Ezh2 骨髓细胞条件敲除小鼠模型中骨吸收减少,The FASEB Journal

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Ezh2 骨髓细胞条件敲除小鼠模型中骨吸收减少
The FASEB Journal ( IF 4.4 ) Pub Date : 2023-06-05 , DOI: 10.1096/fj.202201673rr
Perry C Caviness _{1,

2} , Dongzheng Gai ₃ , Oxana P Lazarenko _{1,

2} , Michael L Blackburn _{1,

2} , Fenghuang Zhan ₃ , Jin-Ran Chen _{1,

2}

Affiliation

源自造血干细胞的破骨细胞控制骨吸收。识别可以表观遗传调节破骨细胞生成的新分子对于开发治疗骨质疏松症和其他与骨退化相关的疾病以及促进健康骨形成的新疗法非常重要。zeste 同源物 2 (Ezh2)（一种组蛋白赖氨酸甲基转移酶）的多梳组 (PcG) 蛋白增强子与许多细胞过程的表观遗传调控相关，但其在骨细胞发育和稳态中的参与尚不清楚。^{在这里，LysM-Cre 小鼠与 Ezh2 flox/flox}小鼠杂交，以删除骨髓细胞谱系成熟巨噬细胞中的 Ezh2。有条件敲除Ezh2(CKO) 骨髓细胞系中的雄性和雌性小鼠在出生后的前 6 个月内骨骼生长显着增加。对于雌性小鼠，在一对染色体中Ezh2缺失的小鼠（f/f Cre ⁺；CKO）中观察到最佳骨量。对于雄性小鼠，仅从一条染色体 (f/− Cre ⁺ ) 中删除Ezh2后发现最佳骨量，并且 f/− Cre ⁺和 CKO 雄性小鼠之间的骨表型没有差异。除了骨表型的性别差异外，Ezh2与对照小鼠相比，CKO 小鼠骨髓中的巨噬细胞 (CD11b+) 显着减少，并且成熟的成骨细胞和骨形成生物标志物 (P1NP、骨钙素) 显着增加。从骨组织中裂解的蛋白质的炎症阵列显示，与对照组相比，Ezh2的缺失降低了雄性和雌性小鼠的炎症环境。出乎意料的是，Ezh2 的骨髓细胞缺失也增加了骨骼中成熟成骨细胞的数量。Ezh2的缺失还导致破骨细胞抑制基因IRF8、MafB和Arg1的基因表达增加由于抑制性 H3K27me3 表观遗传标记的存在减少。这些发现表明，操纵 Ezh2 表达可能是对抗骨质疏松症或关节炎等骨吸收疾病的可行策略。

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Decreased bone resorption in Ezh2 myeloid cell conditional knockout mouse model

Osteoclasts derived from hematopoietic stem cells control bone resorption. Identifying novel molecules that can epigenetically regulate osteoclastogenesis is important for developing novel treatments for osteoporosis and other disorders associated with bone deterioration and promoting healthy bone formation. The polycomb group (PcG) protein enhancer of zeste homolog 2 (Ezh2), a histone lysine methyltransferase, is associated with epigenetic regulation of numerous cellular processes, but its involvement in bone cell development and homeostasis is not yet clear. Here, LysM-Cre mice were crossed with Ezh2^flox/flox mice to delete Ezh2 in myeloid cell lineage mature macrophages. Conditional knockout of Ezh2 (CKO) in myeloid cell line resulted in significant increases in postnatal bone growth in the first 6 months of life for both male and female mice. For female mice, optimal bone mass was seen for mice with Ezh2 deleted in both chromosomes in a pair (f/f Cre⁺; CKO). For male mice, optimal bone mass was found after deletion of Ezh2 from just one chromosome (f/− Cre⁺) with no difference in bone phenotype between f/− Cre⁺ and CKO male mice. In addition to the gender-specific difference in bone phenotype, Ezh2 CKO mice had significantly less macrophages (CD11b+) present in the bone marrow compared with control mice as well as significantly more mature osteoblasts and bone formation biomarkers present (P1NP, osteocalcin). Inflammatory array for protein lysed from bone tissue revealed deletion of Ezh2 decreased inflammatory milieu in both male and female mice compared with controls. Unexpectedly, myeloid cell deletion of Ezh2 also increased the number of mature osteoblast present in the bone. Deletion of Ezh2 also led to an increase in gene expression of osteoclast-suppressive genes IRF8, MafB, and Arg1 due to a decrease in the presence of the suppressive H3K27me3 epigenetic mark. These findings suggest that manipulation of Ezh2 expression may be a viable strategy to combat bone resorptive disorders such as osteoporosis or arthritis.

更新日期：2023-06-06

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