RANKL-stimulated TNFα production in osteoclast precursor cells promotes osteoclastogenesis by modulating RANK signaling pathways

Although TNF alpha is known to be an important factor for bone resorption, particularly in inflammatory bone diseases, the relevance between RANKL and TNF alpha in osteoclastogenesis remains unclear. In this study we examined the mechanism of TNF alpha induced osteoclastogenesis and its downstream signaling. We show that osteoclastogenesis is suppressed by anti-TNF alpha- and anti-TNF receptor type I (TNFRI)-antibodies and in TNF alpha- and TNFRI-deficient mice using in vitro culture systems: (1) co-culture of mouse spleen derived osteoclast precursor cells (pOCs) with osteoblasts, (2) pure pOC culture and (3) RAW264.7 cells in presence of RANKL. Furthermore, TNF alpha production in pOCs was stimulated by RANKL. Endogenous TNF alpha in pOCs induced c-Fos and NFATc1. Expression rates of NFATc1 and c-Fos were significantly decreased in TNF alpha- and TNFRI-deficient pOCs during osteoclastogenesis. These results indicate that TNF alpha is induced by RANKL in pOCs and serves as an autocrine factor promoting osteoclastogenesis through c-Fos and NFATc1 activation. (c) 2007 Elsevier Inc. All rights reserved.