Absence of the lysophosphatidic acid receptor LPA1 results in abnormal bone development and decreased bone mass

Lysophosphatidic acid (LPA) is a lipid mediator that acts in paracrine systems via interaction with a subset of G protein-coupled receptors (GPCRs). LPA promotes cell growth and differentiation, and has been shown to be implicated in a variety of developmental and pathophysiological processes. At least 6 LPA GPCRs have been identified to date: LPA(1)-LPA(6). Several studies have suggested that local production of LPA by tissues and cells contributes to paracrine regulation, and a complex interplay between LPA and its receptors, LPA(1) and LP/N-4, is believed to be involved in the regulation of bone cell activity. In particular, LPA(1) may activate both osteoblasts and osteoclasts. However, its role has not as yet been examined with regard to the overall status of bone in vivo. We attempted to clarify this role by defining the bone phenotype of LPA(1)((-/-)) mice. These mice demonstrated significant bone defects and low bone mass, indicating that LPA(1) plays an important role in osteogenesis. The LPA(1)((-/-)) mice also presented growth and sternal and costal abnormalities, which highlights the specific roles of LPA(1) during bone development. Microcomputed tomography and histological analysis demonstrated osteoporosis in the trabecular and cortical bone of LPA(1)((-/-)) mice. Finally, bone marrow mesenchymal progenitors from these mice displayed decreased osteoblastic differentiation. These results suggest that LPA(1) strongly influences bone development both qualitatively and quantitatively and that, in vivo, its absence results in decreased osteogenesis with no clear modification of osteoclasis. They open perspectives for a better understanding of the role of the LPA/LPA(1) paracrine pathway in bone pathophysiology. (C) 2011 Elsevier Inc. All rights reserved.