A recent study conducted in mice, baboons, and human volunteers has shown that a non-steroidal
anti-inlammatory drug approved by the U.S. Food
and Drug Administration (FDA), called meloxicam,
signiicantly increased the number of blood
(hematopoietic) stem cells (HSCs) and their descendent
hematopoietic progenitor cells (HPCs) entering the
circulation from the bone marrow, where they typically
reside until needed. This inding sheds light on how
the body responds to injury and has implications for
blood cell transplantation. The hematopoietic niche of
the bone marrow supports the survival and self-renewal
of HSCs and HPCs, yet prevents the ill-timed release
of these cells into the circulation. When used to treat
cancers such as non-Hodgkin’s lymphoma and multiple
myeloma, high-dose chemotherapy also destroys
normal cells such as the HSCs and HPCs in the bone
marrow. To replenish the lost cells, HSCs and HPCs
are routinely harvested from a donor’s or patient’s
blood, and then transplanted back into the patient at the
conclusion of the chemotherapy procedure to repopulate
the bone marrow. The levels of HSCs and HPCs
normally found in blood are very low, and strategies
have been devised to mobilize HSCs and progenitor
cells out of the bone marrow and into the circulation.
The naturally occurring protein G-CSF often is used
clinically to mobilize cells, but this strategy does not
work for approximately 10 to 20 percent of individuals.
Research continues in order to identify more effective
strategies to mobilize cells out of the microenvironment
of the marrow and into the circulation.
Building on their previous research indings, which
showed that prostaglandin E2 enhanced HSC
survival and homing to the bone marrow, researchers
demonstrated that meloxicam treatment of mice
greatly increased the numbers HSCs and HPCs in the
circulation. Mice treated with a combination of G-CSF
and meloxicam mobilized signiicantly more cells
than those treated with either drug separately. Similar
to indings in mice, meloxicam treatment of both
baboons and healthy human volunteers increased HSCs
and HPCs in the circulation. Additional experiments
were conducted to determine how meloxicam exerts
its biological effect. Previous research showed
that prostaglandin E2 signals through one or more
of the four E-prostanoid (EP1-4) receptors. Using
genetically altered mouse strains each lacking one
of the EP receptors, it was shown that mice lacking
EP4 receptor had increased HSCs and HPCs in the
circulation and meloxicam had no additional effect.
These indings strongly suggest that meloxicam targets
the prostaglandin E2/EP4 receptor signaling pathway.
Moreover, the researchers showed that mice deicient in
osteopontin, a component of the HSC niche, mobilized
HPCs but not HSCs when treated with meloxicam.
This result demonstrates that meloxicam decreases
osteopontin levels in the HSC niche, which then permits
HSC, but not HPC, mobilization out of the marrow.
This study has several potentially important clinical
implications. Meloxicam in combination with
G-CSF may improve the success rates of blood stem
cell transplantation by making it easier to obtain
suficient numbers of cells for transplant. Meloxicam
is FDA-approved for use and therefore additional
toxicology studies need not be conducted, saving both
time and money. And, meloxicam has comparatively
few side effects compared to other non-steroidal
Hoggatt J, Mohammad KS, Singh P, et al. Differential
stem‑ and progenitor‑cell traficking by prostaglandin E2.
Nature 495: 365-369, 2013.