ROLE OF INTERLEUKIN-6 IN UNCOUPLING OF BONE IN-VIVO IN A HUMAN SQUAMOUS CARCINOMA COPRODUCING PARATHYROID HORMONE-RELATED PEPTIDE AND INTERLEUKIN-6

OCC tumor has been established from a human squamous carcinoma associa ted with humoral hypercalcemia of malignancy (HHM) and shown to overpr oduce parathyroid hormone-related peptide (PTHrP) and cause aggressive hypercalcemia when implanted inter nude rats. In the present study, w e have demonstrated by reverse transcription-polymerase chain reaction and Northern blot analysis that OCC tumor also overexpressed interleu kin 6 (IL-6) mRNA and that tumor-bearing animals exhibited a marked in crease in plasmas IL-6 as well as PTHrP concentrations. When a monoclo nal antibody against human IL-6 was injected to block the activities o f tumor-derived IL-6, bone loss in tumor-bearing animals was significa ntly presented. Quantitative bone histomorphometric analysis revealed that treatment with anti-IL-6 antibody caused a substantial decrease i n both osteoclast number and eroded surface (as parameters of bone res orption) and also a significant increase in the mineral apposition rat e, but little effect on the osteoblastic surface. These results provid e in vivo evidence suggesting that in tumors coproducing IL-6 and PTHr P, IL-6 is involved not only in the acceleration of osteoclastic bone resorption but also, at least in part, in the suppression osteoblastic functions in HHM syndrome.