Locally derived growth factors and cytokines in bone play a crucial role in the regulation of bone remodeling, i.e., bone formation and bone resorption processes. We studied the effect of interleukin (IL)-1, tumor necrosis factor (TNF)-, and Escherichia coli lipopolysaccharide (LPS) on the hormone-activated Ca²⁺ message system in the osteoblastic cell line UMR-106 and in osteoblastic cultures derived from neonatal rat calvariae. In both cell preparations, IL-1, TNF-, and LPS did not alter basal intracellular Ca²⁺ concentration ([Ca²⁺]_i) but attenuated Ca²⁺ transients evoked by parathyroid hormone (PTH) and PGE₂ in a dose (1-100 ng/ml)- and time (8-24 h)-dependent fashion. The cytokines modulated hormonally induced Ca²⁺ influx (estimated by using Mn²⁺ as a surrogate for Ca²⁺) as well as Ca²⁺ mobilization from intracellular stores. The latter was linked to suppressed production of hormonally induced inositol 1,4,5-trisphosphate. The effect of cytokines on [Ca²⁺]_i was abolished by the tyrosine kinase inhibitor herbimycin A (50 ng/ml). The cytokine's effect was, however, independent of nitric oxide (NO) production, since NO donors (sodium nitroprusside) as well as permeable cGMP analogs augment, rather than attenuate, hormonally induced Ca²⁺ transients in osteoblasts. Given the stimulatory role of cytokines on NO production in osteoblasts, the disparate effects of cytokines and NO on the Ca²⁺ signaling pathway may serve an autocrine/paracrine mechanism for modulating the effect of calciotropic hormones on bone metabolism.