Deregulation of the CXCL12/CXCR4 axis in methotrexate chemotherapy-induced damage and recovery of the bone marrow microenvironment.
Cancer chemotherapy disrupts the bone marrow (BM) microenvironment affecting steady-state proliferation, differentiation and maintenance of haematopoietic (HSC) and stromal stem and progenitor cells; yet the underlying mechanisms and recovery potential of chemotherapy-induced myelosuppression and bone loss remain unclear. While the CXCL12/CXCR4 chemotactic axis has been demonstrated to be critical in maintaining interactions between cells of the two lineages and progenitor cell homing to regions of need upon injury, whether it is involved in chemotherapy-induced BM damage and repair is not clear. Here, a rat model of chemotherapy treatment with the commonly used antimetabolite methotrexate (MTX) (five once-daily injections at 0.75 mg/kg/day) was used to investigate potential roles of CXCL12/CXCR4 axis in damage and recovery of the BM cell pool. Methotrexate treatment reduced marrow cellularity, which was accompanied by altered CXCL12 protein levels (increased in blood plasma but decreased in BM) and reduced CXCR4 mRNA expression in BM HSC cells. Accompanying the lower marrow CXCL12 protein levels (despite its increased mRNA expression in stromal cells) was increased gene and protein levels of metalloproteinase MMP-9 in bone and BM. Furthermore, recombinant MMP-9 was able to degrade CXCL12 in vitro. These findings suggest that MTX chemotherapy transiently alters BM cellularity and composition and that the reduced cellularity may be associated with increased MMP-9 expression and deregulated CXCL12/CXCR4 chemotactic signalling.
Sansom Institute for Health Research, University of South Australia, Adelaide, SA, Australia.
Kristen R
KR
Georgiou
Michaela A
MA
Scherer
Tristan J
TJ
King
Bruce K
BK
Foster
Cory J
CJ
Xian
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D001854:Bone Marrow Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002452:Cell Count; D019070:Cell Lineage; D060833:Cellular Microenvironment / Q000187:drug effects; D054377:Chemokine CXCL12 / Q000235:genetics* / Q000378:metabolism; D003114:Colony-Forming Units Assay; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008727:Methotrexate / Q000009:adverse effects*; D023461:Myeloid Progenitor Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D019718:Receptors, CXCR4 / Q000235:genetics* / Q000378:metabolism; D011994:Recombinant Proteins; D015398:Signal Transduction / Q000187:drug effects; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism
D000970:Antineoplastic Agents; D054377:Chemokine CXCL12; C486264:Cxcr4 protein, rat; D012333:RNA, Messenger; D019718:Receptors, CXCR4; D011994:Recombinant Proteins; D019715:Tissue Inhibitor of Metalloproteinase-1; D020780:Matrix Metalloproteinase 9; D008727:Methotrexate