Laura Alejandra Velázquez Villegas, a researcher at the lab of Kristina Schoonjans, has won a fellowship from insurance giant AXA for a research project on osteoporosis.
AXA is a large French multinational insurance firm that engages in global insurance, investment management, and other financial services. AXA also runs the AXA Research Fund, which is “committed to supporting science, contributing to societal progress and encouraging researchers to share their work with the larger public.”
Each year, the Fund offers Fellowships to support research in four fields: Environment, Health, New Tech, and Socio-Economics. With a budget of up to 125.000€ per project, the Fellowships are targeted to scientists within 5 years after receiving their PhD with “proven scientific excellence and high potential for innovation, transformation and dissemination.”
For 2018, the AXA Research Fund focused on women’s health, calling for projects in areas including consumption or behavioral changes and related rising health risks, maternal health, non-communicable diseases, mental diseases, ill health linked to domestic violence, and healthy aging.
One of the awarded candidates is Laura Alejandra Velázquez Villegas, a researcher at the lab of Kristina Schoonjans at EPFL. Velázquez Villegas’s project is titled: “Bile acid mimetics as therapeutics for menopause-induced osteoporosis”. The project will look at the role of the membrane bile acid receptor TGR5, which is a key player in the regulation of bone remodeling. The project will also evaluate synthetic agonists for TGR5 through a pre-clinical study. The long-terms goal is to pharmacological agents for osteoporosis.
"I feel really happy and honored to be granted this fellowship, which will allow me to reach a position of maturity in research and will be the perfect bridge between my postdoctoral training and my goal to become an independent researcher in the metabolic field,” says Velázquez Villegas. “With this grant I will be able to carry out a top-notch project that will contribute not only to a better understanding of bone pathophysiology, but also to the increasing efforts in the prevention and treatment of menopause-induced osteoporosis. In addition, during the development of this proposal I will be able to strengthen my scientific competences, which are a crucial prerequisite for my future career."
Bile acid mimetics as therapeutics for menopause-induced osteoporosis
Bone is an important tissue composed of proteins and minerals that undergoes continuous remodeling to grow, heal and maintain metabolic demand. During the remodeling process, two cell types, known as osteoclasts and osteoblasts, exert concerted and sequential effects on bone resorption and bone formation, respectively. Osteoporosis is the result of an imbalance between osteoblast-dependent bone formation and osteoclast-mediated bone resorption that finally leads to a decreased bone mass and quality. Osteoporosis is a degenerative disease and affects one in three women over the age of 50.
Bile acids are amphipathic molecules produced by the liver from cholesterol and secreted in the intestine upon food intake to increase lipid absorption. These metabolites are also found in the systemic circulation where they can reach every tissue in the body, including the bone, and orchestrate cellular signaling through the activation of dedicated nuclear and membrane receptors. A growing body of evidence shows that bile acids and their cognate nuclear receptor farnesoid x receptor (FXR) regulate skeletal homeostasis through direct effects on osteoblasts and osteoclasts. Indeed, chenodeoxycholic acid (CDCA), one of the main primary bile acids, promotes osteoblast differentiation by activating FXR. In addition to CDCA, lithocholic acid (LCA), a secondary bile acid derived from CDCA, has been reported to induce osteoblast differentiation and mineralization in vitro. In particular, LCA is considered as the most potent endogenous agonist of the membrane bile acid receptor TGR5, indicating that a tight correlation between this receptor and bone remodeling could exist.
TGR5 is a G protein-coupled bile acid receptor that mediates multiple metabolic effects. Its activation by bile acids or synthetic agonists increases energy expenditure in adipose tissue and muscle and reduces body weight in obese mice. It also improves glucose tolerance (through the release of glucagon-like peptide-1 (GLP-1) from enteroendocrine cells) and reduces inflammatory processes. Preliminary data that we obtained in our laboratory confirmed that TGR5 is important to maintain a healthy bone phenotype because genetic deletion of this receptor decreased bone content compared to wild-type mice.
Efficient treatments for osteoporosis without any side effect are currently missing; this is why the search for alternatives is becoming highly relevant. Our project includes a pre-clinical phase to evaluate the use of TGR5 agonists in a mouse model of osteoporosis. If this study is successful it could eventually lead to the development of new pharmacological agents for this disease. The overall goal of this proposal is to elucidate the role of the membrane bile acid receptor TGR5 in the regulation of bone remodeling. The strategy includes the use of a combination of in vitro, in vivo and in silico approaches that, combined, will unveil the role of the bile acid-TGR5 signaling axis in the control of bone homeostasis and evaluate the use of selective TGR5 agonists for the treatment of menopause-induced osteoporosis. In addition, we will use an unbiased systems approach to identify novel biomarkers for this disease.