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

Abstract

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. 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 calvariae. Recent data suggest that both activated lymphocytes and monocytes release factors which could contribute to this activity. Recently, monocyte-derived tumour necrosis factor alpha (TNF-alpha) and lymphocyte-derived tumour necrosis factor beta (TNF-beta) (previously called lymphotoxin), two multifunctional cytokines which have similar cytotoxic effects on neoplastic cell lines, have been purified to homogeneity and their complementary DNAs cloned and expressed in Escherichia coli. As both of these cytokines are likely to be present in activated leukocyte supernatants, we tested purified recombinant preparations for their effects on bone resorption and bone collagen synthesis in vitro, and report here that both cytokines at 10(-7) to 10(-9) M caused osteoclastic bone resorption 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.

Patterns of expression of tumor necrosis factor α, tumor necrosis factor β, and their receptors in synovia of patients with juvenile rheumatoid arthritis and juvenile spondylarthropathy

“…TNFa has been shown to induce bone resorption and to inhibit proteoglycan synthesis (19,20), to induce prostaglandin E, and collagenase release from synovial cells (21), and to stimulate fibroblast growth. It also up-regulates production of other proinflammatory cytokines (such as interleukin-1 and interleukin-6) and the expression of their respective receptors (22).…”

Possible association of psoriasis and reduced bone mineral density due to increased TNF-α and IL-6 concentrations

“…Specifically, TNF-α enhances bone resorption via stimulating osteoclast development and activity and bone formation (12). On the other hand, IL-6 is also a potent stimulator of bone resorption (13).…”

Long‐term efficacy and safety of etanercept in children with polyarticular‐course juvenile rheumatoid arthritis: Interim results from an ongoing multicenter, open‐label, extended‐treatment trial

“…flammatory cytokine tumor necrosis factor (TNF) has been shown to play a central regulatory role in the pathogenesis of rheumatoid arthritis (3)(4)(5)(6)(7)(8)(9)(10), and TNF levels have been shown to be elevated in both serum and synovial fluid from children with JRA (11). Treatment with etanercept (Enbrel; Immunex, Seattle, WA), a fully human fusion protein that inhibits excess TNF and the subsequent inflammatory cytokine cascade, has proved to be beneficial in adults with rheumatoid arthritis and in children with JRA (12).…”