MACROPHAGE INFLAMMATORY PROTEIN-1-ALPHA AND IL-8 STIMULATE THE MOTILITY BUT SUPPRESS THE RESORPTION OF ISOLATED RAT OSTEOCLASTS

Cells of the osteoblastic lineage play a major role in the regulation oi osteoclastic bone resorption. Recent studies have demonstrated prod uction of chemokines by osteoblastic cells. Although these phagocyte-s timulating and proinflammatory cytokines act as chemoattractants and a ctivators for other members of the hemopoietic lineage, their actions on osteoclasts have not been characterized. We found that macrophage i nflammatory protein-1 alpha (MIP-1 alpha) and IL-8 inhibited bone reso rption by rat osteoclasts, primarily through reduction in the proporti on of osteoclasts resorbing bone, a pattern of inhibition previously o bserved in response to macrophage CSF (M-CSF). MIP-2, RANTES, MIP-1 be ta, and monocyte chemotactic protein-1 were without effect on resorpti on. MIP-1 alpha and IL-8, but not the other chemokines, also stimulate d osteoclastic motility and increased the osteoclast spread area in a dose-dependent manner, over the same concentration range as that which inhibited bone resorption. In addition, MIP-1 alpha induced osteoclas t orientation in a gradient of the chemokine, and stimulated osteoclas t migration. We detected no effect of chemokines on osteoclast formati on or survival. Our data suggest that chemokines can promote osteoclas t orientation and migration, processes that might be involved in chemo taxis; it seems appropriate that resorptive functions should be suppre ssed during migration. Because chemokines are proinflammatory, their a ctions on osteoclasts might represent mechanisms by which bone resorpt ion is modulated by the inflammatory process when this occurs in bone. However, given that chemokines are increasingly recognized to be mult ifunctional and that they are produced by cells of the osteoblastic li neage, they may also be components of the physiologic regulation of bo ne resorption.