Temporal sequence of interleukin 1α—mediated stimulation and inhibition of bone formation by isolated fetal rat calvaria cells in vitro

Cytokines released at sites of inflammation and infection may alter normal bone remodeling processes resulting in pathologic bone destruction or bone formation. Interleukin 1, an inflammatory mediator, has been shown to stimulate as well as inhibit parameters associated with bone formation. In this study we have examined temporal aspects of the biphasic effects of recombinant interleukin 1 alpha (IL 1 alpha) on the differentiation of osteoprogenitor cells into bone-forming osteoblasts (bone nodules) in vitro. A dose-dependent stimulation of bone formation over a concentration range of 0.5 to 50 U/mL (1.4 x 10(-12) to 1.4 x 10(-10) M) was observed when preconfluent, primary cultures of fetal rat calvaria (RC) cells were pulsed with IL 1 alpha for 72 to 96 hr from the beginning of the culture period. This was correlated with a stimulation of cell proliferation and alkaline phosphatase activity measured during the late log phase of growth. In contrast, continuous exposure to IL 1 alpha or exposure to IL 1 alpha after confluency resulted in inhibition of bone nodule formation and alkaline phosphatase activity. IL 1 alpha-stimulated prostaglandin E2 (PGE2) production until the RC cells became multilayered, but the addition of the cyclooxygenase inhibitor indomethacin had no effect in reducing the IL 1 alpha-mediated stimulation of cell proliferation or bone nodule formation. However, in cultures continuously exposed to IL 1 alpha, added indomethacin partially reduced the inhibition of bone formation, suggesting that prostaglandin production may play a role in the inhibitory effects of IL 1 alpha on bone formation.