A number of factors, which are thought to act predominantly as local regulator of cellular function, have been shown to have activity on bone cells or bone organ cultures. These include IL- 1, TNF, gamma interferon, CSF, EGF, TGF alpha and TGF beta. However, not all bone culture models respond identically to these potential local regulators. The responses of fetal long bone and newborn calvaria cultures to EGF and TGF alpha differ. In the latter resorption stimulated by these growth factors is dependent on prostaglandin synthesis while in the former it is not. The mechanisms underlying these differences are unknown. Recently, I have found that the addition of subresorptive concentrations of IL-1 to the medium of fetal long bone cultures causes their responses to EGF and TGF alpha to resembled those of newborn calvaria cultures. These results led me to examine whether bone organ cultures spontaneously produce an IL-1 like factor because differences in the rate of the production of such a factor could explain some of the differences that exist between the response of these two bone organ culture models. I have now generated evidence that both fetal long bone and newborn calvaria cultures produce IL- 1-like factors and that parathyroid hormone, a stimulator of resorption, increases the bioactivity of these factors in the conditioned medium of these cultures. These results are significant because IL-1 is among the most potent polypeptide stimulators of in vitro bone cell activity. Hence, its production by bone cultures suggests that it may be a powerful local regulator of bone cell function. TNF alpha is another factor that has potent effects on bone cell function. In addition, it is frequently produced by the same cells that produce IL-1 and the effects of IL-1 and TNF on bone are similar. Hence, the finding that IL-1 like factors are produced in bone suggests that TNF like factors are also. I propose to further examine the mechanisms that regulate the synthesis and release of IL-1 in bone, identify the cells that produce it and determine what role it plays in the responses of bone to other factors. In addition, I wish to examine whether TNF is also spontaneously produced by bone cultures. If it is, I will perform similar studies to determine its role in bone cell function.
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