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Molecular and Cellular Biology, November 2009, p. 5843-5857, Vol. 29, No. 21
0270-7306/09/$08.00+0     doi:10.1128/MCB.01549-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Extracellular Signal-Regulated Kinase 1 (ERK1) and ERK2 Play Essential Roles in Osteoblast Differentiation and in Supporting Osteoclastogenesis{triangledown} ,{dagger}

Takehiko Matsushita,1 Yuk Yu Chan,1 Aya Kawanami,1 Gener Balmes,4 Gary E. Landreth,2 and Shunichi Murakami1,3*

Department of Orthopaedics, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio 44106,1 Department of Neurosciences, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio 44106,2 Department of Genetics, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio 44106,3 Department of Molecular Genetics, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, Texas 770304

Received 3 October 2008/ Returned for modification 4 January 2009/ Accepted 25 August 2009

Osteoblasts and chondrocytes arise from common osteo-chondroprogenitor cells. We show here that inactivation of ERK1 and ERK2 in osteo-chondroprogenitor cells causes a block in osteoblast differentiation and leads to ectopic chondrogenic differentiation in the bone-forming region in the perichondrium. Furthermore, increased mitogen-activated protein kinase signaling in mesenchymal cells enhances osteoblast differentiation and inhibits chondrocyte differentiation. These observations indicate that extracellular signal-regulated kinase 1 (ERK1) and ERK2 play essential roles in the lineage specification of mesenchymal cells. The inactivation of ERK1 and ERK2 resulted in reduced beta-catenin expression, suggesting a role for canonical Wnt signaling in ERK1 and ERK2 regulation of skeletal lineage specification. Furthermore, inactivation of ERK1 and ERK2 significantly reduced RANKL expression, accounting for a delay in osteoclast formation. Thus, our results indicate that ERK1 and ERK2 not only play essential roles in the lineage specification of osteo-chondroprogenitor cells but also support osteoclast formation in vivo.

* Corresponding author. Mailing address: Dept. of Orthopaedics, Case Western Reserve University, 2109 Adelbert Road, BRB 329, Cleveland, OH 44106. Phone: (216) 368-1371. Fax: (216) 368-1332. E-mail: shun{at}case.edu

{triangledown} Published ahead of print on 8 September 2009.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, November 2009, p. 5843-5857, Vol. 29, No. 21
0270-7306/09/$08.00+0     doi:10.1128/MCB.01549-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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