Possible involvement of MIP-1α in the recruitment of osteoclast progenitors to the distal tibia in rats with adjuvant-induced arthritis

In the rat model of rheumatoid arthritis, a marked formation of osteoclasts is found in the distal tibia and the metatarsal bone. It was therefore postulated that osteoclast progenitors would be increased in the bone marrow cavities of rats with adjuvant-induced arthritis (AA rats). Bone marrow cells obtained from tibia of AA rats were cultured to form cells in the osteoclast lineage to access the number of osteoclast progenitors. Unexpectedly, only a suppressed level of osteoclast progenitors was detected in the diaphyseal bone marrow of tibia in AA rats. Distribution of osteoclast progenitors in the bone marrow cavity was examined, and it was shown that osteoclast progenitors accumulated in the distal tibia. Macrophage inflammatory protein (MIP)-1α, an osteoclastogenic CC chemokine, was expressed in ED-1-positive macrophages localizing in the distal tibia with marked bone destruction. Chemotaxis studies showed that MIP-1α expressed significant activity towards bone marrow cells. The suppressed level of osteoclastogenesis in bone marrow cells of AA rats was restored to a normal level by the addition of MIP-1α. It was suggested that MIP-1α is involved in the migration of osteoclast progenitors to the distal tibia as well as in osteoclastogenesis in AA rats. In these rats, in situ hybridization of the distal tibia with a high level of bone destruction showed significant expression of Receptor activator nuclear factor κB ligand (RANKL) messenger RNA in aggregates of multinucleated osteoclast-like cells present in the bone marrow cavity, a unique pathological feature for these rats. Migrated osteoclast progenitors are thought to be efficiently differentiated into osteoclasts in response to RANKL expressed by the aggregates of osteoclast-like cells under the influence of the MIP-1α. Such positive-feedback regulation of osteoclastogenesis could result in the highest recruitment of active osteoclasts in the area of marked bone destruction.