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条件性敲除骨组织中的 E11/Podoplanin 可预防去卵巢诱导的破骨细胞形成和活性增加。

Conditional deletion of E11/Podoplanin in bone protects against ovariectomy-induced increases in osteoclast formation and activity.

机构信息

School of Applied Sciences, Edinburgh Napier University, Sighthill Campus, Edinburgh, U.K.

Comparative Biomedical Sciences, Royal Veterinary College, Royal College Street, London, U.K.

出版信息

Biosci Rep. 2020 Jan 31;40(1). doi: 10.1042/BSR20190329.


DOI:10.1042/BSR20190329
PMID:31894854
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6954370/
Abstract

E11/Podoplanin (Pdpn) is implicated in early osteocytogenesis and the formation of osteocyte dendrites. This dendritic network is critical for bone modelling/remodelling, through the production of receptor activator of nuclear factor κ B (RANK)-ligand (RANKL). Despite this, the role of Pdpn in the control of bone remodelling is yet to be established in vivo. Here we utilised bone-specific Pdpn conditional knockout mice (cKO) to examine the role of Pdpn in the bone loss associated with ovariectomy (OVX). MicroCT revealed that Pdpn deletion had no significant effect on OVX-induced changes in trabecular microarchitecture. Significant differences between genotypes were observed in the trabecular pattern factor (P<0.01) and structure model index (P<0.01). Phalloidin staining of F-actin revealed OVX to induce alterations in osteocyte morphology in both wild-type (WT) and cKO mice. Histological analysis revealed an expected significant increase in osteoclast number in WT mice (P<0.01, compared with sham). However, cKO mice were protected against such increases in osteoclast number. Consistent with this, serum levels of the bone resorption marker Ctx were significantly increased in WT mice following OVX (P<0.05), but were unmodified by OVX in cKO mice. Gene expression of the bone remodelling markers Rank, Rankl, Opg and Sost were unaffected by Pdpn deletion. Together, our data suggest that an intact osteocyte dendritic network is required for sustaining osteoclast formation and activity in the oestrogen-depleted state, through mechanisms potentially independent of RANKL expression. This work will enable a greater understanding of the role of osteocytes in bone loss induced by oestrogen deprivation.

摘要

E11/ Podoplanin (Pdpn) 参与早期成骨细胞分化和骨细胞树突的形成。这个树突网络对于骨改建/重塑至关重要,因为它可以产生核因子 κ B 受体激活剂(RANK)配体(RANKL)。尽管如此,Pdpn 在控制骨重塑中的作用在体内尚未得到证实。在这里,我们利用骨特异性 Pdpn 条件性敲除小鼠(cKO)来研究 Pdpn 在卵巢切除(OVX)相关骨丢失中的作用。MicroCT 显示,Pdpn 缺失对 OVX 引起的小梁微结构变化没有显著影响。基因型之间在小梁图案因子(P<0.01)和结构模型指数(P<0.01)方面存在显著差异。鬼笔环肽标记的 F-肌动蛋白显示 OVX 诱导了 WT 和 cKO 小鼠骨细胞形态的改变。组织学分析显示 WT 小鼠破骨细胞数量显著增加(P<0.01,与假手术组相比)。然而,cKO 小鼠对破骨细胞数量的增加有保护作用。与此一致的是,WT 小鼠 OVX 后血清中骨吸收标志物 Ctx 的水平显著升高(P<0.05),但 cKO 小鼠的 OVX 对其没有影响。骨重塑标志物 Rank、Rankl、Opg 和 Sost 的基因表达不受 Pdpn 缺失的影响。综上所述,我们的数据表明,在雌激素缺乏状态下,完整的骨细胞树突网络对于维持破骨细胞的形成和活性是必需的,其机制可能独立于 RANKL 表达。这项工作将使我们更好地理解骨细胞在雌激素缺乏诱导的骨丢失中的作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26e8/6954370/d51cf0cee6d6/bsr-40-bsr20190329-g5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26e8/6954370/61debdfe74a4/bsr-40-bsr20190329-g1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26e8/6954370/512a28cd84b8/bsr-40-bsr20190329-g2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26e8/6954370/64fad11925a0/bsr-40-bsr20190329-g3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26e8/6954370/a19121d13627/bsr-40-bsr20190329-g4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26e8/6954370/d51cf0cee6d6/bsr-40-bsr20190329-g5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26e8/6954370/61debdfe74a4/bsr-40-bsr20190329-g1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26e8/6954370/512a28cd84b8/bsr-40-bsr20190329-g2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26e8/6954370/64fad11925a0/bsr-40-bsr20190329-g3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26e8/6954370/a19121d13627/bsr-40-bsr20190329-g4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26e8/6954370/d51cf0cee6d6/bsr-40-bsr20190329-g5.jpg

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本文引用的文献

[1]
Effects of estrogen status in osteocyte autophagy and its relation to osteocyte viability in alveolar process of ovariectomized rats.

Biomed Pharmacother. 2017-12-27

[2]
Hypomorphic conditional deletion of E11/Podoplanin reveals a role in osteocyte dendrite elongation.

J Cell Physiol. 2017-11

[3]
E11/Podoplanin Protein Stabilization Through Inhibition of the Proteasome Promotes Osteocyte Differentiation in Murine in Vitro Models.

J Cell Physiol. 2016-6

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Ablation of p38α MAPK Signaling in Osteoblast Lineage Cells Protects Mice From Bone Loss Induced by Estrogen Deficiency.

Endocrinology. 2015-12

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J Clin Pharmacol. 2014-2

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Endocr Rev. 2013-10

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