Macrophage inflammatory protein-1 alpha (MIP-1 alpha) is a member of the
CC chemokine family and is primarily associated with cell adhesion and
migration. It is produced by myeloma (MM) cells and directly stimulates
osteoclast formation and differentiation in a dose dependent way. MIP-1
alpha protein levels were elevated in the bone marrow plasma of MM
patients and correlated with disease stage and activity. MIP-1 alpha was
also elevated in the serum of myeloma patients with severe bone disease
and correlated positively with bone resorption markers providing
evidence for a causal role of MIP-1 alpha in the development of lytic
bone lesions in MM. MIP-1 alpha has also been found to stimulate
proliferation, migration and survival of plasma cells. Mice, which were
inoculated with myeloma cells and treated with a monoclonal rat
anti-mouse MIP-1 alpha antibody, showed a reduction of both paraprotein
and lytic lesions. In addition, MIP-1 alpha enhanced adhesive
interactions between myeloma and marrow stromal cells, increasing the
expression of RANKL and IL-6, which further increased bone destruction
and tumor burden. Myeloma patients with high MIP-1 alpha serum levels
have poor prognosis. The positive correlation between MIP-1 alpha and
beta(2)-microglobulin that has been observed in MM patients at diagnosis
further supports the notion that MIP-1 alpha is not only a chemokine
with osteoclast activity function but is also implicated in myeloma
growth and survival. Therefore, MIP-1 alpha pathway may serve as a
target for the development of novel anti-myeloma therapies
