ABOVE: A mouse osteocyte visualized with electron microscopy

Exercise helps beef up bones, but exactly how hasn’t been clear. A study published today (December 13) in Cell points to irisin, dubbed the “exercise hormone,” as a messenger between muscle and bone tissue that triggers the process of replacing old or damaged bone cells with new ones. Researchers also found the receptors for irisin, a group of proteins called αV integrins, in fat and bone cells. 

“This is a pretty big discovery because in the past years, nobody has identified the receptor for this particular hormone,” says Jake Chen, a bone biologist at Tufts University who studies irisin but was not involved with this work. 

Irisin is a hormone secreted from muscles during exercise. In animal studies, researchers have found it plays a part in strengthening bones and burning calories.

Previous studies on irisin were...

This new research sought to understand exactly how irisin works in bones, with the ultimate goal of exploiting the knowledge to treat diseases such as osteoporosis.

See “Irisin Redeemed

Earlier studies have shown that low doses of irisin build stronger bones in mice. In this latest study, Spiegelman’s team injected mice with low doses of irisin and observed a boost in the production of sclerostin in mouse osteocytes, one of the major types of bone cells. Sclerostin is a protein that helps break down bone, presumably so that the tissue can be rebuilt. Based on his team’s results, Spiegelman says, he likens irisin to a message from the muscle that gives instructions to bone to begin this process of reconstruction.

To find irisin’s cellular target in bones, the researchers used the hormone itself to fish for the receptor in mouse osteocyte cells. They bound the irisin to the cells and then pulled it out with its attached receptors, which they then identified as primarily integrin αV/β5 using mass spectrometry.

The researchers also used female mice with their ovaries removed to study what happens when the gene for the irisin precursor FNDC5 is knocked out. The ovariectomy model is helpful for observing changes in bone because mice whose ovaries are removed typically experience a loss of bone density, says the study’s first author Hyeonwoo (Chad) Kim, a postdoc who works with Spiegelman. These changes resemble the osteoporosis that occurs in menopausal women who also experience bone loss in response to the changing levels of estrogen, says Kim. 

Curiously, in this case, removing the irisin actually prevented bone loss and the mice did not develop osteoporosis, unlike animals that kept their irisin production, which the researchers say points to the nuanced role of irisin in the bone remodeling process. In the case of osteoporosis, blocking the binding of irisin may lead to a potential therapy, says Kim.

“These results are interesting,” says Chen of the ovariectomy results. They paint a different picture than previous findings in the literature, including results from his own lab, on mice whose ovaries were not removed. These studies showed more clearly positive effects of irisin on bone formation.

Maria Grano, a biologist of the University of Bari in Italy who also studies irisin, has questions about the ovariectomy model, too, and in particular the role of estrogen in the action of irisin on bone. She also notes that integrin αV/β5 may be one of multiple receptors of irisin in other tissues, whose discovery may reveal more about irisin’s function. “This is the beginning of a very interesting story that needs further study,” she says. 

Although irisin’s role in osteoporosis is unclear, its effects on fat burning and bone building in lab experiments have led researchers down the path of attempting to develop the hormone as a therapeutic. “It could be a very important drug if we are able to develop it for people that cannot practice physical exercise,” says Grano. 

Towards that goal of using irisin clinically, Spiegelman and his colleagues are working to engineer a longer-acting irisin, as the hormone has a relatively short half-life at less than one hour in the blood. And Spiegelman also wonders whether irisin may be speaking to other tissues, including the brain and motor nerves, where there might be other opportunities for therapeutic applications. 

“The whole idea of the project, 15 years ago when we started going in this direction, was to perhaps capture some of the benefits of exercise in molecular form,” Spiegelman says. 

See “How Exercise Reprograms the Brain

H. Kim, et al., “Irisin mediates effects on bone and fat viaaV integrin receptors,” Cell, doi:10.1016/j.cell.2018.10.025, 2018.

Clarification (December 13): We changed the subheading of the article to clarify that therapeutics would be geared toward people who are unable to exercise. The Scientist regrets any confusion. 

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