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. LPA1 is the most ubiquitous LPA receptor among the six LPA receptor family members (LPA1-6). To better understand the specific role of LPA via its receptor LPA1 in osteoblastic cell lineage we generated osteoblast-specific Lpar1 knockout mice (Lpar1-∆Ob) by crossing Lpar1flox/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.

中文翻译：

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成骨细胞谱系中1型溶血磷脂酸受体的表达可控制骨矿化和骨细胞规格。

溶血磷脂酸（LPA）是一种主要的天然生物活性脂质介体，其生物学功能会影响多个器官。如全球Lpar1基因敲除小鼠（Lpar1-/-）所显示的，这些动物具有骨骼生长缺陷。LPA作用于所有骨骼细胞，包括负责骨骼形成的成骨细胞和破骨细胞（破骨细胞，后者是吸收骨骼的专门细胞）。LPA在骨骼重塑期间显示为潜在的新偶联分子。LPA1是六个LPA受体家族成员（LPA1-6）中最普遍存在的LPA受体。为了更好地了解LPA通过其受体LPA1在成骨细胞谱系中的特定作用，我们通过跨Lpar1flox / flox和Osx：Cre +小鼠品系生成了成骨细胞特异性Lpar1基因敲除小鼠（Lpar1-ΔOb）。Lpar1-ΔOb小鼠不能概括Lpar1-/-小鼠的骨缺损，但显示出骨矿化减少和皮质厚度降低，以及与骨细胞腔区域增加和细胞凋亡相关的骨孔隙率增加。在体外，原代Lpar1-ΔOb和永生化的cl1-Ob-Lpar1-/-成骨细胞显示出碱性磷酸酶的过早表达，与YAP-P核积累减少相关的细胞增殖减少和矿化活性降低。在富含Lpar1-ΔOb小鼠骨外植体的骨细胞级分中，早期（E11）和晚期（DMP1，DKK1，SOST）骨细胞标记物的体外表达降低证明了，成骨细胞的规格明显受损。此外，在原代Lpar1-ΔOb和永生化的cl1-Ob-Lpar1-/-成骨细胞中，FGF2诱导的E11表达和枝晶形成均明显受损。总之，这些结果表明，LPA在通过骨矿化和骨细胞功能控制骨量方面具有新的作用。