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

Abstract

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: LPA1–LPA6. 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, LPA1 and LPA4, is believed to be involved in the regulation of bone cell activity. In particular, LPA1may 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 LPA1(−/−) mice. These mice demonstrated significant bone defects and low bone mass, indicating that LPA1 plays an important role in osteogenesis. The LPA1(−/−) mice also presented growth and sternal and costal abnormalities, which highlights the specific roles of LPA1 during bone development. Microcomputed tomography and histological analysis demonstrated osteoporosis in the trabecular and cortical bone of LPA1(−/−) mice. Finally, bone marrow mesenchymal progenitors from these mice displayed decreased osteoblastic differentiation. These results suggest that LPA1 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/LPA1 paracrine pathway in bone pathophysiology.

LPA receptor signaling: pharmacology, physiology, and pathophysiology

“…This is in contrast to Lpar1 Ϫ/Ϫ mice, which display decreased bone mass (176). This suggests that LPA 4 negatively regulates osteogenesis and may counteract LPA 1 -initiated osteogenesis.…”

Lysophosphatidic Acid Receptor Type 1 (LPA1) Plays a Functional Role in Osteoclast Differentiation and Bone Resorption Activity

“…LPA plays a key role during bone development as revealed by a low bone mass phenotype of Lpar1 Ϫ/Ϫ mice associated with a low osteoblastic activity and growth retardation due to inhibition of chondrocyte proliferation, defects in endochondral ossification (28), and increased bone formation in Lpar4 Ϫ/Ϫ animals (33). These reports suggest that LPA 1 and LPA 4 might have opposite functions in osteoblasts during bone development.…”

“…As a consequence, activation of different cell types in bone may underlie the complex mode of action of LPA in bone pathophysiology (18). Lpar1 Ϫ/Ϫ mice have revealed a rich biology and pathophysiology, affecting the brain (19 -23) as well as other organ systems like the lung (24), the intestine (25), cardiovascular system (26), the adipose tissue (27), and bone (28). Lpar2 Ϫ/Ϫ mice do not exhibit an obvious phenotype (29).…”

Lysophosphatidic acid signalling in development

“…Lpar4-null mice exhibit increased volume, number and thickness of bone trabeculae, consistent with a role for LPA 4 in inhibiting osteogenic differentiation. Lpar1-null mice also display significant bone defects, such as low bone mass and osteoporosis, which are likely produced by decreased osteoblastic differentiation from bone marrow mesenchymal progenitors (Gennero et al, 2011). LPA can also induce pleiotropic effects on osteoclast activity and function, acting via LPA 1 , which can elevate intracellular Ca 2+ , activate nuclear factor of activated T cells (NFATc1) and promote their survival, and via an unidentified second Gα 12/13 -coupled LPAR, which can evoke and maintain retraction through reorganization of the actin cytoskeleton (Lapierre et al, 2010).…”