TY - JOUR
T1 - Achondroplasia
T2 - Development, pathogenesis, and therapy
AU - Ornitz, David M.
AU - Legeai-Mallet, Laurence
N1 - Funding Information:
We thank the large number of researchers who contributed to the work reviewed here. We apologize to the investigators whose work could not be cited due to space limitations and our inadvertent omissions. We thank I. Boime for critically reading the manuscript. D.M.O. was supported by an NIH grant, and L.L.M. was funded by the European Community's Seventh Framework Programme.
Publisher Copyright:
© 2016 Wiley Periodicals, Inc.
PY - 2017/4/1
Y1 - 2017/4/1
N2 - Autosomal dominant mutations in fibroblast growth factor receptor 3 (FGFR3) cause achondroplasia (Ach), the most common form of dwarfism in humans, and related chondrodysplasia syndromes that include hypochondroplasia (Hch), severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), and thanatophoric dysplasia (TD). FGFR3 is expressed in chondrocytes and mature osteoblasts where it functions to regulate bone growth. Analysis of the mutations in FGFR3 revealed increased signaling through a combination of mechanisms that include stabilization of the receptor, enhanced dimerization, and enhanced tyrosine kinase activity. Paradoxically, increased FGFR3 signaling profoundly suppresses proliferation and maturation of growth plate chondrocytes resulting in decreased growth plate size, reduced trabecular bone volume, and resulting decreased bone elongation. In this review, we discuss the molecular mechanisms that regulate growth plate chondrocytes, the pathogenesis of Ach, and therapeutic approaches that are being evaluated to improve endochondral bone growth in people with Ach and related conditions. Developmental Dynamics 246:291–309, 2017.
AB - Autosomal dominant mutations in fibroblast growth factor receptor 3 (FGFR3) cause achondroplasia (Ach), the most common form of dwarfism in humans, and related chondrodysplasia syndromes that include hypochondroplasia (Hch), severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), and thanatophoric dysplasia (TD). FGFR3 is expressed in chondrocytes and mature osteoblasts where it functions to regulate bone growth. Analysis of the mutations in FGFR3 revealed increased signaling through a combination of mechanisms that include stabilization of the receptor, enhanced dimerization, and enhanced tyrosine kinase activity. Paradoxically, increased FGFR3 signaling profoundly suppresses proliferation and maturation of growth plate chondrocytes resulting in decreased growth plate size, reduced trabecular bone volume, and resulting decreased bone elongation. In this review, we discuss the molecular mechanisms that regulate growth plate chondrocytes, the pathogenesis of Ach, and therapeutic approaches that are being evaluated to improve endochondral bone growth in people with Ach and related conditions. Developmental Dynamics 246:291–309, 2017.
KW - FGF
KW - FGFR3
KW - achondroplasia
KW - chondrogenesis
KW - endochondral ossification
KW - fibroblast growth factor receptor
KW - growth plate
KW - hypochondroplasia
KW - skeletal dysplasia
KW - thanatophoric dysplasia
KW - therapy
UR - http://www.scopus.com/inward/record.url?scp=85014084824&partnerID=8YFLogxK
U2 - 10.1002/dvdy.24479
DO - 10.1002/dvdy.24479
M3 - Review article
C2 - 27987249
AN - SCOPUS:85014084824
VL - 246
SP - 291
EP - 309
JO - Developmental Dynamics
JF - Developmental Dynamics
SN - 1058-8388
IS - 4
ER -