Stimulation of bone resorption and inhibition of bone formation in vitro by human tumour necrosis factors

When leukocytes are exposed to mitogens or antigens in vitro, they release bone-resorbing activity into the culture supernatants which can be detected by bioassay^1,2. Like many lymphocyte-monocyte products, this activity has been difficult to purify because of its low abundance in activated leukocyte cultures and the unwieldy bioassay required to detect biological activity. Partially purified preparations of this activity inhibit bone collagen synthesis in organ cultures of fetal rat calvariae³. Recent data suggest that both activated lymphocytes and monocytes release factors which could contribute to this activity². Recently, monocyte-derived tumour necrosis factor α (TNF-α) and lymphocyte-derived tumour necrosis factor β (TNF-β) (previously called lymphotoxin), two multifunctional cytokines which have similar cytotoxic effects on neoplastic cell lines, have been purified to homogeneity^4,5 and their complementary DNAs cloned and expressed in Escherichia coli^6,7. As both of these cytokines are likely to be present in activated leukocyte supernatants, we tested purified recombinant preparations for their effects on bone r(c)sorption and bone collagen synthesis in vitro, and report here that both cytokines at 10 ^-7 to ^10-9M caused osteoclastic bone r(c)sorption and inhibited bone collagen synthesis. These data suggest that at least part of the bone-resorbing activity present in activated leukocyte culture supernatants may be due to these cytokines.