title: Mutant activated FGFR3 impairs endochondral bone growth by preventing SOX9 downregulation in differentiating chondrocytes.
abstract: Fibroblast growth factor receptor 3 (FGFR3) plays a critical role in the control of endochondral ossification, and bone growth and mutations that cause hyperactivation of FGFR3 are responsible for a collection of developmental disorders that feature poor endochondral bone growth. FGFR3 is expressed in proliferating chondrocytes of the cartilaginous growth plate but also in chondrocytes that have exited the cell cycle and entered the prehypertrophic phase of chondrocyte differentiation. Achondroplasia disorders feature defects in chondrocyte proliferation and differentiation, and the defects in differentiation have generally been considered to be a secondary manifestation of altered proliferation. By initiating a mutant activated knockin allele of FGFR3 (FGFR3K650E) that causes Thanatophoric Dysplasia Type II (TDII) specifically in prehypertrophic chondrocytes, we show that mutant FGFR3 induces a differentiation block at this stage independent of any changes in proliferation. The differentiation block coincided with persistent expression of SOX9, the master regulator of chondrogenesis, and reducing SOX9 dosage allowed chondrocyte differentiation to proceed and significantly improved endochondral bone growth in TDII. These findings suggest that a proliferation-independent and SOX9-dependent differentiation block is a key driving mechanism responsible for poor endochondral bone growth in achondroplasia disorders caused by mutations in FGFR3.
authors.affiliation: Shriners Hospitals for Children, 3101 SW Sam Jackson Park Road, Portland, OR 97239, USA.
authors.forename: Zi-Qiang
authors.initials: ZQ
authors.lastname: Zhou
authors.affiliation: Shriners Hospitals for Children, 3101 SW Sam Jackson Park Road, Portland, OR 97239, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Ota
authors.affiliation: Genetics of Development and Disease Branch, National Institute of Diabetes, Digestive and Kidney Diseases, US National Institutes of Health, 10 Center Drive, Bethesda, MD 20892, USA.
authors.forename: Chuxia
authors.initials: C
authors.lastname: Deng
authors.affiliation: Department of Orthopedics, Gifu University, Gifu 501-1194, Japan.
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Akiyama
authors.affiliation: Shriners Hospitals for Children, 3101 SW Sam Jackson Park Road, Portland, OR 97239, USA, Department of Cell and Developmental Biology and Knight Cancer Institute, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA pjh@shcc.org.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Hurlin
mesh_terms: D000818:Animals; D019902:Chondrocytes / Q000473:pathology; D020219:Chondrogenesis / Q000235:genetics*; D015536:Down-Regulation; D018507:Gene Expression Regulation, Developmental; D051379:Mice; D020125:Mutation, Missense; D010012:Osteogenesis / Q000235:genetics*; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics*; D055758:SOX9 Transcription Factor / Q000235:genetics*; D012886:Skull / Q000002:abnormalities*; D013796:Thanatophoric Dysplasia / Q000209:etiology / Q000235:genetics*
chemical_list: D055758:SOX9 Transcription Factor; C527933:Sox9 protein, mouse; C496366:Fgfr3 protein, mouse; D051498:Receptor, Fibroblast Growth Factor, Type 3