ISCRM Researchers Identify Gene With Dual Influence on Bone and Muscle Development

We know just by living that our bones and muscles are connected. When we flex our muscles, our bones move with them, while our bones hold our bodies together. We also know that strong bones and muscles are essential for daily functioning and injury prevention.

Our bones and muscles can be connected in other ways too. After we are born, bone and muscle grow in mass until we reach the age of about 30, and then decline in concert. As we age, sarcopenia, a condition of muscle weakness and loss of muscle mass, often occurs in people suffering from osteoporosis, a disease of bone fragility. This condition, known as osteosarcopenia, is known as a hazardous duet because muscle weakness increases risk of falling, which can lead to fractures in already fragile osteoporotic bones.

But the mechanisms that explain how bone and muscle are coupled are still not fully understood. Now, a new study from the Musculoskeletal Systems Biology Lab (MSBL) led by ISCRM faculty member Ronald Young Kwon, PhD, points to a protein-coding gene that seems to play a dual role in bone and muscle development.

The paper appears in the journal PLoS Genetics. The lead authors of the study include Claire Watson, PhD, a former acting instructor in the MSBL, Joyce Tang, MS, a current Research Scientist in the lab, and Maria Rojas, BA, a former ISCRM REU Fellow and postbac trainee in the MSBL. Other contributors include Björn Busse, PhD at the University Medical Center Hamburg-Eppendorf, Lisa Maves, PhD, an investigator with appointments at UW and Seattle Children’s, and Yi-Hsiang Hsu, MD, ScD, a statistical geneticist affiliated with Harvard Medical School.

Advantages of Zebrafish as a Research Model

In their investigation, the researchers set out to better understand how humans inherit bone and muscle mass. The team was interested in how genetic variants (sequences of DNA that differ between individuals) influence bone- and muscle-related traits. Previous studies had pinpointed a region in chromosome 7 harboring genetic variants that seemed to influence such traits in children. However, how they exerted dual influence on bone and muscle was not known. To study these questions, the team turned to zebrafish, a species that shares 70% of its genes with humans.

Zebrafish have several advantages over mice and other commonly used animal models. First, zebrafish are easy to genetically manipulate and develop rapidly, which reduces the amount of time before effects of genetic mutations become apparent. Second, the effects of mutations are easier to see because zebrafish embryos grow outside the body.

The ability to rapidly create mutations aided Kwon and his team in their search for a gene in the aforementioned region on chromosome 7 that might underlie the region’s influence on bone- and muscle-related traits. Genetic analysis performed with MicroCT imaging and CRISPR-based gene editing technology led them to a gene known as wnt16.

“We knew wnt16 was important for bone, however there was no known role for wnt16 in muscle development,” says Kwon. “So we didn’t suspect it at first. But when we started to investigate how this gene was working, we realized it has a critical role in muscle and bone development.”

Rapid Screening Methods Lead to a Discovery

The findings from the team indicate that wnt16 acts as a sort-of signal splitter rendering its expression into dual effects on bone and muscle. Specifically, Wnt16 is secreted in parallel in two different cell populations adjacent to developing muscle and bone, where it guides the shape and size of each tissue. Moreover, rapid genetic screening methods developed by the team helped the researchers establish that among the different genes in the chromosome region, only wnt16 was necessary for both bone and muscle mass – further evidence that in humans, genetic variants act through WNT16 to influence bone and muscle health. “We think this helps explain why these bone- and muscle-related traits can be inherited together,” says Kwon.

“This discovery advances our understanding of how bone and muscle are coupled in development,” says Kwon. “Moreover, because WNT16 is actively being explored as a target for osteoporosis therapy, we can now also ask whether it may be targeted to treat muscle simultaneously.”

Kwon adds that the findings also help to further validate zebrafish as a model for studying bone biology in humans. “While a role for Wnt16 in bone was known from studies in mice, prior studies could not explain the effects that genetic variants near this gene have on both bone and muscle . The attributes of zebrafish played a key role in helping us to uncover its dual role in bone and muscle development. For us, that’s one of the exciting outcomes from this study.”