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Bone morphogenetic protein 6 (BMP6) antagonises experimental proliferative vitreoretinopathy established by TGF-β2 stimulation in retinal pigment epithelial cells through modulation of the p38 and JNK MAPK pathways

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Abstract

The formation of the epiretinal fibrotic membrane by retinal pigment epithelial (RPE) cells is a primary pathological change for proliferative vitreoretinopathy (PVR). Bone morphogenetic protein 6 (BMP6) is an antifibrogenic factor in various cells. To date, it is still unknown whether BMP6 can interfere with the fibrogenesis of RPE cells during the progression of PVR. This work aimed to address the relationship between BMP6 and transforming growth factor-β2 (TGF-β2)-elicited fibrogenesis of RPE cells, an experimental model for studying PVR in vitro. The BMP6 level was down-regulated, while the TGF-β2 level was up-regulated in the vitreous humor of PVR patients. The BMP6 level was down-regulated in human RPE cells challenged with TGF-β2. The treatment of RPE cells with TGF-β2 resulted in significant increases in proliferation, migration, epithelial-to-mesenchymal transition (EMT), and extracellular matrix (ECM) remodelling. These effects were found to be inhibited by the overexpression of BMP6 or exacerbated by the knockdown of BMP6. BMP6 overexpression reduced the phosphorylation of p38 and JNK in TGF-β2-stimulated RPE cells, while BMP6 knockdown showed the opposite effects. The inhibition of p38 or JNK partially reversed the BMP6-silencing-induced promoting effects on TGF-β2-elicited fibrogenesis in RPE cells. Taken together, BMP6 demonstrates the ability to counteract the proliferation, migration, EMT, and ECM remodelling of RPE cells induced by TGF-β2. This is achieved through the regulation of the p38 and JNK MAPK pathways. These findings imply a potential connection between BMP6 and PVR, and highlight the potential application of BMP6 in therapeutic interventions for PVR.

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Data availability

The datasets used during the present study are available from the corresponding author on reasonable request.

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Funding

The work was supported by the Key Research and Development Program of Shaanxi Province (No. 2020SF-268 and No.2022SF-311), the Key Research and Development Program of Shaanxi Province (No. 2024SFYBXM-328).

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Authors and Affiliations

  1. Department of Ophthalmology, The First Affiliated Hospital of Xi’an Jiaotong University, No. 277 Yanta West Road, Xi’an, 710061, China

    Xuan Liu & Li Chen

  2. Department of Ophthalmology, Xi’an No. 1 Hospital, Xi’an, 710002, China

    Ming Liu

  3. Shaanxi Institute of Ophthalmology, Xi’an, 710002, China

    Ming Liu

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  1. Xuan Liu
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  2. Ming Liu
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Contributions

Xuan Liu designed the work, performed the experiments and wrote the manuscript. Ming Liu performed the experiments. Li Chen contributed to conceptualization and reviewed the manuscript.

Corresponding author

Correspondence to Li Chen.

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Research involving human participants and/or animals

The collection and use of human clinical vitreous humor samples were approved by the Institutional Ethics Committee of The First Affiliated Hospital of Xi’an Jiaotong University and the study was performed in accordance with the 1964 Helsinki Declaration.

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Informed consent was obtained from all individual participants included in the study.

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Liu, X., Liu, M. & Chen, L. Bone morphogenetic protein 6 (BMP6) antagonises experimental proliferative vitreoretinopathy established by TGF-β2 stimulation in retinal pigment epithelial cells through modulation of the p38 and JNK MAPK pathways. Cell Tissue Res 396, 103–117 (2024). https://doi.org/10.1007/s00441-024-03870-1

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