Analysis of the mechanism of bone destruction by neutrophils

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In this study, we investigated the possibility whether neutrophils in rheumatoid arthritis could destruct calcified bone in vivo and in vitro. Aminobisphosphonate (ABP), an inhibitor of osteoclastic bone resorption, was used to inhibit osteoclast activity in collagen-induced arthritis (CIA). Severe bone destruction in CIA was observed in the CIA mice treated with ABP. In the areawhere bone destruction was detected, many neutrophils were aligned along the destructed bone surface. Some of neutrophils were ruptured and scattered intracellular granules on and in the destructed bone. Bone lining cells were no longer deteted in this region. Some osteoclasts were also detected in this region. However, these osteoclast detached from bone surface and had no ruffled borders and clear zones, which indicated that osteoclast had no capacity to resorb bone. Furthermore, no collagen fibers were detected in the destructed bone matrix. These results strongly suggeted the possibility that neutrophils directly destructed calcified bone. Therefore, we next cocultured neutrophils from rheumatoid arthritis patients and bone fragments and investigated the changes of bone matrix ay the ultrastructural level. Typical collagen fibers in the bone fragments cocultured with neutrophils were disappeared. Destruction of collagen fibers in this culture system was inhibited by the addition of the inhibitors of MMP or elastase. These results indicated that neutrophils destructed bone matrix by their intrinsic proteases such as MMP and elastase.