Department of Biochemistry and Molecular Biology Virginia Commonwealth University, Richmond, VA, USA.
Department of Cell, Developmental, and Integrative Biology, USA; Comprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, AL, USA.
Prostaglandins Other Lipid Mediat. 2022 Feb;158:106605. doi: 10.1016/j.prostaglandins.2021.106605. Epub 2021 Dec 16.
Bone modeling can be modulated by lipid signals such as arachidonic acid (AA) and its cyclooxygenase 2 (COX2) metabolite, prostaglandin E (PGE), which are recognized mediators of optimal bone formation. Hydrolysis of AA from membrane glycerophospholipids is catalyzed by phospholipases A (PLAs). We reported that mice deficient in the Ca- independent PLAbeta (iPLAβ), encoded by Pla2g6, exhibit a low bone phenotype, but the cause for this remains to be identified. Here, we examined the mechanistic and molecular roles of iPLAβ in bone formation using bone marrow stromal cells and calvarial osteoblasts from WT and iPLAβ-deficient mice, and the MC3T3-E1 osteoblast precursor cell line. Our data reveal that transcription of osteogenic factors (Bmp2, Alpl, and Runx2) and osteogenesis are decreased with iPLAβ-deficiency. These outcomes are corroborated and recapitulated in WT cells treated with a selective inhibitor of iPLA β (10 μM S-BEL), and rescued in iPLAβ-deficient cells by additions of 10 μM PGE. Further, under osteogenic conditions we find that PGE production is through iPLAβ activity and that this leads to induction of Runx2 and iPLAβ transcription. These findings reveal a strong link between osteogenesis and iPLAβ-derived lipids and raise the intriguing possibility that iPLAβ-derived PGE participates in osteogenesis and in the regulation of Runx2 and also iPLAβ.
骨形成可以通过脂质信号（如花生四烯酸（AA）及其环氧化酶 2（COX2）代谢物前列腺素 E（PGE））进行调节，这些信号被认为是最佳骨形成的介质。AA 从膜甘油磷脂中的水解由磷脂酶 A（PLAs）催化。我们报道了 Ca 独立的 PLAβ（由 Pla2g6 编码）缺乏的小鼠表现出低骨表型，但原因仍有待确定。在这里，我们使用 WT 和 iPLAβ 缺陷型小鼠的骨髓基质细胞和颅盖骨成骨细胞以及 MC3T3-E1 成骨前体细胞系，研究了 iPLAβ 在骨形成中的机制和分子作用。我们的数据表明，成骨因子（Bmp2、Alpl 和 Runx2）的转录和骨形成减少与 iPLAβ 缺陷有关。这些结果在 WT 细胞中用 iPLAβ 的选择性抑制剂（10 μM S-BEL）处理得到证实和再现，并在 iPLAβ 缺陷型细胞中通过添加 10 μM PGE 得到挽救。此外，在成骨条件下，我们发现 PGE 的产生是通过 iPLAβ 活性，这导致 Runx2 和 iPLAβ 转录的诱导。这些发现揭示了骨形成与 iPLAβ 衍生脂质之间的紧密联系，并提出了一个有趣的可能性，即 iPLAβ 衍生的 PGE 参与骨形成和 Runx2 以及 iPLAβ 的调节。
