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Notochord vacuoles absorb compressive bone growth during zebrafish spine formation.

ABSTRACT: The vertebral column or spine assembles around the notochord rod which contains a core made of large vacuolated cells. Each vacuolated cell possesses a single ?uid-?lled vacuole, and loss or fragmentation of these vacuoles in zebrafish leads to spine kinking. Here, we identified a mutation in the kinase gene dstyk that causes fragmentation of notochord vacuoles and a severe congenital scoliosis-like phenotype in zebrafish. Live imaging revealed that Dstyk regulates fusion of membranes with the vacuole. We find that localized disruption of notochord vacuoles causes vertebral malformation and curving of the spine axis at those sites. Accordingly, in dstyk mutants the spine curves increasingly over time as vertebral bone formation compresses the notochord asymmetrically, causing vertebral malformations and kinking of the axis. Together, our data show that notochord vacuoles function as a hydrostatic scaffold that guides symmetrical growth of vertebrae and spine formation.

SUBMITTER: Bagwell J

PROVIDER: S-EPMC7012607 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Notochord vacuoles absorb compressive bone growth during zebrafish spine formation.

Bagwell Jennifer J Norman James J Ellis Kathryn K Peskin Brianna B Hwang James J Ge Xiaoyan X Nguyen Stacy V SV McMenamin Sarah K SK Stainier Didier Yr DY Bagnat Michel M

eLife 20200129

The vertebral column or spine assembles around the notochord rod which contains a core made of large vacuolated cells. Each vacuolated cell possesses a single ﬂuid-ﬁlled vacuole, and loss or fragmentation of these vacuoles in zebrafish leads to spine kinking. Here, we identified a mutation in the kinase gene <i>dstyk</i> that causes fragmentation of notochord vacuoles and a severe congenital scoliosis-like phenotype in zebrafish. Live imaging revealed that Dstyk regulates fusion of membranes wit ...[more]

PMID: 31995030

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Project description:Background contextPseudarthrosis following spinal fusion remains problematic despite modern surgical and grafting techniques. In surgical spinal fusion, new bone forms via intramembranous and endochondral ossification, with endochondral ossification occurring in the hypoxic zones of the fusion bed. During bone development and fracture healing, the key cellular mediator of endochondral ossification is the hypertrophic chondrocyte given its ability to function in hypoxia and induce neovascularization and ossification. We therefore hypothesize that hypertrophic chondrocytes may be an effective bone graft alternative.PurposeSpinal fusion procedures have increased substantially; yet 5% to 35% of all spinal fusions may result in pseudoarthrosis. Pseudoarthrosis may occur because of implant failure, infection, or biological failure, among other reasons. Advances in surgical techniques and bone grafting have improved fusion; however pseudarthrosis rates remain unacceptably high. Thus, the goal of this study is to investigate hypertrophic chondrocytes as a potential biological graft alternative.MethodsUsing a validated murine fracture model, hypertrophic chondrocytes were harvested from fracture calluses and transplanted into the posterolateral spines of identical mice. New bone formation was assessed by X-ray, microcomputed tomography (μCT), and in vivo fluorescent imaging. Results were compared against a standard iliac crest bone graft and a sham surgery control group. Funding for this work was provided by the Department of Orthopaedics and Rehabilitation, the OREF (Grant #16-150), and The Caitlin Lovejoy Fund.ResultsRadiography, μCT, and in vivo fluorescent imaging demonstrated that hypertrophic chondrocytes promoted bone formation at rates equivalent to iliac crest autograft. Additionally, μCT analysis demonstrated similar fusion rates in a subset of mice from the iliac crest and hypertrophic chondrocyte groups.ConclusionsThis proof-of-concept study indicates that hypertrophic chondrocytes can promote bone formation comparable to iliac crest bone graft. These findings provide the foundation for future studies to investigate the potential therapeutic use of hypertrophic chondrocytes in spinal fusion.

Dataset Information

Notochord vacuoles absorb compressive bone growth during zebrafish spine formation.

Publications

Notochord vacuoles absorb compressive bone growth during zebrafish spine formation.

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