanne; Luka, Marine; Fiedler, Imke A.K.; Binder, Olivia; Pellé, Olivier; Patton, E. Elizabeth; Busse, Björn; Ménager, Mickaël; Sohm, Frédéric; Legeai-Mallet, Laurence

doi:10.1101/2020.01.02.884155

Cited by 4 publications

(3 citation statements)

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“…These results do not rule out a role of Fgfr3 activation in the regulation of osteoprogenitor proliferation (Kawane et al, 2018). Our data on Fgfr3's likely role in OB homeostasis during calvarium development are in line with our recent studies of an fgfr3 loss-of-function zebrafish model, which displayed major cranial vault defects, and impairments in immature OB expansion and differentiation (Dambroise et al, 2020).…”

Section: Discussionsupporting

confidence: 65%

AnFgfr3-activating mutation in immature murine osteoblasts affects the appendicular and craniofacial skeleton

Duplan

Dambroise

Estibals

et al. 2021

Disease Models &Amp; Mechanisms

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Achondroplasia (ACH), the most common form of dwarfism is caused by a missense mutation in the gene coding for fibroblast growth factor receptor 3 (FGFR3). The resulting increase in FGFR3 signaling perturbs the proliferation and differentiation of chondrocytes (CCs), alters the process of endochondral ossification and thus reduces bone elongation. Increased FGFR3 signaling in osteoblasts (OBs) might also contribute to bone anomalies in ACH. In the present study of a mouse model of ACH, we sought to determine whether or not FGFR3 overactivation in OBs leads to bone modifications. The model carries an Fgfr3 activating mutation (Fgfr3Y367C/+) that accurately mimics ACH; we targeted the mutation to either immature OBs and hypertrophic CCs or to mature OBs by using the Osx-cre and collagen 1α1 (2.3kb-Col1α1)-cre mouse strains, respectively. We observed that Fgfr3 activation in immature OBs and hypertrophic CCs (Osx-Fgfr3) not only perturbed the hypertrophic cells of the growth plate (thus affecting long bone growth) but also led to osteopenia and low cortical thickness in long bones in adult (3-month-old) mice but not in growing (3-week-old) mice. Importantly, craniofacial membranous bone defects were present in the adult mice. In contrast, activation of Fgfr3 in mature OBs (Col1-Fgfr3) had very limited effects on skeletal shape, size and micro-architecture. In vitro, we observed that Fgfr3 activation in immature OBs was associated with low mineralization activity. In conclusion, immature OBs appears to be affected by Fgfr3 overactivation, which might contribute to the bone modifications observed in ACH independently of CCs.

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Section: Discussionsupporting

confidence: 65%

AnFgfr3-activating mutation in immature murine osteoblasts affects the appendicular and craniofacial skeleton

Duplan

Dambroise

Estibals

et al. 2021

Disease Models &Amp; Mechanisms

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“…Atp6v1c1 crispants revealed a similar phenotype of that observed for zic1 mutants, including abnormal osteoblast condensation at the ossification centres, abnormal bone growth and ectopic sutures. Recent findings demonstrate that craniosynostosis genes (i.e., FGFR3 70 and TWIST1 and TCF12 71 ) when mutated in zebrafish might lead to abnormal calvaria bone growth and suture mis-patterning, reinforcing a potential role of ATP6V1C1 in craniosynostosis. ATP6V1C1 is a subunit of the V-ATPase complex, which regulates pH by pumping cytosolic protons into intracellular organelles 72 and has an essential function in osteoclast mediated bone resorption 57 .…”

Section: Discussionmentioning

confidence: 99%

Genome Wide Association Metanalysis Of Skull Bone Mineral Density Identifies Loci Relevant For Osteoporosis And Craniosynostosis

Medina‐Gomez

Mullin

Chesi

et al. 2021

Preprint

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Skull bone mineral density (SK-BMD) provides a suitable trait for the discovery of genes important to bone biology in general, and particularly for identifying components unique to intramembranous ossification, which cannot be captured at other skeletal sites. We assessed genetic determinants of SK-BMD in 43,800 individuals, identifying 59 genome-wide significant loci (4 novel), explaining 12.5% of its variance. Pathway and enrichment analyses of the association signals resulted in clustering within gene-sets involved in regulating the development of the skeleton; overexpressed in the musculoskeletal system; and enriched in enhancer and transcribed regions in osteoblasts. From the four novel loci (mapping to ZIC1, PRKAR1A, ATP6V1C1, GLRX3), two (ZIC1 and PRKAR1A) have previously been related to craniofacial developmental defects. Functional validation of skull development in zebrafish revealed abnormal cranial bone initiation that culminated in ectopic sutures and reduced BMD in mutated zic1 and atp6v1c1 fish and asymmetric bone growth and elevated BMD in mutated prkar1a fish. We confirmed a role of ZIC1 loss-of-function in suture patterning and discovered ATP6V1C1 gene associated with suture development. In light of the evidence presented suggesting that SK-BMD is genetically related to craniofacial abnormalities, our study opens new avenues to the understanding of the pathophysiology of craniofacial defects and towards the effective pharmacological treatment of bone diseases.

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“…Radiographs and µCT are commonly applied in adults, permitting longitudinal studies and post-mortem BMD (cortical bone density) calculations, respectively (286,319). Higher-resolution µCTs (< 5µm voxel size), used to study osteocyte lacunar parameters (number, orientation and shape) (287,294,314,319), are therefore suitable to investigate the effect of osteoporosis genes in the 3D organization of osteocytes. The superficial position of the skulls, fins, and scales also permit the acquisition of in vivo and longitudinal images using transgenic lines, making them attractive systems for drug screens (315), and studies of skeletal development, regeneration (fin amputation, scale plucking, and skull trephination) and bone fragility (fin and scale fractures) (321)(322)(323)(324)(325).…”

Section: Zebrafish As Animal Model For Functional Studies Of Candidate Loci In Skeletal Diseasesmentioning

confidence: 99%

Perspective of the GEMSTONE Consortium on Current and Future Approaches to Functional Validation for Skeletal Genetic Disease Using Cellular, Molecular and Animal-Modeling Techniques

Rauner¹,

Foessl

Formosa

et al. 2021

Front. Endocrinol.

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The availability of large human datasets for genome-wide association studies (GWAS) and the advancement of sequencing technologies have boosted the identification of genetic variants in complex and rare diseases in the skeletal field. Yet, interpreting results from human association studies remains a challenge. To bridge the gap between genetic association and causality, a systematic functional investigation is necessary. Multiple unknowns exist for putative causal genes, including cellular localization of the molecular function. Intermediate traits (“endophenotypes”), e.g. molecular quantitative trait loci (molQTLs), are needed to identify mechanisms of underlying associations. Furthermore, index variants often reside in non-coding regions of the genome, therefore challenging for interpretation. Knowledge of non-coding variance (e.g. ncRNAs), repetitive sequences, and regulatory interactions between enhancers and their target genes is central for understanding causal genes in skeletal conditions. Animal models with deep skeletal phenotyping and cell culture models have already facilitated fine mapping of some association signals, elucidated gene mechanisms, and revealed disease-relevant biology. However, to accelerate research towards bridging the current gap between association and causality in skeletal diseases, alternative in vivo platforms need to be used and developed in parallel with the current -omics and traditional in vivo resources. Therefore, we argue that as a field we need to establish resource-sharing standards to collectively address complex research questions. These standards will promote data integration from various -omics technologies and functional dissection of human complex traits. In this mission statement, we review the current available resources and as a group propose a consensus to facilitate resource sharing using existing and future resources. Such coordination efforts will maximize the acquisition of knowledge from different approaches and thus reduce redundancy and duplication of resources. These measures will help to understand the pathogenesis of osteoporosis and other skeletal diseases towards defining new and more efficient therapeutic targets.

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FGFR3 is a positive regulator of osteoblast expansion and differentiation during zebrafish skull vault development

Cited by 4 publications

References 59 publications

AnFgfr3-activating mutation in immature murine osteoblasts affects the appendicular and craniofacial skeleton

AnFgfr3-activating mutation in immature murine osteoblasts affects the appendicular and craniofacial skeleton

Genome Wide Association Metanalysis Of Skull Bone Mineral Density Identifies Loci Relevant For Osteoporosis And Craniosynostosis

Perspective of the GEMSTONE Consortium on Current and Future Approaches to Functional Validation for Skeletal Genetic Disease Using Cellular, Molecular and Animal-Modeling Techniques

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