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

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dc.citation.articleNumber217009en_US
dc.citation.journalTitleCancer Lettersen_US
dc.citation.volumeNumber596en_US
dc.contributor.authorPan, Tianhongen_US
dc.contributor.authorLiu, Fengshuoen_US
dc.contributor.authorHao, Xiaoxinen_US
dc.contributor.authorWang, Shuboen_US
dc.contributor.authorWasi, Murtazaen_US
dc.contributor.authorSong, Jian H.en_US
dc.contributor.authorLewis, Valerae O.en_US
dc.contributor.authorLin, Patrick P.en_US
dc.contributor.authorMoon, Bryanen_US
dc.contributor.authorBird, Justin E.en_US
dc.contributor.authorPanaretakis, Theocharisen_US
dc.contributor.authorLin, Sue-Hwaen_US
dc.contributor.authorWu, Danielleen_US
dc.contributor.authorFarach-Carson, Mary C.en_US
dc.contributor.authorWang, Liyunen_US
dc.contributor.authorZhang, Ningyanen_US
dc.contributor.authorAn, Zhiqiangen_US
dc.contributor.authorZhang, Xiang H. -F.en_US
dc.contributor.authorSatcher, Robert L.en_US
dc.date.accessioned2024-08-02T13:32:06Zen_US
dc.date.available2024-08-02T13:32:06Zen_US
dc.date.issued2024en_US
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.en_US
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.2024.217009en_US
dc.identifier.digital1-s20-S0304383524004038-mainen_US
dc.identifier.doihttps://doi.org/10.1016/j.canlet.2024.217009en_US
dc.identifier.urihttps://hdl.handle.net/1911/117550en_US
dc.language.isoengen_US
dc.publisherElsevieren_US
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.en_US
dc.rights.urihttps://creativecommons.org/licenses/by-nc/4.0/en_US
dc.titleBIGH3 mediates apoptosis and gap junction failure in osteocytes during renal cell carcinoma bone metastasis progressionen_US
dc.typeJournal articleen_US
dc.type.dcmiTexten_US
dc.type.publicationpublisher versionen_US
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