Exploring the musculoskeletal role of FGF19 and its potential as an anti-osteosarcopenia agent – BonTon19

Old age, sedentary lifestyle and illness are often associated with osteosarcopenia (osteopenia and sarcopenia), which significantly increases morbidity and negatively impacts the quality of life and degree of independence of the affected person. Osteopenia is defined as a moderate loss of bone mass, without the overt clinical manifestations of osteoporosis. Sarcopenia is defined as a loss in muscle mass and strength, often linked to aging and cancer, which can be accelerated by malnutrition and a sedentary lifestyle, leading to a deterioration in muscle strength and physical performance. It is well established that healthy bones and muscles are necessary to maintain a good level of physical exercise and, conversely, that exercise will maintain a functional musculo-skeletal system. In frail, sick and/or aged individuals, osteopenia and sarcopenia establish a vicious circle, where one condition triggers and accelerates the development of the other. At present there are no efficient treatments to slow down or to break that vicious circle.

The hormone FGF19, produced by the intestine, has a strong influence on metabolism. Our teams have demonstrated that this enterokine additionally regulates muscle mass and strength in healthy mice and in mice with sarcopenia (Benoit et al, Nature Medicine, 2017). Furthermore, pilot experiments in our groups showed that FGF19 receptors are expressed in bone and that treatment with FGF19 can protect the degradation of the skeleton observed in an animal model of osteoporosis. Our consortium now wants to better understand the relationship between FGF19 and bone physiology and to explore whether FGF19 can efficiently counter both osteopenia and sarcopenia.

The proposed project will reveal the role and mode of action of FGF19 in the skeleton of mice of different ages and in various models of osteosarcopenia, where bone and muscle loss is induced by aging, hind limb disuse (mimicking bed rest), or ovarian hormone deficiency (mimicking post-menopausal osteosarcopenia). After identifying the target cells in bones, signalling pathways will be analysed through in vitro studies. To understand the roles played by FGF19 in bone versus muscle in the context of the observed skeletal phenotypes, we will investigate tissue-specific genetic knock-out models of ß-klotho, an essential co-receptor for FGF19 action.

Beyond mechanistic studies in animal models, we also want to translate these findings to humans. By determining the levels of FGF19 in the serum in different cohorts of osteosarcopenic individuals, we aim to better understand how FGF19 levels correlate with bone and/or muscle biology and function in humans. To do so, we will assess FGF19 concentrations in cosmonauts and immobilized subjects, as well as in a large cohort of elderly patients, and we will probe possible links with several parameters of their musculoskeletal physiopathology.

Our results will lead to a better understanding of the role of FGF19 in bone and muscle physiology and should contribute to the development of new therapeutic strategies to prevent or to fight osteosarcopenia, based on FGF19 or FGF19 analogs.