INTERLEUKIN-6 PRODUCTION IN FETAL-RAT LONG-BONE CULTURES IS CORRELATED WITH PGE(2) RELEASE AND DOES NOT CORRELATE WITH THE EXTENT OF BONE-RESORPTION

Reports from several laboratories have suggested that interleukin 6 (IL-6) may play a role in the process of bone resorption. We have extended these studies by examining the role of IL-6 in fetal rat long bone (FRLB) resorption stimulated by a variety of agents, including parathyroid hormone (PTH); 1,25 dihydroxyvitamin D3 (1,25(OH)2D3); interleukin 1 (IL-1); tumour necrosis factor alpha (TNF-α) and lipopolysaccharide (LPS). This model of bone resorption does not require the generation of osteoclasts in order to elicit a resorptive response and allowed us to assess whether IL-6 can directly affect osteoclastic bone resorption. We confirmed previous studies which showed that exogenous recombinant murine or human IL-6 does not stimulate bone resorption and demonstrated that IL-6, when added prior to the addition of parathyroid hormone, caused a significant but somewhat variable inhibition at 120 hours. Exogenous PGE2 stimulated both IL-6 production and resorption in FRLB cultures in a concentration-dependent manner. Endogenous production of IL-6 in fetal rat long bone (FRLB) cultures was stimulus dependent and generally correlated with prostaglandin E2 (PGE2) levels in the same cultures. However, endogenous IL-6 production did not correlate with the extent of bone resorption, except when IL-1 and PGE2 were used as stimuli. Addition of indomethacin and diclofenac to IL-1 stimulated cultures demonstrated that both the IL-6 production and bone resorption were largely PGE-2 dependent. Neutralizing anti-IL-6 antibodies inhibited IL-6 activity in FRLB cultures but did not affect bone resorption, even in the IL-1 stimulated cultures. Taken together, these data suggest that, in general, IL-6 produced by fetal rat long bones correlates with prostaglandin production and is not directly related to resorption in FRLB cultures, irrespective of the stimulus employed. However this does not exclude the possibility that IL-6 may be involved in the maturation or differentiation of osteoclasts. © 1994.