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

Abstract

Lysphosphatidic acid (LPA) is a major natural bioactive lipid mediator whose biological functions affect multiple organs. These include bone as demonstrated by global Lpar1knockout 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 Lpar1 knockout mice (Lpar1-∆Ob) by crossing Lpar1 flox/flox and Osx:Cre + mouse lines. Lpar1-∆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-∆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-∆Ob mouse bone explants. In addition, E11 expression and dendrite formation induced by FGF2 are markedly impaired in both primary Lpar1-∆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.

Expressions and Prognostic Values of LPARs in Human Breast Cancer

“…The manipulation of LPAR1 level or function can change the survival and metastasis ability of BC cells in vivo and in vitro [28] . Some studies have also shown that LPAR1 promoting the metastatic ability of BC [29] . LPAR1 siRNA don't inhibited cancer cell metastasis, but also alters primary tumor size [30] .…”

Current Understanding of Osteoimmunology in Certain Osteoimmune Diseases

“…Lysophosphatidic acid (LPA), a physiologic extracellular lipid, mediate Hippo-YAP signaling to play promising regulatory roles in osteoimmunology around implants via LPA receptors (LPARs) . As for LPAR1, a recent study showed that LPA activated macrophages via LPAR1 and affected immune response in microenvironment (Fransson et al, 2021); LPAR1 was also discovered to mediate the regulation of osteoblast function through downstream YAP signaling (Alioli et al, 2020). Therefore, we suppose that the LPA/LPAR1-YAP axis may have a prospective impact on osteoimmune-mediated osseointegration, but its specific regulatory mechanism needs further clarification.…”

Role of Hippo-YAP Signaling in Osseointegration by Regulating Osteogenesis, Angiogenesis, and Osteoimmunology

“…LPA's unique physiological and pathological roles are revealed to be driven by extracellular signals through particular GPCRs which are called LPA1-6 (Choi et al, 2010). Specifically, the regulation effects of LPA on bone metabolism are mainly mediated by LPA1, LPA3, and LPA4 (Liu et al, 2010;Chen et al, 2019;Wu et al, 2019;Alioli et al, 2020); LPA4 and LPA6 play a facilitating role in developmental angiogenesis and LPA1 and LPA3 are found to mediate LPA/PKD-1-CD36 axis regulating proangiogenic and proarteriogenic reprogramming and de novo arteriogenesis (Ren et al, 2016;Dong et al, 2017;Yasuda et al, 2019); it is also worth noticing that LPA contributes to the formation of macrophages from monocytes in both mice and humans (Ray and Rai, 2017) and promotes LPA1 and LPA3 mediated conversion to foam cells (Chen et al, 2017). Numerous LPA-induced biological effects have been described and those cooperative and antagonistic signaling regulates cell activity in a highly complex manner.…”