PDF(Pubmed)
Abstract：
BACKGROUND: Osteoporosis and its primary complication, fragility fractures, contribute to substantial global morbidity and mortality. Gaucher disease (GD) is caused by glucocerebrosidase (GBA1) deficiency, leading to skeletal complications. This study aimed to investigate the impact of the GBA1 gene on osteoporosis progression in GD patients and the specific populations.
METHODS: We selected 8115 patients with osteoporosis (T-score ≤ - 2.5) and 55,942 healthy individuals (T-score > - 1) from a clinical database (N = 95,223). Monocytes from GD patients were evaluated in relation to endoplasmic reticulum (ER) stress, inflammasome activation, and osteoclastogenesis. An in vitro model of GD patient\'s cells treated with adeno-associated virus 9 (AAV9)-GBA1 to assess GBA1 enzyme activity, chitotriosidase activity, ER stress, and osteoclast differentiation. Longitudinal dual-energy X-ray absorptiometry (DXA) data tracking bone density in patients with Gaucher disease (GD) undergoing enzyme replacement therapy (ERT) over an extended period.
RESULTS: The GBA1 gene variant rs11264345 was significantly associated [P < 0.002, Odds Ratio (OR) = 1.06] with an increased risk of bone disease. Upregulation of Calnexin, NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) and Apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC) was positively associated with osteoclastogenesis in patients with GD. In vitro AAV9-GBA1 treatment of GD patient cells led to enhanced GBA1 enzyme activity, reduced chitotriosidase activity, diminished ER stress, and decreased osteoclast differentiation. Long-term bone density data suggests that initiating ERT earlier in GD leads to greater improvements in bone density.
CONCLUSIONS: Elevated ER stress and inflammasome activation are indicative of osteoporosis development, suggesting the need for clinical monitoring of patients with GD. Furthermore, disease-associated variant in the GBA1 gene may constitute a risk factor predisposing specific populations to osteoporosis.
METHODS: We selected 8115 patients with osteoporosis (T-score ≤ - 2.5) and 55,942 healthy individuals (T-score > - 1) from a clinical database (N = 95,223). Monocytes from GD patients were evaluated in relation to endoplasmic reticulum (ER) stress, inflammasome activation, and osteoclastogenesis. An in vitro model of GD patient\'s cells treated with adeno-associated virus 9 (AAV9)-GBA1 to assess GBA1 enzyme activity, chitotriosidase activity, ER stress, and osteoclast differentiation. Longitudinal dual-energy X-ray absorptiometry (DXA) data tracking bone density in patients with Gaucher disease (GD) undergoing enzyme replacement therapy (ERT) over an extended period.
RESULTS: The GBA1 gene variant rs11264345 was significantly associated [P < 0.002, Odds Ratio (OR) = 1.06] with an increased risk of bone disease. Upregulation of Calnexin, NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) and Apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC) was positively associated with osteoclastogenesis in patients with GD. In vitro AAV9-GBA1 treatment of GD patient cells led to enhanced GBA1 enzyme activity, reduced chitotriosidase activity, diminished ER stress, and decreased osteoclast differentiation. Long-term bone density data suggests that initiating ERT earlier in GD leads to greater improvements in bone density.
CONCLUSIONS: Elevated ER stress and inflammasome activation are indicative of osteoporosis development, suggesting the need for clinical monitoring of patients with GD. Furthermore, disease-associated variant in the GBA1 gene may constitute a risk factor predisposing specific populations to osteoporosis.
摘要：
背景：骨质疏松症及其主要并发症，脆性骨折,导致大量的全球发病率和死亡率。戈谢病（GD）是由葡萄糖脑苷脂酶（GBA1）缺乏引起的，导致骨骼并发症.本研究旨在探讨GBA1基因对GD患者和特定人群骨质疏松症进展的影响。
方法：我们从临床数据库（N=95,223）中选择了8115名骨质疏松症患者（T评分≤-2.5）和55,942名健康个体（T评分>-1）。来自GD患者的单核细胞评估与内质网（ER）应激的关系，炎症体激活，和破骨细胞生成。用腺相关病毒9（AAV9）-GBA1处理的GD患者细胞的体外模型评估GBA1酶活性，壳三糖苷酶活性，ER压力,和破骨细胞分化。纵向双能X线骨密度仪（DXA）数据追踪接受长时间酶替代疗法（ERT）的戈谢病（GD）患者的骨密度。
结果：GBA1基因变异体rs11264345与骨病风险增加显著相关[P<0.002,比值比(OR)=1.06]。钙连蛋白上调,NOD-,含有LRR和pyrin结构域的蛋白3（NLRP3）和含有C末端caspase募集结构域（ASC）的凋亡相关斑点样蛋白与GD患者的破骨细胞形成呈正相关。GD患者细胞的体外AAV9-GBA1处理导致GBA1酶活性增强，降低的壳三糖苷酶活性，减少ER压力，和减少破骨细胞分化。长期骨密度数据表明，在GD中更早地启动ERT会导致骨密度的更大改善。
结论：内质网应激和炎症体激活升高是骨质疏松症发展的指示，提示需要对GD患者进行临床监测。此外，GBA1基因的疾病相关变异可能是导致特定人群发生骨质疏松症的危险因素.
方法：我们从临床数据库（N=95,223）中选择了8115名骨质疏松症患者（T评分≤-2.5）和55,942名健康个体（T评分>-1）。来自GD患者的单核细胞评估与内质网（ER）应激的关系，炎症体激活，和破骨细胞生成。用腺相关病毒9（AAV9）-GBA1处理的GD患者细胞的体外模型评估GBA1酶活性，壳三糖苷酶活性，ER压力,和破骨细胞分化。纵向双能X线骨密度仪（DXA）数据追踪接受长时间酶替代疗法（ERT）的戈谢病（GD）患者的骨密度。
结果：GBA1基因变异体rs11264345与骨病风险增加显著相关[P<0.002,比值比(OR)=1.06]。钙连蛋白上调,NOD-,含有LRR和pyrin结构域的蛋白3（NLRP3）和含有C末端caspase募集结构域（ASC）的凋亡相关斑点样蛋白与GD患者的破骨细胞形成呈正相关。GD患者细胞的体外AAV9-GBA1处理导致GBA1酶活性增强，降低的壳三糖苷酶活性，减少ER压力，和减少破骨细胞分化。长期骨密度数据表明，在GD中更早地启动ERT会导致骨密度的更大改善。
结论：内质网应激和炎症体激活升高是骨质疏松症发展的指示，提示需要对GD患者进行临床监测。此外，GBA1基因的疾病相关变异可能是导致特定人群发生骨质疏松症的危险因素.
