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Updated: Mar 20, 2026
Three-Dimensional Bone Extracellular Matrix Model for Osteosarcoma
Published on: April 12, 2019
Downregulation of CXCR4 Expression and Functionality After Zoledronate Exposure in Canine Osteosarcoma
M L Byrum1, H C Pondenis1, R L Fredrickson2
1Department of Veterinary Clinical Medicine, University of Illinois, Urbana, IL.
Background:
The establishment and progression of metastases remains the life-limiting factor for dogs diagnosed with osteosarcoma (OS). The pattern of metastases is likely regulated through interactions between chemokine receptors and chemokines, and perturbations in these signaling cascades responsible for cytoskeletal organization and directional migration have the potential to alter metastatic cell trafficking behaviors.
Hypothesis:
Zoledronate will impair directional migration of OS cells through downregulation of chemokine (C-X-C motif) receptor 4 (CXCR4) expression and functionality.
Samples:
Nineteen archived tumor specimens and plasma from 20 dogs with OS.
Methods:
Prospectively, the expressions of CXCR4 were studied in OS cell lines and spontaneous tumor samples. The effect of zoledronate on CXCR4 expression and functionality was investigated by characterizing responses in 3 OS cell lines. In 19 OS specimens and 20 dogs with OS, changes in CXCR4 expression and circulating CXCR4 concentrations were characterized in response to zoledronate therapy respectively.
Results:
All canine OS cells express CXCR4, and zoledronate reduces CXCR4 expression and functionality by 27.7% (P < .0001), through augmented proteasome degradation and reduced prenylation of heterotrimeric G-proteins in 33% of tumor cell lines evaluated. In OS-bearing dogs, zoledronate reduces CXCR4 expressions by 40% within the primary tumor compared to untreated controls (P = .03) and also decreases the circulating concentrations of CXCR4 in 18 of 20 dogs with OS.
Conclusions And Clinical Importance:
Zoledronate can alter CXCR4 expression and functionality in OS cells, and consequent perturbations in CXCR4 intracellular signaling cascades might influence patterns of metastases.
Insights
Zoledronate treatment significantly reduces chemokine receptor 4 (CXCR4) expression and functionality in canine osteosarcoma (OS) cells and tumors. This finding suggests zoledronate may impact the metastatic potential of OS in dogs.
Area of Science:
- Veterinary Oncology
- Cancer Metastasis
- Molecular Biology
Background:
- Metastasis is the primary cause of mortality in dogs with osteosarcoma (OS).
- Chemokine receptor and chemokine interactions are implicated in regulating metastatic patterns.
- Signaling pathways controlling cell migration may influence metastatic cell trafficking.
Purpose of the Study:
- To investigate the effect of zoledronate on canine OS cell migration.
- To determine if zoledronate downregulates chemokine (C-X-C motif) receptor 4 (CXCR4) expression and functionality.
Main Methods:
- Analysis of CXCR4 expression in canine OS cell lines and tumor samples.
- Assessment of zoledronate's impact on CXCR4 expression and function in vitro.
- Measurement of CXCR4 expression in primary tumors and circulating concentrations in dogs receiving zoledronate therapy.
Main Results:
- All canine OS cells express CXCR4.
- Zoledronate reduced CXCR4 expression and functionality by 27.7% in cell lines.
- Zoledronate decreased primary tumor CXCR4 expression by 40% and circulating CXCR4 in 90% of dogs.
Conclusions:
- Zoledronate alters CXCR4 expression and functionality in canine OS.
- Modulation of CXCR4 signaling by zoledronate may influence osteosarcoma metastasis patterns.
