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bioRxiv · 10.1101/2025.05.06.652563

Latent transforming growth factor binding protein-2 (LTBP2), an IPF biomarker of clinical decline, promotes TGF-beta signaling and lung fibrosis in mice

Bodmer, N. K.·Choudhury, M.·Mirza, H.·Yin, Y.·Mecham, R. P.·Brody, S. L.·Ornitz, D. M.·Koenitzer, J. R.
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Abstract

The identification of clinically predictive serum biomarkers for pulmonary fibrosis is a significant challenge and important goal. Multiple recent proteomic biomarker studies have identified latent transforming growth factor binding protein-2 (LTBP2) as a circulating factor associated with disease progression in fibrotic lung diseases in humans (including IPF), but its role in the development of fibrosis is incompletely defined. LTBP2 competes with the large latent transforming growth factor-beta (TGF{beta}) complex (LLC) for binding to the N-terminus of fibrillin and is thought to promote the release of active TGF{beta}. We hypothesized that LTBP2 deficiency would promote LLC sequestration in matrix and reduce TGF{beta} signaling. We recently reported an LTBP2 knockout (Ltbp2-/-) mouse with no baseline lung abnormalities. Here we show that Ltbp2-/- mice exposed to either bleomycin or silica have a significant reduction in fibrosis compared to wild type controls. Consistent with reduced fibrosis, after bleomycin Ltbp2-/- mouse lungs have reduced TGF{beta} signaling and isolated fibroblasts from Ltbp2-/-mice exhibit impaired migration in an in vitro wound closure assay. Transcriptomic analysis of bleomycin-treated control and Ltbp2-/- mouse lung tissue identified multiple LTBP2-regulated genes, including the lncRNA antisense of IGFR2 non-coding RNA (Airn) which has reported antifibrotic effects. Interestingly, we also observed that Ltbp2-/- mice had impaired epithelial repair after bleomycin treatment, a phenotype that also occurred in a naphthalene model of club cell injury. These findings provide evidence that LTBP2 is profibrotic and facilitates TGF{beta} signaling but is also required for normal airway epithelial repair.

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Bodmer, N. K., Choudhury, M., Mirza, H., Yin, Y., Mecham, R. P., Brody, S. L., Ornitz, D. M., Koenitzer, J. R.. 2025-05-11. Latent transforming growth factor binding protein-2 (LTBP2), an IPF biomarker of clinical decline, promotes TGF-beta signaling and lung fibrosis in mice. https://doi.org/10.1101/2025.05.06.652563

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