Department of Orthopaedics, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio 44106, USA.
J Orthop Res. 2011 Mar;29(3):375-9. doi: 10.1002/jor.21262. Epub 2010 Oct 4.
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.
FGFR3 激活突变导致人类最常见的侏儒症形式：软骨发育不全和致死性发育不良。在软骨发育不全的小鼠模型中，最近的研究表明 ERK MAPK 通路（FGFR3 激活的通路）在骨生长减少中起作用。我们最近的研究表明，软骨细胞中 Fgfr3 和 ERK MAPK 信号的增加也会导致颅底和脊椎的骺板过早闭合，从而导致软骨发育不全中延髓孔和椎管的有时致命狭窄。相反，ERK1 和 ERK2 的减少或失活是否促进骨生长并延迟骺板闭合仍有待研究。在这项研究中，我们使用 Col2a1-Cre 和 Col2a1-CreER 转基因在 ERK1 缺失小鼠的软骨细胞中失活 ERK2。我们发现，软骨细胞中 ERK1 和 ERK2 的遗传失活增强了软骨状骨骼成分的生长。我们还发现，软骨细胞中 ERK1 和 ERK2 的出生后失活延迟了骺板闭合并扩大了椎管。这些观察结果使 ERK1 和 ERK2 成为治疗软骨发育不全和其他 FGFR3 相关骨骼综合征的有吸引力的靶标。
