ERK1 and ERK2 play essential roles in osteoblast differentiation and in supporting osteoclastogenesis

Abstract 2 Osteoblasts and chondrocytes arise from common osteo-chondroprogenitor ce lls. We show here 3 that inactivation of ERK1 and ERK2 in osteo-chondroprogenitor cells causes a block in 4 osteoblast differentiation and l eads to ectopic chondrogenic differentiation in the bone forming 5 region in the perichondrium. Furthermore, incr eased MAPK signaling in mesenchymal cells 6 enhances osteoblast differentiation and inhibits chondrocyte differentiation. These observations 7 indicate that ERK1 and ERK2 play essential roles in the lineage specification of mesenchymal 8 cells. The inactivation of ERK1 and ERK2 re sulted in reduced beta-catenin expression, 9 suggesting a role for canonical Wnt signaling in ERK1 and ERK2 regulation of skeletal lineage 10 specification. Furthermore, inactivation of ERK1 and ERK2 significantly reduced RANKL 11 expression, accounting for a delay in osteoclast fo rmation. Thus, our results indicate that ERK1 12 and ERK2 not only play essential roles in th e lineage specification of osteo-chondroprogenitor