Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2019 Sep-Oct;128(1-2):62-67.
doi: 10.1016/j.ymgme.2019.07.014. Epub 2019 Jul 23.

Aberrant progranulin, YKL-40, cathepsin D and cathepsin S in Gaucher disease

Yuliya Afinogenova  1 , Jiapeng Ruan  2 , Ruhua Yang  2 , Nathaniel Kleytman  2 , Gregory Pastores  3 , Andrew Lischuk  4 , Pramod K Mistry  5
Affiliations

Aberrant progranulin, YKL-40, cathepsin D and cathepsin S in Gaucher disease

Yuliya Afinogenova et al. Mol Genet Metab. 2019 Sep-Oct.

Abstract

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.

Keywords: Biomarkers; Cathepsins; Gaucher disease; Progranulin; YKL-40.

PubMed Disclaimer

Figures

Figure 1A.
Figure 1A.
Progranulin levels in subjects pre- and post-ERT and healthy controls. Values are expressed as mean, SEM. Abbreviations: ERT, enzyme replacement therapy.
Figure 1B.
Figure 1B.
YKL-40 levels in subjects pre- and post-ERT and healthy controls. Values are expressed as mean, SEM. Abbreviations: ERT, enzyme replacement therapy.
Figure 1C.
Figure 1C.
Cathepsin D levels in subjects pre- and post-ERT and healthy controls. Values are expressed as mean, SEM. Abbreviations: ERT, enzyme replacement therapy.
Figure 1D.
Figure 1D.
Cathepsin S levels in subjects pre- and post-ERT and healthy controls. Values are expressed as mean, SEM. Abbreviations: ERT, enzyme replacement therapy.
Figure 2.
Figure 2.
Comparison of YKL-40 values based on Spleen Size in post-ERT Group. Mean YKL-40 level was 63.0±6.4 in patients whose spleen volume remained greater than or equal to 4 times the upper limit of normal post-ERT. Mean YKL-40 level was 46.4±4.3 in patients whose spleen volume was reduced to less than 4 times the upper limit of normal post-ERT. Values expressed as mean, SEM. Abbreviations: SV, spleen volume. ULN, upper limit of normal. ERT, enzyme replacement therapy.
Figure 3.
Figure 3.
Comparison of YKL-40 values based on Hermann Bone Severity Score in post-ERT Group. Mean YKL-40 level was 70.1±4.3 in patients with moderate to severe bone disease post-ERT as indicated by Hermann Score 3, 4, or 5. Mean YKL-40 level was 48.1±3.7 in patients with mild bone disease post-ERT as indicated by Hermann Score 1 or 2. Values expressed as mean, SEM. Abbreviations: ERT, enzyme replacement therapy.
Figure 4.
Figure 4.
ROC curves for progranulin and YKL-40. Abbreviations: ROC, received operating curve.
See this image and copyright information in PMC

References

    1. Brady RO, Benefits from unearthing “a biochemical Rosetta Stone”. J Biol Chem, 2010. 285(53): p. 41216–21. - PMC - PubMed
    1. Grabowski GA, Phenotype, diagnosis, and treatment of Gaucher’s disease. Lancet, 2008. 372(9645): p. 1263–71. - PubMed
    1. Boot RG, et al., Marked elevation of the chemokine CCL18/PARC in Gaucher disease: a novel surrogate marker for assessing therapeutic intervention. Blood, 2004. 103(1): p. 33–9. - PubMed
    1. Hollak CE, et al., Marked elevation of plasma chitotriosidase activity. A novel hallmark of Gaucher disease. J Clin Invest, 1994. 93(3): p. 1288–92. - PMC - PubMed
    1. Khan A, et al., Risk factors for fractures and avascular osteonecrosis in type 1 Gaucher disease: a study from the International Collaborative Gaucher Group (ICGG) Gaucher Registry. J Bone Miner Res, 2012. 27(8): p. 1839–48. - PubMed

Publication types