Tumor Necrosis Factor-α Inhibits Collagen Synthesis and Alkaline Phosphatase Activity Independently of Its Effect on Deoxyribonucleic Acid Synthesis in Osteoblast-Enriched Bone Cell Cultures*

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Abstract
Tumor necrosis factor-.alpha. (TNF.alpha.), a product of activated monocytes, induces tissue wasting in certain solid tumors in vivo and in in vitro model systems. Recent studies indicate that TNF.alpha. also regulates cell replication and expression of differentiated function in a variety of nonneoplastic cell systems. Since monocyte products could accumulate in bone with trauma, inflammation, or other disease states, bone cell activity might be altered by the presence of these pathophysiological molecules. Using cells obtained by sequential enzyme release from fetal rat parietal bone, we find that TNF.alpha. has acute stimulatory and inhibitory effects on bone cell macromolecular synthesis. Within 24 h of exposure, recombinant human TNF.alpha. at 0.3-100 nM progressively increases the rate of DNA synthesis in osteoblast-enriched cell cultures up to 3- to 4-fold, and 3-100 nM TNF.alpha. reduces collagen production and alkaline phosphatase activity by 20-30%. These decreases are not altered by 1 mM hydroxyurea, which blocks the mitogenic effect of TNF.alpha. by 85-90%. In addition, hydroxyproline levels in the culture medium do not increase relative to the control value after TNF.alpha. treatment, suggesting that decreased collagen production results from less synthesis rather than increased collagen degradation. Hybridization studies with cDNA encoding the .alpha.1-chain of rat type I collagen show that TNF.alpha. increases type I collagen mRNA to an extent similar to its effect on cell replication. Therefore, TNF.alpha. appears to inhibit collagen synthesis and alkaline phosphatase activity in osteoblast-enriched cell cultures by mechanisms that are not related to its effects on cell replication.

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