p44/42 MAPK activation is necessary for receptor activator of nuclear factor-κB ligand induction by high extracellular calcium

Although extracellular calcium (Ca-o(2+)) has been suggested to modulate bone remodeling, the exact mechanism is unclear. This study was performed to explore the signaling pathways of high Ca-o(2+) that are responsible for controlling the expression of receptor activator of NF-kappaB ligand (RANKL) in mouse osteoblastic cells. As previously reported, high Ca-o(2+) increased RANKL expression. However, the G protein-coupled Ca-o(2+)-sensing receptor (CaSR) was not detected in the primary cultured mouse osteoblastic cell. The inhibition of the pertussis-sensitive G protein, phospholipase C, protein kinase C, intracellular calcium mobilization, p38 MAPK, or phosphoinositide 3-kinase did not block RANKL induction caused by high Ca-o(2+). In contrast, the inhibition of p44/42 MAPK pathway reduced the RANKL expression induced by high Ca-o(2+). Moreover, high Ca-o(2+) activated p44/42 MAPK and MEK1/2. These results suggest that RANKL induction by high Ca-o(2+) might not be mediated by CaSR and its putative downstream signaling pathways, but the pathway employing p44/42 MAPK is involved in the high Ca-o(2+)-induced RANKL expression in mouse osteoblastic cells. (C) 2003 Elsevier Science (USA). All rights reserved.