In Gaucher disease, several macrophage-specific biomarkers have been validated for use in the clinic. However, Gaucher disease is more complex involving system-wide pathophysiology beyond the macrophage, and based on gene array analysis in our Gaucher disease mouse model and other emerging pathophysiologic insights, we evaluated serum levels of cathepsins D and S, YKL-40 and progranulin in Gaucher disease patients. We assessed their biomarker potential in Gaucher disease and compared them to established Gaucher disease biomarkers, chitotriosidase, chemokine ligand 18 (CCL18), and other indicators of disease severity and response to therapy. Mean YKL-40 and cathepsin D and S levels were significantly higher in Gaucher disease patients compared to healthy controls; in contrast, mean progranulin levels were lower in Gaucher disease patients compared to healthy controls. Enzyme replacement therapy resulted in a significant reversal of elevated cathepsin D and S but there was no change in progranulin and YKL-40 levels. Patients with persistent splenomegaly after long-term enzyme replacement therapy had significantly higher serum YKL-40 than patients with smaller spleens (63.0 ± 6.4 ng/ml vs. 46.4 ± 4.3 ng/ml, p = .03). Serum YKL-40 levels were higher in subjects with severe bone involvement (Hermann Score 3 to 5) compared to those with milder bone involvement (Hermann Score 1 to 2) (70.1 ± 4.3 ng/ml vs. 48.1 ± 3.7 ng/ml, p = .0002). YKL-40 was only weakly associated with chitotriosidase (r = 0.2, p = .008) and CCL18 (r = 0.3, p = .0004), and cathepsin S was moderately associated with chitotriosidase (r = 0.4, p = .01) and CCL18 (r = 0.6, p < .0001). Receiver operating curves for progranulin and YKL-40 demonstrated areas under the curves of 0.80 and 0.70, respectively. In conclusion, while these biomarkers do not meet robust properties of established macrophage-specific biomarkers, they may inform severity of skeletal disease, contribution of fibrosis to residual splenomegaly, and other disease manifestations. These findings, including markedly low progranulin levels that do not change upon enzyme replacement therapy, are intriguing to prompt further investigations to decipher their role in pathophysiology and relevance to diverse phenotypes of Gaucher disease.

中文翻译：

---

Gaucher病中异常的前颗粒蛋白，YKL-40，组织蛋白酶D和组织蛋白酶S。

在高雪氏病中，已验证了几种巨噬细胞特异性生物标志物可用于临床。但是，Gaucher病比巨噬细胞更复杂，涉及到整个系统的病理生理学，根据我们在Gaucher病小鼠模型中的基因阵列分析和其他新兴的病理生理学见解，我们评估了组织蛋白酶D和S，YKL-40和前颗粒蛋白的血清水平。高雪氏病患者。我们评估了它们在高雪氏病中的生物标志物潜力，并将它们与已建立的高雪氏病生物标志物，壳三糖苷酶，趋化因子配体18（CCL18）以及疾病严重程度和对治疗的反应的其他指标进行了比较。与健康对照组相比，戈谢病患者的平均YKL-40和组织蛋白酶D和S水平显着更高；相比之下，与健康对照组相比，戈谢病患者的平均前颗粒蛋白水平较低。酶替代疗法导致组织蛋白酶D和S升高的显着逆转，但前颗粒蛋白和YKL-40水平没有变化。长期酶​​替代治疗后持续性脾肿大的患者血清YKL-40明显高于脾脏较小的患者（63.0±6.4 ng / ml与46.4±4.3 ng / ml，p = .03）。严重骨骼受累（Hermann评分3至5）的受试者的血清YKL-40水平高于轻微骨骼受累（Hermann评分1至2）的受试者（70.1±4.3 ng / ml对48.1±3.7 ng / ml， p = .0002）。YKL-40仅与壳三糖苷酶（r = 0.2，p = .008）和CCL18（r = 0.3，p = .0004）弱关联，而组织蛋白酶S与壳三糖苷酶（r = 0.4，p =。01）和CCL18（r = 0.6，p <.0001）。原粒蛋白和YKL-40的受体工作曲线分别显示在0.80和0.70曲线下的面积。总之，尽管这些生物标志物不符合已建立的巨噬细胞特异性生物标志物的稳健特性，但它们可能会告知骨骼疾病的严重程度，纤维化对残余脾肿大的贡献以及其他疾病表现。这些发现，包括在酶替代疗法后不会改变的明显低的前颗粒蛋白水平，很有趣，促使人们进行进一步的研究，以了解其在病理生理中的作用以及与高雪氏病多种表型的相关性。尽管这些生物标记物不符合已建立的巨噬细胞特异性生物标记物的稳健特性，但它们可能会告知骨骼疾病的严重程度，纤维化对残余脾肿大的贡献以及其他疾病表现。这些发现，包括在酶替代疗法后不会改变的明显低的前颗粒蛋白水平，吸引着人们进行进一步的研究以破译它们在病理生理中的作用以及与高雪氏病多种表型的相关性。尽管这些生物标记物不符合已建立的巨噬细胞特异性生物标记物的稳健特性，但它们可能会告知骨骼疾病的严重程度，纤维化对残余脾肿大的贡献以及其他疾病表现。这些发现，包括在酶替代疗法后不会改变的明显低的前颗粒蛋白水平，很有趣，促使人们进行进一步的研究，以了解其在病理生理中的作用以及与高雪氏病多种表型的相关性。