Candidate pleiotropic genes participating in the regulation of the musculoskeletal system’s homeostasis

Osteosarcopenia is a recently described widespread and age-related syndrome, which combines features of both osteoporosis and sarcopenia. Genome-Wide Association study (GWAS) reveals new candidate genes associated with total body lean mass (TB-LM) and bone mineral density (BMD) and complex diseases, such as osteoporosis and sarcopenia. Novel musculoskeletal genes discovered by GWAS require experimental validations to bridge the gap between in-silico discoveries and the mechanisms through which these genes function.

In this study, we aim to validate genes identified by GWAS and find novel genes participating in homeostasis regulation of the musculoskeletal system, using a zebrafish model. We performed preliminary expression screening for genes emerging from GWAS for BMD and TB-LM, first by Real-Time PCR for RNA in larvae at different stages and then for bone, muscle, and fins tissues from adult fish. We then selected relevant candidate genes for mutagenesis by CRISPR-Cas9 technology and generation of stable zebrafish mutant lines. Our preliminary analysis showed potential for pleiotropy of the genes ctnnb1, hdac1, and myoc. Mutant lines of these genes will allow phenotypic and functional characterization by histology, immunohistochemistry, and micro-CT techniques.

Identifying novel regulators of bone and muscle interactions would promote a better understanding of osteosarcopenia pathophysiology and could potentially find new therapeutic targets or re-purpose existing drugs for this syndrome.