The effect of activin A, an antagonist of IL-1 and IL-6, on osteoclast formation.

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The skeleton is a dynamic organ in which mineralized bone is continuously resorbed by osteoclasts, and new bone is formed by osteoblasts. This process, known as bone remodeling, is normally highly regulated with maintenance of a normal amount of bone. Chronic infection of the periodontal tissue and menopause put the process out of balance and enhance bone resorption by stimulating production of factors such as interleukin-1 (IL-1) and IL-6. Our previous study demonstrated that activin A, a member of transforming growth factor beta (TGF-β), inhibited the production of IL-1β and enhanced secretion of IL-1 receptor antagonist in monocytic cells stimulated by phorbol ester and lipopolysaccharide. Activin-A also inhibits the biological activities of IL-6 in various types of cells. In this study, we examined the role of TGF-β family members including activin-A in the osteoclast formation and obtained interesting results as follows : when mouse bone marrow cells were co-cultured with bone stromal cells, all the TGF-β family members tested (TGF-β1, activin-A, BMP-2) stimulated vitamin D3- and IL-1α-mediated osteoclast formation ; enhancement of osteoclast formation by BMP-2 appeared to be mediated through accumulation of osteoclast differentiation factor (ODF) mRNA in bone stromal cells ; when bone marrow cells were cultured in the presence of M-CSF and ODF, activin-A strongly enhanced osteoclast formation. These results suggest that TGF-β family members play an important role in osteoclastogenesis and that inhibitors of activin-A can be used as a therapeutic agent of osteoporosis and periodontitis.