A novel role of IL-15 in the development of osteoclasts: Inability to replace its activity with IL-2

IL-15 shares many activities with IL-2 on stimulating lymphocytes, hematopo ietic progenitor cells, and macrophages, However, the role of IL-15 in oste oclastogenesis has not been elucidated. The recent finding of abundant IL-1 5 in rheumatoid arthritis synovial fluids suggested a possible role for thi s cytokine in the pathological destruction of bone and prompted us to deter mine whether IL-15 stimulates osteoclast formation. IL-15 stimulated the fo rmation of multinucleated osteoclast-like cells in rat bone marrow cultures . In stroma-free cultures, IL-15 increased the number of mononuclear preost eoclast-like cells in the early stage of osteoclast formation. The stimulat ion was observed even after treatment with IL-15 for only 24 or 48 h of cul ture. Moreover, low IL-15 concentration (0.1 ng/ml) strongly increased the level of calcitonin receptor mRNA of mononuclear preosteoclast-like cells. Although IL-15 is known as a potent stimulator of TNF-alpha, its activity w as not abolished by addition of anti-TNF-alpha Ab, Interestingly, IL-2 and IL-7, which utilize some IL-ISR components, had no effect on osteoclast dif ferentiation, but pretreatment with IL-2 or IL-7 of bone marrow cells befor e the addition of IL-15 inhibited the enhancing activity of IL-15, In summa ry, IL-15 has a novel activity to stimulate the differentiation of osteocla st progenitors into preosteoclasts, which cannot be replaced by IL-2 but ma y use components in common with IL-2R to mediate its effects.