Osteoprotegerin production by human osteoblast lineage cells is stimulated by vitamin D, bone morphogenetic protein-2, and cytokines.

Osteoprotegerin (OPG), a newly discovered member of the tumor necrosis factor receptor family, is a potent inhibitor of osteoclastogenesis. The overexpression of OPG in transgenic mice leads to osteopetrosis, whereas targeted ablation of OPG in knock-out mice leads to severe osteoporosis. However, the production and regulation of OPG in normal human bone has not been studied. Thus, we assessed OPG mRNA expression and protein secretion in human osteoblastic lineage cells. 1,25-Dihydroxyvitamin D3 (10(-7) M) increased OPG mRNA levels by 90 and 50% in a fetal osteoblastic cell line (hFOB) and normal trabecular osteoblastic cells (hOB) cells, respectively, but did not affect OPG mRNA levels in a marrow stromal preosteoblastic (hMS) cell line. Interleukin (IL)-1beta (5 x 10(-9) M), tumor necrosis factor (TNF)-alpha (9 x 10(-9) M), and bone morphogenetic protein (BMP)-2 (100 ng/ml) also increased OPG mRNA levels in hFOB cells by 4-, 6-, and 4-fold, respectively. Treatment with 1,25-dihydroxyvitamin D3, IL-1beta, TNF-alpha, and BMP-2 increased OPG protein production by hFOB cells by 60, 390, 300, and 80%, respectively (P < 0.001). Because it is expressed in various types of human osteoblastic cells, and is stimulated by vitamin D, BMP-2 and cytokines, OPG may be an important paracrine modulator of bone remodeling.