Effects of human 17 kDa interleukin 1, 25-31 kDa thymocyte stimulating activity and the 6-9 kDa interleukin 1 inhibitor on calcium release in the newborn murine calvarial assay.

The effects of human monokines on calcium release from cultured newborn murine calvarium were studied. Highly purified interleukin 1 (IL-1) (17 kDa) and recombinant IL-1 beta in the concentration range 0.2-20 U/ml released significant amounts of calcium. Mean resorption indices (RI) at 0.2 U/ml were 1.28 and 1.49, and at 20 U/ml, were 1.82 and 1.72, respectively. Calcium release was abrogated by the cyclooxygenase inhibitor piroxicam. Thymocyte stimulating activity (TSA) 25-31 kDa alone at 0.14 U/ml released calcium in a prostaglandin dependent manner with a mean RI of 2.13, a significantly greater calcium release than that obtained by 17 kDa IL-1 at 20 U/ml. The 6-9 kDa inhibitor of IL-1 induced thymocyte proliferation alone also released calcium in a prostaglandin dependent manner with a mean RI of 2.29 at 200 inhibitory U/ml. Addition of 6-9 kDa IL-1 inhibitor to the 25-31 kDa material did not significantly change the calcium release, whereas addition of the inhibitor to 17 kDa IL-1 produced a significant increase in calcium release.

The metabolism and immunology of bone.

Many cells and their cytokines produce a significant effect on bone metabolism. Bone matrix synthesis is a function of the osteoblast (Fig 1), influenced directly by numerous local and systemic factors (Tables 1 and 2). Locally synthesized factors such as SGF, BMP, and BDGF may be particularly important in stimulating new bone formation at sites of bone resorption or following bony injury. Of the systemic factors, GH; somatomedin C (IGF-1); high concentrations of insulin, testosterone, PDGF and TGF beta; and low concentrations of PGE2 and IL-1 appear to stimulate bone formation in vitro. These latter factors may be more important in maintaining skeletal growth and bone mass. Bone resorption by osteoclasts (Figs 2 and 3) is also controlled by the osteoblast, as this cell produces a leukotriene-dependent polypeptide that stimulates osteoclastic bone resorption. Osteoblasts cover the periosteal and endosteal bone-surfaces and limit exposure of the underlying bone to osteoclasts. PTH, vitamin D, PGE2, and other systemic factors interact directly with the osteoblast, not the osteoclast. Surface receptor binding of PTH increases intracellular cAMP and calcium and results in release of the factor that stimulates osteoclastic bone resorption. PGE2 induces osteoblasts to activate osteoclasts and is a major controlling factor in bone metabolism; the osteoblast produces PGE2, which can then modify osteoblastic function by positive feedback. Although low concentrations of PGE2 stimulate bone formation, higher concentrations promote osteoblast-mediated bone resorption. Furthermore, many of the systemic factors stimulate bone resorption via a PGE2-associated mechanism. Immune cytokines also appear to exert a profound influence on bone metabolism. INF-gamma inhibits osteoclastic resorption, whereas IL-1, TNF, and LT strongly stimulate bone resorption. However, low concentrations of IL-1 paradoxically result in stimulation of bone formation. These cytokines, particularly in various combinations, may prove extremely important in understanding and treating the bone loss associated with malignancies, osteoporosis, and rheumatoid arthritis.