DS0403 - Exploration des systèmes et organes leur fonctionnement normal et pathologique : physiologie, physiopathologie, vieillissement

Lysophosphatidic acid and bone mass control – LYSBONE

Submission summary

Bone is a complex tissue whose integrity is maintained throughout the life thanks to the continuous process of bone remodeling. This process is controlled by two cell types: osteoclasts, which resorb bone, and osteoblasts, which form new bone. Crosstalk and exchanges between these cells, as well as many signals from the bone environment, control bone remodeling. Partners 1 and 2 of the project were pioneers in demonstrating that the natural bioactive lysophospholipid, lysophosphatidic acid (LPA) is produced in the bone wherein it controls the physiological process of bone growth and the development and progression of certain types of bone diseases such as bone metastases and bone loss induced by estrogen deprivation. LPA activates at least six different G-coupled receptors (LPA1-6). These receptors are expressed in a wide variety of cell types including osteoblasts and osteoclasts. Because LPA appears as a new molecule involved in coupling formation/resorption of bone remodeling, understanding the role of LPA receptors in the physiology and pathophysiology of bone is a major challenge for the development of new therapies.
The project focuses on the role of the type 1 receptor of LPA (LPA1) because it is the most ubiquitous of all LPA receptors in mammals. This choice was also supported because of previous studies published by Partner 1 and Partner 2 on the global knockout mice lpar1 demonstrating the functional involvement of this receptor in both osteoclasts and osteoblasts. The objective of the project is to elucidate the role of LPA via its LPA1 receptor in the acquisition of bone mass during puberty and bone loss in aging (osteoporosis). The project will determine the role of LPA as a new coupling factor of the formation and bone resorption in bone remodeling. The project will also characterize the functional implications of LPA on bone structure and biodynamic parameters. Through the use of Lpar1flox/flox and OSX:GFP-Cre/+ mouse lines the project will develop animal invalidated in Lpar1 specifically in osteoblasts. Also thanks to the GFP-Cre transgene osteoblasts are fluorescent and can be visualized in situ by using fluorescent imaging techniques. By exploiting analyses of microCT, histology, biomechanics, cell biology and fluorescence imaging, the project will define the role of LPA1 receptor in endochondral growth, formation of the skeleton, acquisition of peak bone mass, bone mineralization, bone biodynamic, and intracellular activation pathways in osteoblasts and coupling the activity of osteoblasts and osteoclasts.
The strength of the project results in the development of an original axis of the societal challenge " Santé Bien-être" on the role of a bioactive lysolipid specifically in the bone. The project objectives are supported by state of the art technology and highly complementary partners. In conclusion, the project will define the functions of LPA in bone homeostasis, during puberty and defects in ageing.

Project coordination

Olivier Peyruchaud (Physiopathologie, diagnostic et traitements des maladies osseuses)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

INSERM U823 Institut Albert Bonniot
CPTP UMR 1043 INSERM UMR 1043, Centre de Physiopathologie de Toulouse Purpan
LYOS Physiopathologie, diagnostic et traitements des maladies osseuses

Help of the ANR 275,000 euros
Beginning and duration of the scientific project: September 2015 - 30 Months

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