MMP-2 is required for bone marrow stromal cell support of pro-B-cell chemotaxis.
OBJECTIVE
We have previously demonstrated that bone marrow stromal cells (BMSCs) exposed to etoposide (VP-16) have reduced support of CXCR4(+) cell chemotaxis and diminished stromal cell derived factor-1 (CXCL12) in the supernatants. Based on the identification of CXCL12 as a matrix metalloproteinase-2 (MMP-2) substrate, we investigated potential dysregulation of MMP-2 expression or activity in chemotherapy-treated BMSCs.


METHODS
BMSCs exposed to VP-16 were evaluated for MMP-2 expression by gelatin zymography, ELISA, and western blot. Chemotaxis assays were completed to evaluate pro-B cell chemotaxis toward either MMP-2(-/-) BMSCs or BMSCs exposed to MMP-2 inhibitors.


RESULTS
BMSC exposure to VP-16 resulted in an immediate, transient, increase in MMP-2, followed by reduced MMP-2 protein expression. MMP-2 reduction correlated with diminished CXCL12 protein and reduced support of pro-B cell chemotaxis. BMSCs derived from MMP-2 knockout mice had less chemotactic support of CXCR4(+) cells than wild-type controls. Inhibition of BMSC MMP-2 activity by OA-Hy also reduced chemotactic support and CXCL12 protein detected in BMSC supernatants. VP-16-induced reduction of BMSC support of hematopoietic cell migration was restored by supplementing cultures with recombinant MMP-2 protein.


CONCLUSIONS
These data suggest that MMP-2 is sensitive to chemotherapy-induced stress, and may regulate BMSC support of pro-B cell chemotaxis. Increased MMP-2 expression during the acute phase of chemotherapy exposure potentially inactivates CXCL12. Subsequently, chronic exposure to chemotherapy, with the associated downregulation of MMP-2, interrupts CXCL12 release from the extracellular matrix, also blunting BMSC support of pro-B cell migration.
Clutter
Suzanne D
SD
Department of Microbiology, Immunology, and Cell Biology, West Virginia University, Morgantown, WV 26506, USA.
Fortney
James
J
Gibson
Laura F
LF
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D001854:Bone Marrow Cells / Q000166:cytology* / Q000502:physiology; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000187:drug effects* / Q000502:physiology; D015536:Down-Regulation / Q000187:drug effects; D005047:Etoposide / Q000494:pharmacology*; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis*; D051379:Mice; D014176:Protein Biosynthesis / Q000187:drug effects; D019718:Receptors, CXCR4 / Q000378:metabolism; D017154:Stromal Cells / Q000166:cytology / Q000502:physiology
D000972:Antineoplastic Agents, Phytogenic; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D019718:Receptors, CXCR4; D005047:Etoposide; D020778:Matrix Metalloproteinase 2