Zebrafish as an Emerging Model for Osteoporosis: A Primary Testing Platform for Screening New Osteo-Active Compounds

Bergen, Dylan J. M.; Kague, Érika; Hammond, Chrissy L.

doi:10.3389/fendo.2019.00006

Cited by 117 publications

(104 citation statements)

References 168 publications

(126 reference statements)

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“…Such pathologies cannot easily be modeled with knockout strategies in the mouse and due to the complex anatomical nature of many skeletal disorders, often cannot be modeled in vitro even when allele‐specific cell lines are constructed. A large number of skeletal disease models have been identified in zebrafish, and this number is steadily increasing.…”

Section: Geneticsmentioning

confidence: 99%

Zebrafish: An Emerging Model for Orthopedic Research

Busse

Galloway

Gray

et al. 2019

Journal Orthopaedic Research

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Advances in next-generation sequencing have transformed our ability to identify genetic variants associated with clinical disorders of the musculoskeletal system. However, the means to functionally validate and analyze the physiological repercussions of genetic variation have lagged behind the rate of genetic discovery. The zebrafish provides an efficient model to leverage genetic analysis in an in vivo context. Its utility for orthopedic research is becoming evident in regard to both candidate gene validation as well as therapeutic discovery in tissues such as bone, tendon, muscle, and cartilage. With the development of new genetic and analytical tools to better assay aspects of skeletal tissue morphology, mineralization, composition, and biomechanics, researchers are emboldened to systematically approach how the skeleton develops and to identify the root causes, and potential treatments, of skeletal disease.

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Section: Geneticsmentioning

confidence: 99%

Zebrafish: An Emerging Model for Orthopedic Research

Busse

Galloway

Gray

et al. 2019

Journal Orthopaedic Research

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“…Skeletal genetic defects have been typically studied in two animal models, i.e., mouse [reviewed by Maynard et al ( 187 )] and zebrafish [reviewed by Bergen et al ( 188 )]. Expectedly, CRISPR/Cas9 gene editing in these mouse and zebrafish models of human skeletal disease has swiftly evolved as comprehensively reviewed, by Wu et al ( 189 ).…”

Section: Current Progress In Gene Editing For Monogenic and Complex Bmentioning

confidence: 99%

Genomic Medicine: Lessons Learned From Monogenic and Complex Bone Disorders

Trajanoska

Rivadeneira

2020

Front. Endocrinol.

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Current genetic studies of monogenic and complex bone diseases have broadened our understanding of disease pathophysiology, highlighting the need for medical interventions and treatments tailored to the characteristics of patients. As genomic research progresses, novel insights into the molecular mechanisms are starting to provide support to clinical decision-making; now offering ample opportunities for disease screening, diagnosis, prognosis and treatment. Drug targets holding mechanisms with genetic support are more likely to be successful. Therefore, implementing genetic information to the drug development process and a molecular redefinition of skeletal disease can help overcoming current shortcomings in pharmaceutical research, including failed attempts and appalling costs. This review summarizes the achievements of genetic studies in the bone field and their application to clinical care, illustrating the imminent advent of the genomic medicine era.

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“…We also examined Smad9 protein expression in the developing zebrafish skeleton (38) at 6 and 7 days post fertilization (dpf) (Fig. 3A).…”

Section: Smad9 Expression In Zebrafish Skeletal Tissuementioning

confidence: 99%

A Rare Mutation in SMAD9 Associated With High Bone Mass Identifies the SMAD-Dependent BMP Signaling Pathway as a Potential Anabolic Target for Osteoporosis

Gregson

Bergen

Leo

et al. 2019

Journal of Bone and Mineral Research

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Novel anabolic drug targets are needed to treat osteoporosis. Having established a large national cohort with unexplained high bone mass (HBM), we aimed to identify a novel monogenic cause of HBM and provide insight into a regulatory pathway potentially amenable to therapeutic intervention. We investigated a pedigree with unexplained HBM in whom previous sequencing had excluded known causes of monogenic HBM. Whole exome sequencing identified a rare (minor allele frequency 0.0023), highly evolutionarily conserved missense mutation in SMAD9 (c.65T>C, p.Leu22Pro) segregating with HBM in this autosomal dominant family. The same mutation was identified in another two unrelated individuals both with HBM. In silico protein modeling predicts the mutation severely disrupts the MH1 DNA‐binding domain of SMAD9. Affected individuals have bone mineral density (BMD) Z‐scores +3 to +5, mandible enlargement, a broad frame, torus palatinus/mandibularis, pes planus, increased shoe size, and a tendency to sink when swimming. Peripheral quantitative computed tomography (pQCT) measurement demonstrates increased trabecular volumetric BMD and increased cortical thickness conferring greater predicted bone strength; bone turnover markers are low/normal. Notably, fractures and nerve compression are not found. Both genome‐wide and gene‐based association testing involving estimated BMD measured at the heel in 362,924 white British subjects from the UK Biobank Study showed strong associations with SMAD9 (PGWAS = 6 × 10−16; PGENE = 8 × 10−17). Furthermore, we found Smad9 to be highly expressed in both murine cortical bone–derived osteocytes and skeletal elements of zebrafish larvae. Our findings support SMAD9 as a novel HBM gene and a potential novel osteoanabolic target for osteoporosis therapeutics. SMAD9 is thought to inhibit bone morphogenetic protein (BMP)‐dependent target gene transcription to reduce osteoblast activity. Thus, we hypothesize SMAD9 c.65T>C is a loss‐of‐function mutation reducing BMP inhibition. Lowering SMAD9 as a potential novel anabolic mechanism for osteoporosis therapeutics warrants further investigation. © 2019 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.

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Zebrafish as an Emerging Model for Osteoporosis: A Primary Testing Platform for Screening New Osteo-Active Compounds

Cited by 117 publications

References 168 publications

Zebrafish: An Emerging Model for Orthopedic Research

Zebrafish: An Emerging Model for Orthopedic Research

Genomic Medicine: Lessons Learned From Monogenic and Complex Bone Disorders

A Rare Mutation in SMAD9 Associated With High Bone Mass Identifies the SMAD-Dependent BMP Signaling Pathway as a Potential Anabolic Target for Osteoporosis

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