Utilizing CRISPR-Cas13d-knockdown in zebrafish to study a rare monogenic bone fragility syndrome

Three blue-stained fish larvae are shown in side view against a white background, highlighting their eyes and internal structures. The specimens are arranged in three horizontal rows, each displaying a slightly different orientation.

Osteoporosis is a multifactorial disease with a strong genetic component. Pathogenic variants in the SGMS2 gene cause a rare form of primary osteoporosis, “Calvarial doughnut lesions with bone fragility” (CDL). Since the mechanisms by which disrupted SGMS2 lead to skeletal fragility are still largely unknown, we set out to explore the gene’s function in a zebrafish model. Zebrafish has two orthologs of the human SGMS2 gene, sgms2a and sgms2b.

A graphical abstract

First, we studied expression profiles of both sgms2a and sgms2b genes in a wild-type zebrafish at different developmental stages. Second, we made both genes non-functional during the early days of development and analyzed the outcome. We discovered that both genes are expressed in muscle and skeletal tissue during early development and sgms2a gene is only expressed in calvarial bone cells during the juvenile stage. We also observed that when sgms2 genes are non-functional, zebrafish embryos develop defectively and present with deformed notochord and craniofacial structures.

Our findings from zebrafish studies provide new information on the SGMS2 gene’s function and its role in early musculoskeletal development. The obtained zebrafish model may prove helpful in understanding the disease mechanisms in SGMS2-related osteoporosis (CDL) and in discovering new therapies for osteoporosis.

Original article:
Utilizing CRISPR-Cas13d-knockdown in zebrafish to study a rare monogenic bone fragility syndrome. 
Määttä K, Chen YC, Pihlström S, Mäkitie RE, Dambroise E, Legeai-Mallet L, Panula P, Mäkitie O, Pekkinen M. Journal of Bone and Mineral Research. 2025.

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