Osteoprotegerin is elevated in pulmonary fibrosis and associates with IPF progression

Habibie, H.; Putri, K.; Boorsma, C. E.; Brass, D.; Heukels, P.; Wijsenbeek-Lourens, M.; Kool, M.; van der Berge, M.; Borghuis, T.; Brandsma, C. A.; Gan, T.; Olinga, P.; Timens, W.; Kahn, N.; Kreuter, M.; Burgess, J.; Melgert, B. N.

doi:10.1101/2020.12.02.408062

bioRxiv · 10.1101/2020.12.02.408062

Osteoprotegerin is elevated in pulmonary fibrosis and associates with IPF progression

Habibie, H.·Putri, K.·Boorsma, C. E.·Brass, D.·Heukels, P.·Wijsenbeek-Lourens, M.·Kool, M.·van der Berge, M.·Borghuis, T.·Brandsma, C. A.·Gan, T.·Olinga, P.·Timens, W.·Kahn, N.·Kreuter, M.·Burgess, J.·Melgert, B. N.

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Abstract

Osteoprotegerin (OPG), a decoy receptor for receptor activator of NF-kB ligand (RANKL), is used as a biomarker for assessing severity of liver fibrosis. However, its expression and role in pulmonary fibrosis are unknown. We hypothesized that OPG also has a role in pulmonary fibrosis. Human and mouse control and fibrotic lung tissue were used to examine OPG expression, and mouse precision-cut lung slices to study OPG regulation in pulmonary fibrosis. Serum from idiopathic pulmonary fibrosis (IPF) patients and controls was analysed to investigate whether OPG levels correlate with disease status as measured by lung function. OPG-protein levels were significantly higher in mouse and human fibrotic lung tissue compared to control. OPG-mRNA and protein production were induced in mouse precision-cut-lung slices upon TGF{beta} stimulation and could be inhibited with galunisertib, a TGF{beta} receptor kinase inhibitor. OPG-protein levels in fibrotic mouse lung tissue correlated with degree of fibrosis. Isolated lung fibroblasts from IPF patients had higher OPG-protein levels than control fibroblasts. Serum OPG levels in IPF patients, at first presentation, negatively correlated with diffusing capacity to carbon monoxide. Finally, serum OPG levels higher than 1234 pg/ml at first presentation were associated with progression of disease in IPF patients. In conclusion, OPG is produced in lung tissue, associates with fibrosis, and may be a potential prognostic biomarker for IPF disease progression. Validation in a larger cohort is warranted to further explore the role of OPG in pulmonary fibrosis and its potential for assessing the prognosis of fibrotic lung disease in individual patients. Take home messageOsteoprotegerin is present in fibrotic lung tissue and high serum levels correlate with low lung function and IPF disease progression in this small study, indicating osteoprotegerin may have value as a biomarker to predict IPF progression

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Habibie, H., Putri, K., Boorsma, C. E., Brass, D., Heukels, P., Wijsenbeek-Lourens, M., Kool, M., van der Berge, M., Borghuis, T., Brandsma, C. A., Gan, T., Olinga, P., Timens, W., Kahn, N., Kreuter, M., Burgess, J., Melgert, B. N.. 2020-12-03. Osteoprotegerin is elevated in pulmonary fibrosis and associates with IPF progression. https://doi.org/10.1101/2020.12.02.408062

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