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Genetic inactivation of ERK1 and ERK2 in chondrocytes promotes bone growth and enlarges the spinal canal
Author(s) -
Sebastian Arjun,
Matsushita Takehiko,
Kawanami Aya,
Mackem Susan,
Landreth Gary E.,
Murakami Shunichi
Publication year - 2011
Publication title -
journal of orthopaedic research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.041
H-Index - 155
eISSN - 1554-527X
pISSN - 0736-0266
DOI - 10.1002/jor.21262
Subject(s) - achondroplasia , synchondrosis , mapk/erk pathway , medicine , chondrocyte , dwarfism , cartilage , anatomy , biology , endocrinology , microbiology and biotechnology , signal transduction , genetics , surgery , gene
Activating mutations in FGFR3 cause the most common forms of human dwarfism: achondroplasia and thanatophoric dysplasia. In mouse models of achondroplasia, recent studies have implicated the ERK MAPK pathway, a pathway activated by FGFR3, in creating reduced bone growth. Our recent studies have indicated that increased Fgfr3 and ERK MAPK signaling in chondrocytes also causes premature synchondrosis closure in the cranial base and vertebrae, accounting for the sometimes fatal stenosis of the foramen magnum and spinal canal in achondroplasia. Conversely, whether the decrease—or inactivation—of ERK1 and ERK2 promotes bone growth and delays synchondrosis closure remains to be investigated. In this study, we inactivated ERK2 in the chondrocytes of ERK1 ‐null mice using the Col2a1‐Cre and Col2a1‐CreER transgenes. We found that the genetic inactivation of ERK1 and ERK2 in chondrocytes enhances the growth of cartilaginous skeletal elements. We also found that the postnatal inactivation of ERK1 and ERK2 in chondrocytes delays synchondrosis closure and enlarges the spinal canal. These observations make ERK1 and ERK2 an attractive target for the treatment of achondroplasia and other FGFR3‐related skeletal syndromes. © 2010 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 29:375–379, 2011