Osteoporosis is a degenerative disease where the bone density and quality are reduce. This disease is associated with substantial pain and disability leading to devastating long term physical and psychological consequences. In Europe, the total osteoporosis economic burden was estimate at 30.7 billion euros in 2010, and is expect to reach 76.7 billion in 2050, base on changes in demography.
Osteoporosis is highly prevalent and actually affects one in three women over the age of 50. Over the next 50 years, the number of hip fracture is expect to more than double meaning that the prevalence of osteoporosis will continue to rise and become a significant burden on health-care systems and life quality, especially in women.
The oestrogen deficiency
Sterols (fat-like compounds that occur naturally in plants, animals, or fungi and exert multiple physiological roles in the cells); so are major actors of bone remodeling processes. Among these sterols, oestrogen inhibits osteoclast formation (“differentiation”), therefore preventing bone resorption. It means that oestrogen deficiency; hence like the one observe during the menopause; so can promote an accelerate bone turnover rate increasing the risk to develop osteoporosis.
Bile acids are small metabolic molecules that are produce in the liver from another famous “sterol,” cholesterol. They are the main constituents of bile. After someone eats, bile acids are secrete into the intestinal lumen; so to participate in the absorption of dietary lipids by emulsifying them. During enterohepatic recirculation (their way back from the intestine to the liver); so bile acids spill over in the systemic circulation and can reach every tissue in our body including the bone.
In addition to their lipid emulsifying function, bile acids are now consider versatile signaling molecules that can activate dedicate receptors and induce cellular responses. A growing body of evidence shows that bile acids regulate skeletal homeostasis through direct effects on osteoblasts and osteoclasts. In particular, when add to osteoblast cell cultures some bile acid species are able to activate them and to promote bone mineralization.
Candidates for future drugs
If these results are confirm in animals, these molecules could be good candidates for future drugs to treat osteoporosis. As an AXA grante post-doctoral researcher at the School of Life Sciences of EPFL (Ecole Polytechnique Fédérale de Lausanne), my goal is to contribute, together with my research team, to the elucidation of the role of one of the main bile acid-signaling mediators in bone remodeling, the cell-surface receptor TGR5.
In vitro, they will explore the role of TGR5 in osteoblast and osteoclast cell models. In vivo, they will test the efficacy of synthetic bile acid mimetics intend to activate TGR5 for the treatment of menopause; so induce osteoporosis using mice whose ovaries have been remove to mimic the menopause conditions. In silico, they will apply bioinformatic tools to identify novel biomarkersl so that could be use for the prevention or early detection of this disease.
Our hope is that by comparing the genetic and metabolic profile of a mice population; so exhibiting a predisposition to develop osteoporosis with a normal population; so they will identify an impairment of some enzymes or metabolites relate to bile acid metabolism or function. With this innovative investigation approach; so they will contribute to a better understanding of the development of this pathology; also to the increasing efforts for its prevention and treatment.