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Abstract：
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.
摘要：
Paget骨病（PDB）是一种代谢性骨病，其特征是破骨细胞功能失调，导致骨重建的局灶性异常。它会导致疼痛，骨折,骨畸形.G蛋白偶联受体激酶3（GRK3）是G蛋白偶联受体（GPCR）信号的重要负调节因子。已知GRK3在成骨细胞和前成骨细胞中调节GPCR功能,但其在破骨细胞中的调节功能尚不明确。这里,我们报道了在人和小鼠原代细胞和已建立的细胞系中破骨细胞分化过程中，Grk3表达增加。我们还表明，缺乏Grk3的老年小鼠会出现与人类PDB和其他Paget疾病小鼠模型相似的骨损伤。我们表明，Grk3表达的缺乏增强了体外破骨细胞的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组相比,PDB患者外周血单个核细胞中Grk3的表达降低.我们的数据表明，GRK3与破骨细胞分化的调节有关，并且可能与PDB和其他与破骨细胞活化相关的代谢性骨疾病的发病机理有关。
