Expression of the type 1 lysophosphatidic acid receptor in osteoblastic cell lineage controls both bone mineralization and osteocyte specification

Lysphosphatidic acid (LPA) is a major natural bioactive lipid mediator whose biological functions affect multiple organs. These include bone as demonstrated by global Lpar1-knockout mice (Lpar1(-/-)) which present a bone growth defect. LPA acts on all bone cells including osteoblasts, that are responsible for bone formation, and osteoclasts, which are specialized cells that resorb bone. LPA appears as a potential new coupling molecule during bone remodeling. LPA(1) is the most ubiquitous LPA receptor among the six LPA receptor family members (LPA(1-6)). To better understand the specific role of LPA via its receptor LPA(1) in osteoblastic cell lineage we generated osteoblast-specific Lpar(1) knockout mice (Lpar1-Delta Ob) by crossing Lpar1(flox/flox) and Osx:Cre(+) mouse lines. Lpar1-Delta Ob mice do not recapitulate the bone defects of Lpar1(-/-) mice but revealed reduced bone mineralization and decreased cortical thickness, as well as increased bone porosity associated with an augmentation in the lacunae areas of osteocyte and their apoptotic yield. In vitro, primary Lpar1-Delta Ob and immortalized cl1-Ob-Lpar1(-/-) osteoblasts revealed a remarkable premature expression of alkaline phosphatase, reduced cell proliferation associated with decreased YAP-P nuclear accumulation, and reduced mineralization activity. Osteocyte specification is markedly impaired as demonstrated by reduced expression of early (E11) and late (DMP1, DKK1, SOST) osteocyte markers ex vivo in enriched osteocytic fractions of Lpar1-Delta Ob mouse bone explants. In addition, E11 expression and dendrite formation induced by FGF2 are markedly impaired in both primary Lpar1-Delta Ob and immortalized cl1-Ob-Lpar1(-/-) osteoblasts. Taken together these results suggest a new role for LPA in bone mass control via bone mineralization and osteocyte function.