Receptor for IRISIN — the exercise-induced hormone, has now been identified

One might consider the topic for today’s gene-environment interactions a bit unusual: “exercise” in this case is “the environment”, and the response to this environmental signal is “the genes” in the signaling pathways that aid in bone formation and burning of adipose tissue.

Physical activity has been shown to benefit several metabolic disorders (e.g. obesity, diabetes, and fatty liver disease). Earlier studies suggest that exercise might prevent age-related bone loss. Loss of bone mass with age has significant socioeconomic and medical implications, because of heightened susceptibility to fractures. Osteopenia — and the more serious disorder osteoporosis — impair mobility, increase comorbidities, reduce quality of life, and can even shorten lifespan.

Evidence that an exercise program can prevent bone loss is somewhat controversial, in part because different types of physical activity affect the skeleton at distinct sites in different ways. Sclerostin (a local modulator of bone remodeling) is produced almost exclusively by osteocytes (bone cells that are formed when an osteoblast becomes embedded in the matrix that it has secreted) — which might be considered the ‘‘command and control’’ cells of the bone-remodeling unit. Osteocytes arise from mature osteoblasts (cells that secrete the matrix for bone formation), are imbedded in the cortical matrix, and comprise nearly 90% of the cellular composition of bone; therefore, osteocytes are thought to be transducers of mechanical signals arising from physical activity.

In turn, osteocytes — through an elaborate network of canaliculi — communicate with both osteoblasts and osteoclasts (cells that break down bone and are responsible for bone resorption), thereby regulating bone remodeling (under tight control). Emerging evidence suggests that osteocytes can also directly resorb bone during periods of excessive calcium demand, or after ovariectomy (removal of ovaries); therefore, osteocytes have become a prime target for treating osteoporosis with parathyroid hormone (PTH) and/or monoclonal anti-sclerostin antibodies. Anti-sclerostin antibodies increase bone mass dramatically in humans, but may also have cardiovascular side-effects that could limit their use in clinical practice.

Authors [see attached paper] demonstrate that IRISIN functions by binding to a subset of aV-integrin receptors to promote osteocyte survival and sclerostin secretion. Biophysical studies identified interacting surfaces between irisin and aV/b5 integrin. Chemical inhibition of the aV integrins blocks signaling and inhibits irisin’s function in osteocytes and adipocytes (fat cells). Irisin increases both osteocyte survival and production of sclerostin. Moreover, genetic deletion of the Fndc5 gene (encoding irisin) in C57BL/6 mice results in complete resistance — at the trabecular and cortical compartments — to bone loss caused by ovariectomy. Thus, these data identify the functioning receptor for irisin. These findings should facilitate future studies of irisin as a possible treatment for bone loss, as well as perhaps other tissues that respond to physical activity.


Cell 2o18; 175: 1756–1768

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