Work

C–C chemokine receptor (CCR) 3 deficiency disrupts chemokine receptor expression in bone marrow–derived macrophages and osteoclast precursors

Year: 2025

Type: article

Abstract: In mice, deficiency of the C-C chemokine receptor (CCR)3 leads to the formation of giant, hypernucleated osteoclasts with enhanced bone resorptive activity. CCR3-deficient cells also show increased expression of the genes encoding CCR2 and CCR5, which regulate osteoclastogenesis. Loss of CCR3 does not change the expression levels of core transcriptional regulators of osteoclast differentiation, however, implying that CCR3 may modulate osteoclast biology through alternative gene regulatory pathways. To investigate this possibility, we performed genome-wide transcriptomic profiling using stranded RNA sequencing on CCR3-proficient and -deficient bone marrow-derived macrophages (BMMs) and osteoclast precursors. We identified 24 differentially expressed genes in BMMs and 17 in osteoclast precursor cells. Ccr2 and Ccr5 were upregulated in CCR3-deficient BMMs, whereas Cxcr6 was downregulated in osteoclast precursors. Two genes near the Ccr3 locus, Fyco1 and Gm39469, also showed altered expression in CCR3-deficient osteoclast precursors. To control for potential off-target effects of germline gene deletion, we generated CRISPR/Cas9-mediated Ccr3 inactivation in RAW264.7 macrophages. These cells mirrored the upregulation of Ccr2 and Ccr5 seen in primary cells, supporting the presence of a compensatory mechanism within the chemokine receptor network. Together, these findings suggest that CCR3 influences osteoclast differentiation and function through broad regulatory interactions with other chemokine receptors. Compensatory gene expression changes, particularly involving Ccr2 and Ccr5, may contribute to the abnormal osteoclast phenotype observed in CCR3-deficient cell cultures. Further investigation into the roles of Fyco1, Gm39469, and Cxcr6 in osteoclastogenesis is warranted.

Source: Biochemical and Biophysical Research Communications

DOI: 10.1016/j.bbrc.2025.152658

Authors: Sara Rosendahl, Anita Lie, Pernilla Lundberg

Institution: Umeå University

Language: English

Topic: Bone Metabolism and Diseases

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $3,110