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Molecular and Cellular Biology, January 2008, p. 344-357, Vol. 28, No. 1
0270-7306/08/$08.00+0     doi:10.1128/MCB.00617-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

A-Raf and B-Raf Are Dispensable for Normal Endochondral Bone Development, and Parathyroid Hormone-Related Peptide Suppresses Extracellular Signal-Regulated Kinase Activation in Hypertrophic Chondrocytes

Sylvain Provot,^1,2 Gregory Nachtrab,¹ Jennifer Paruch,¹ Adele Pin Chen,^3, Alcino Silva,³ and Henry M. Kronenberg^1*

Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, 50 Blossom Street, Boston, Massachusetts 02114,¹ Department of Anatomy, University of California, San Francisco, 513 Parnassus Avenue, Box 0452, San Francisco, California 94143,² Departments of Neurobiology, Psychiatry, and Psychology and Brain Research Institute, University of California, Los Angeles, Room 2357, Gonda Building, Box 951761, 695 Charles Young Drive South, Los Angeles, California³

Received 9 April 2007/ Returned for modification 16 May 2007/ Accepted 17 October 2007

Parathyroid hormone-related peptide (PTHrP) and the parathyroid hormone-PTHrP receptor increase chondrocyte proliferation and delay chondrocyte maturation in endochondral bone development at least partly through cyclic AMP (cAMP)-dependent signaling pathways. Because data suggest that the ability of cAMP to stimulate cell proliferation involves the mitogen-activated protein kinase kinase kinase B-Raf, we hypothesized that B-Raf might mediate the proliferative action of PTHrP in chondrocytes. Though B-Raf is expressed in proliferative chondrocytes, its conditional removal from cartilage did not affect chondrocyte proliferation and maturation or PTHrP-induced chondrocyte proliferation and PTHrP-delayed maturation. Similar results were obtained by conditionally removing B-Raf from osteoblasts. Because A-raf and B-raf are expressed similarly in cartilage, we speculated that they may fulfill redundant functions in this tissue. Surprisingly, mice with chondrocytes deficient in both A-Raf and B-Raf exhibited normal endochondral bone development. Activated extracellular signal-regulated kinase (ERK) was detected primarily in hypertrophic chondrocytes, where C-raf is expressed, and the suppression of ERK activation in these cells by PTHrP or a MEK inhibitor coincided with a delay in chondrocyte maturation. Taken together, these results demonstrate that B-Raf and A-Raf are dispensable for endochondral bone development and they indicate that the main role of ERK in cartilage is to stimulate not cell proliferation, but rather chondrocyte maturation.

Published ahead of print on 29 October 2007.

Present address: Key Laboratory of Systems Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031 China.

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