Blood, 1 September 2001, Vol. 98, No. 5, pp. 1279-1280
It's the proteases, stupid!
Despite its clinical importance, no intellectually satisfying
mechanistic explanations have been provided for G-CSF-induced stem
cell mobilization. Insights, however, from studies addressing the
mechanism of IL-8-induced mobilization in normal or
G-CSF-receptor deficient mice have been obtained. A pool of
normal neutrophils and their liberated proteases are found to be
critical both in G-CSF- and IL-8-induced mobilization,
bolstering the concept that diffusible factors are responsible for
mobilization. As a result of neutrophil activation by G-CSF, increases
in circulating elastase (NE), cathepsin G (CG), and matrix
metalloproteinase 9 (MMP9) have been documented after G-CSF
mobilization (Van Os et al, Blood. 1999;94(suppl):637a). But the mode
of action of these proteases in vivo, their specific substrates, and
their interplay with other molecules was not previously addressed.
Lévesque and colleagues (page 1289) present compelling evidence
that integrates the function of proteases and of adhesion molecules in
G-CSF-induced mobilization. NE and CG can cleave vascular cell
adhesion molecule-1 (VCAM-1) within the confines of bone marrow (BM).
The sequestered BM microenvironment with its tight cell-cell and
cell-matrix interactions and membrane presentation of proteases
provides a favorable environment for effective proteolytic activity
evading the action of inhibitors. A progressive decrease in bone marrow
VCAM-1 levels and concomitant increases in sVCAM-1 in circulation,
together with increases in serine proteases is corroborating evidence.
The specificity of NE and CG on BM VCAM-1 cleavage, but not of other
proteases tested, is of interest, especially when VCAM-1 in other
tissues is cleaved by activated MMPs instead (Hummel et al, J
Neuropathol Exp Neurol. 2001;60:320-327). Despite this enlightening
scenario, lingering questions remain. To what extent do mice deficient
in NE or CG or dipeptidyl peptidase I (DPPI) (Pham et al, Proc Natl
Acad Sci U S A. 1999;96: 8627-8632) mobilize in response to
G-CSF? Are other targets besides VCAM-1 involved? Why is soluble VCAM-1
increased after SCF or IL-3 treatment? If VCAM-1 shedding occurs fairly quickly, why does progenitor mobilization lag for 2 or 3 days after
G-CSF administration? Despite these caveats, the present data
open a new window of observation and may eventually suggest new
strategies to improve mobilization.
Thalia Papayannopoulou
University of Washington
