Faculty, Staff and Student Publications

Publication Date

8-1-2024

Journal

Cancer Letters

Abstract

Renal 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.

Keywords

Osteocytes, Humans, Animals, Bone Neoplasms, Carcinoma, Renal Cell, Apoptosis, Kidney Neoplasms, Gap Junctions, Extracellular Matrix Proteins, Mice, Disease Progression, Connexin 43, Cell Line, Tumor, Transforming Growth Factor beta, Osteolysis, Female

DOI

10.1016/j.canlet.2024.217009

PMID

38849015

PMCID

PMC11964150

PubMedCentral® Posted Date

4-2-2025

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

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