Delayed bone age due to a dual effect of FGFR3 mutation in Achondroplasia

Autor: Jean-Philippe Jais, Laurence Legeai-Mallet, Emilie Mugniery, Catherine Benoist-Lasselin, Aurélie Jonquoy, T. Odent, Stéphanie Pannier, Arnold Munnich
Rok vydání: 2010
Předmět:
Zdroj: Bone. 47(5)
ISSN: 1873-2763
Popis: Achondroplasia (ACH), the most common form of human dwarfism is caused by a mutation in the Fibroblast Growth Factor Receptor 3 (FGFR3) gene, resulting in constitutive activation of the receptor. Typical radiological features include shortening of the tubular bones and macrocephaly, due to disruption of endochondral ossification. Consequently, FGFR3 has been described as a negative regulator of bone growth. Studying a large cohort of ACH patients, a delay in bone age was observed shortly after birth (for boys p=2.6×10(-9) and for girls p=1.2×10(-8)). This delay was no longer apparent during adolescence. In order to gain further insight into bone formation, bone development was studied in a murine model of chondrodysplasia (Fgfr3(Y367C/+)) from birth to 6weeks of age. Delayed bone age was also observed in Fgfr3(Y367C/+) mice at 1week of age followed by an accelerated secondary ossification center formation. A low level of chondrocyte proliferation was observed in the normal growth plate at birth, which increased with bone growth. In the pathological condition, a significantly high level of proliferative cells was present at birth, but exhibited a transient decrease only to rise again subsequently. Histological and in situ analyses suggested the altered endochondral ossification process may result from delayed chondrocyte differentiation, disruption of vascularization and osteoblast invasion of the femur. All these data provide evidence that FGFR3 regulates normal chondrocyte proliferation and differentiation during bone growth and suggest that constitutive activation of the receptor disrupts both processes. Therefore, the consequences of FGFR3 activation on the physiological process of bone development appear to be dependent on spatial and temporal occurrence. In conclusion, these observations support the notion that FGFR3 has a dual effect, as both a negative and a positive regulator of the endochondral ossification process during post-natal bone development.
Databáze: OpenAIRE