Aged G Protein-Coupled Receptor Kinase 3 (Grk3)-Deficient Mice Exhibit Enhanced Osteoclastogenesis and Develop Bone Lesions Analogous to Human Paget's Disease of Bone.
Aged G Protein-Coupled Receptor Kinase 3 (Grk3)-Deficient Mice Exhibit Enhanced Osteoclastogenesis and Develop Bone Lesions Analogous to Human Paget's Disease of Bone.
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骨佩吉特病（PDB）是一种代谢性骨病，其特征在于破骨细胞功能失调，导致骨重建的局灶性异常。它会导致疼痛、骨折和骨骼畸形。G蛋白偶联受体激酶3（GRK3）是G蛋白偶联受体（GPCR）信号转导的重要负调节因子。已知GRK3调节成骨细胞和前成骨细胞中的GPCR功能，但其在破骨细胞中的调节功能尚未明确。在这里，我们报告说，Grk3的表达增加破骨细胞分化过程中，在人类和小鼠的原代细胞和建立的细胞系。我们还表明，缺乏Grk 3的老年小鼠出现与人PDB和其他佩吉特病小鼠模型中所见相似的骨病变。我们发现，Grk3表达的缺陷增强体外破骨细胞生成和体内造血破骨细胞前体的增殖，但不影响破骨细胞介导的骨吸收功能或细胞衰老途径。值得注意的是，我们还观察到与年龄和性别匹配的健康对照相比，PDB患者外周血单核细胞中Grk3表达降低。我们的数据表明GRK3与破骨细胞分化的调节相关，并且它可能与PDB和与破骨细胞活化相关的其他代谢性骨疾病的发病机制相关。
Paget’s Disease of Bone (PDB) is a metabolic bone disease that is characterized by dysregulated osteoclast function leading to focal abnormalities of bone remodeling. It can lead to pain, fracture, and bone deformity. G protein-coupled receptor kinase 3 (GRK3) is an important negative regulator of G protein-coupled receptor (GPCR) signaling. GRK3 is known to regulate GPCR function in osteoblasts and preosteoblasts, but its regulatory function in osteoclasts is not well defined. Here, we report that Grk3 expression increases during osteoclast differentiation in both human and mouse primary cells and established cell lines. We also show that aged mice deficient in Grk3 develop bone lesions similar to those seen in human PDB and other Paget’s Disease mouse models. We show that a deficiency in Grk3 expression enhances osteoclastogenesis in vitro and proliferation of hematopoietic osteoclast precursors in vivo but does not affect the osteoclast-mediated bone resorption function or cellular senescence pathway. Notably, we also observe decreased Grk3 expression in peripheral blood mononuclear cells of patients with PDB compared with age- and gender-matched healthy controls. Our data suggest that GRK3 has relevance to the regulation of osteoclast differentiation and that it may have relevance to the pathogenesis of PDB and other metabolic bone diseases associated with osteoclast activation.
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DOI：
10.1186/1745-7580-4-5
发表时间：
2008-04-29
期刊：
Immunome research
影响因子：
--
作者：
Lattin JE;Schroder K;Su AI;Walker JR;Zhang J;Wiltshire T;Saijo K;Glass CK;Hume DA;Kellie S;Sweet MJ
通讯作者：
Sweet MJ
全基因组关联研究将CSF1，OPTN和TNFRSF11A的变体确定为Paget骨骼疾病的遗传危险因素。
影响因子：
30.8
作者：
通讯作者：
--
影响因子：
6.2
作者：
Daroszewska, A;Hocking, LJ;Ralston, SH
通讯作者：
Ralston, SH
影响因子：
--
作者：
Galson DL;Roodman GD
通讯作者：
Roodman GD
影响因子：
16.6
作者：
Liao, Jie;Qian, Jingyang;Fang, Yin;Chen, Zhuo;Zhuang, Xiang;Zhang, Ningyu;Shao, Xin;Hu, Yining;Yang, Penghui;Cheng, Junyun;Hu, Yang;Yu, Lingqi;Yang, Haihong;Zhang, Jinlu;Lu, Xiaoyan;Shao, Li;Wu, Dan;Gao, Yue;Chen, Huajun;Fan, Xiaohui
通讯作者：
Fan, Xiaohui