IN-VITRO PRODUCTION OF CYTOKINES BY BONE SURFACE-DERIVED OSTEOBLASTIC CELLS IN NORMAL AND OSTEOPOROTIC POSTMENOPAUSAL WOMEN - RELATIONSHIP WITH CELL-PROLIFERATION

To evaluate the role of cytokines produced by osteoblasts in the pathophysiology of bone lesions in postmenopausal osteoporosis (PMOP), we have determined by RIA and immunoradiometric assays the levels of prostaglandin E2 (PGE2), interleukin-1beta (IL-1), tumor necrosis factor-alpha (TNFalpha), and IL-6 released by cultured bone surface-derived osteoblastic (OB) cells isolated from 24 untreated PMOP women with high, low, or normal bone turnover on bone biopsy. OB cells isolated from patients with high bone formation had a 2-fold increased proliferation rate in vitro compared to OB cells from patients with normal or low bone formation or OB cells from age-matched controls. The spontaneous in vitro production per cell protein of PGE2, IL-1, and TNFalpha, but not of IL-6, was 2- to 3-fold lower in rapidly proliferating OB cells isolated from PMOP patients with high bone formation compared to OB cells from patients with normal or low proliferation or control cells. Treatment with 10 nmol/L 1,25-dihydroxyvitamin D (48 h) increased PGE2 levels to normal values in OB cells with a high proliferation rate, but decreased PGE, production in cells with low proliferation and in control cells, suggesting that the release of PGE2 was dependent on the stage of maturation of OB cells. Significant correlations were found between IL-1 and TNFalpha (r = 0.87; P < 0.001), IL-1 and PGE2 (r = 0.46; P < 0.05), IL-6 and IL-1 (r = 0.39; P < 0.05), and IL-6 and TNFalpha (r = 0.49; P < 0.05), suggesting that the production of these cytokines was under reciprocal control. The results indicate that the in vitro production of PGE2, IL-1, and TNFalpha, but not IL-6, by OB cells isolated from patients with PMOP is related to the proliferation rate of these cells and the rate of bone formation. The variable production of cytokines by OB cells may contribute to the histological heterogeneity of bone formation in PMOP.