A serologically assessed neo-epitope biomarker of cellular fibronectin degradation is related to pulmonary fibrosis
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A serologically assessed neo-epitope biomarker of cellular fibronectin degradation is related to pulmonary fibrosis. / Hansen, Annika Hummersgaard; Breisnes, Helene Wallem; Prior, Thomas Skovhus; Hilberg, Ole; Rasmussen, Daniel Guldager Kring; Genovese, Federica; Lukassen, Marie Vestergaard; Svensson, Birte; Langholm, Lasse Løcke; Manon-Jensen, Tina; Karsdal, Morten Asser; Leeming, Diana Julie; Bendstrup, Elisabeth; Sand, Jannie Marie Bülow.
I: Clinical Biochemistry, Bind 118, 110599, 2023.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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T1 - A serologically assessed neo-epitope biomarker of cellular fibronectin degradation is related to pulmonary fibrosis
AU - Hansen, Annika Hummersgaard
AU - Breisnes, Helene Wallem
AU - Prior, Thomas Skovhus
AU - Hilberg, Ole
AU - Rasmussen, Daniel Guldager Kring
AU - Genovese, Federica
AU - Lukassen, Marie Vestergaard
AU - Svensson, Birte
AU - Langholm, Lasse Løcke
AU - Manon-Jensen, Tina
AU - Karsdal, Morten Asser
AU - Leeming, Diana Julie
AU - Bendstrup, Elisabeth
AU - Sand, Jannie Marie Bülow
N1 - Publisher Copyright: © 2023 The Authors
PY - 2023
Y1 - 2023
N2 - Background: Idiopathic pulmonary fibrosis (IPF) is characterized by excessive extracellular matrix (ECM) remodeling, herein ECM degradation. Fibronectin (FN) is an important component of the ECM that is produced by multiple cell types, including fibroblasts. Extra domain B (EDB) is specific for a cellular FN isoform which is found in the ECM. We sought to develop a non-invasive test to investigate whether matrix metalloproteinase 8 (MMP-8) degradation of EDB in cellular FN results in a specific protein fragment that can be assessed serologically and if levels relate to pulmonary fibrosis. Method: Cellular FN was cleaved in vitro by MMP-8 and a protein fragment was identified by mass spectrometry. A monoclonal antibody (mAb) was generated, targeting a neo-epitope originating from EDB in cellular FN. Utilizing this mAb, a neo-epitope specific enzyme-linked immunosorbent assay (FN-EDB) was developed and technically validated. Serum FN-EDB was assessed in an IPF cohort (n = 98), registered at clinicaltrials.gov (NCT02818712), and in healthy controls (n = 35). Results: The FN-EDB assay had high specificity for the MMP-8 degraded neo-epitope and was technically robust. FN-EDB serum levels were not influenced by age, sex, ethnicity, or BMI. Moreover, FN-EDB serum levels were significantly higher in IPF patients (median 31.38 [IQR 25.79–46.84] ng/mL) as compared to healthy controls (median 28.05 [IQR 21.58–33.88] ng/mL, p = 0.023). Conclusion: We developed the neo-epitope specific FN-EDB assay, a competitive ELISA, as a tool for serological assessment of MMP-8 mediated degradation of EDB in cellular FN. This study indicates that degradation of EDB in cellular FN is elevated in IPF and warrants further investigation.
AB - Background: Idiopathic pulmonary fibrosis (IPF) is characterized by excessive extracellular matrix (ECM) remodeling, herein ECM degradation. Fibronectin (FN) is an important component of the ECM that is produced by multiple cell types, including fibroblasts. Extra domain B (EDB) is specific for a cellular FN isoform which is found in the ECM. We sought to develop a non-invasive test to investigate whether matrix metalloproteinase 8 (MMP-8) degradation of EDB in cellular FN results in a specific protein fragment that can be assessed serologically and if levels relate to pulmonary fibrosis. Method: Cellular FN was cleaved in vitro by MMP-8 and a protein fragment was identified by mass spectrometry. A monoclonal antibody (mAb) was generated, targeting a neo-epitope originating from EDB in cellular FN. Utilizing this mAb, a neo-epitope specific enzyme-linked immunosorbent assay (FN-EDB) was developed and technically validated. Serum FN-EDB was assessed in an IPF cohort (n = 98), registered at clinicaltrials.gov (NCT02818712), and in healthy controls (n = 35). Results: The FN-EDB assay had high specificity for the MMP-8 degraded neo-epitope and was technically robust. FN-EDB serum levels were not influenced by age, sex, ethnicity, or BMI. Moreover, FN-EDB serum levels were significantly higher in IPF patients (median 31.38 [IQR 25.79–46.84] ng/mL) as compared to healthy controls (median 28.05 [IQR 21.58–33.88] ng/mL, p = 0.023). Conclusion: We developed the neo-epitope specific FN-EDB assay, a competitive ELISA, as a tool for serological assessment of MMP-8 mediated degradation of EDB in cellular FN. This study indicates that degradation of EDB in cellular FN is elevated in IPF and warrants further investigation.
KW - Biomarker
KW - EDB
KW - Extracellular matrix
KW - Fibronectin
KW - Idiopathic pulmonary fibrosis
KW - Neo-epitope
KW - Non-invasive test
KW - Serological biomarker
U2 - 10.1016/j.clinbiochem.2023.110599
DO - 10.1016/j.clinbiochem.2023.110599
M3 - Journal article
C2 - 37343745
AN - SCOPUS:85162201232
VL - 118
JO - Clinical Biochemistry
JF - Clinical Biochemistry
SN - 0009-9120
M1 - 110599
ER -
ID: 358429717