BIGH3 mediates apoptosis and gap junction failure in osteocytes during renal cell carcinoma bone metastasis progression

Simple item page
dc.citation.articleNumber217009
dc.citation.journalTitleCancer Letters
dc.citation.volumeNumber596
dc.contributor.authorPan, Tianhong
dc.contributor.authorLiu, Fengshuo
dc.contributor.authorHao, Xiaoxin
dc.contributor.authorWang, Shubo
dc.contributor.authorWasi, Murtaza
dc.contributor.authorSong, Jian H.
dc.contributor.authorLewis, Valerae O.
dc.contributor.authorLin, Patrick P.
dc.contributor.authorMoon, Bryan
dc.contributor.authorBird, Justin E.
dc.contributor.authorPanaretakis, Theocharis
dc.contributor.authorLin, Sue-Hwa
dc.contributor.authorWu, Danielle
dc.contributor.authorFarach-Carson, Mary C.
dc.contributor.authorWang, Liyun
dc.contributor.authorZhang, Ningyan
dc.contributor.authorAn, Zhiqiang
dc.contributor.authorZhang, Xiang H. -F.
dc.contributor.authorSatcher, Robert L.
dc.date.accessioned2024-08-02T13:32:06Z
dc.date.available2024-08-02T13:32:06Z
dc.date.issued2024
dc.description.abstractRenal cell carcinoma (RCC) bone metastatis progression is driven by crosstalk between tumor cells and the bone microenvironment, which includes osteoblasts, osteoclasts, and osteocytes. RCC bone metastases (RCCBM) are predominantly osteolytic and resistant to antiresorptive therapy. The molecular mechanisms underlying pathologic osteolysis and disruption of bone homeostasis remain incompletely understood. We previously reported that BIGH3/TGFBI (transforming growth factor-beta-induced protein ig-h3, shortened to BIGH3 henceforth) secreted by colonizing RCC cells drives osteolysis by inhibiting osteoblast differentiation, impairing healing of osteolytic lesions, which is reversible with osteoanabolic agents. Here, we report that BIGH3 induces osteocyte apoptosis in both human RCCBM tissue specimens and in a preclinical mouse model. We also demonstrate that BIGH3 reduces Cx43 expression, blocking gap junction (GJ) function and osteocyte network communication. BIGH3-mediated GJ inhibition is blocked by the lysosomal inhibitor hydroxychloroquine (HCQ), but not osteoanabolic agents. Our results broaden the understanding of pathologic osteolysis in RCCBM and indicate that targeting the BIGH3 mechanism could be a combinational strategy for the treatment of RCCBM-induced bone disease that overcomes the limited efficacy of antiresorptives that target osteoclasts.
dc.identifier.citationPan, T., Liu, F., Hao, X., Wang, S., Wasi, M., Song, J. H., Lewis, V. O., Lin, P. P., Moon, B., Bird, J. E., Panaretakis, T., Lin, S.-H., Wu, D., Farach-Carson, M. C., Wang, L., Zhang, N., An, Z., Zhang, X. H.-F., & Satcher, R. L. (2024). BIGH3 mediates apoptosis and gap junction failure in osteocytes during renal cell carcinoma bone metastasis progression. Cancer Letters, 596, 217009. https://doi.org/10.1016/j.canlet.2024.217009
dc.identifier.digital1-s20-S0304383524004038-main
dc.identifier.doihttps://doi.org/10.1016/j.canlet.2024.217009
dc.identifier.urihttps://hdl.handle.net/1911/117550
dc.language.isoeng
dc.publisherElsevier
dc.rightsExcept where otherwise noted, this work is licensed under a Creative Commons Attribution-NonCommercial (CC BY-NC) license.  Permission to reuse, publish, or reproduce the work beyond the terms of the license or beyond the bounds of fair use or other exemptions to copyright law must be obtained from the copyright holder.
dc.rights.urihttps://creativecommons.org/licenses/by-nc/4.0/
dc.titleBIGH3 mediates apoptosis and gap junction failure in osteocytes during renal cell carcinoma bone metastasis progression
dc.typeJournal article
dc.type.dcmiText
dc.type.publicationpublisher version
Files
Original bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
1-s20-S0304383524004038-main.pdf
Size:
12.48 MB
Format:
Adobe Portable Document Format
Download
Collections
Faculty Publications
Bioengineering Publications
BioSciences Publications