title: FGFR3 induces degradation of BMP type I receptor to regulate skeletal development.
abstract: Fibroblast growth factors (FGFs) and their receptors (FGFRs) play significant roles in vertebrate organogenesis and morphogenesis. FGFR3 is a negative regulator of chondrogenesis and multiple mutations with constitutive activity of FGFR3 result in achondroplasia, one of the most common dwarfisms in humans, but the molecular mechanism remains elusive. In this study, we found that chondrocyte-specific deletion of BMP type I receptor a (Bmpr1a) rescued the bone overgrowth phenotype observed in Fgfr3 deficient mice by reducing chondrocyte differentiation. Consistently, using in vitro chondrogenic differentiation assay system, we demonstrated that FGFR3 inhibited BMPR1a-mediated chondrogenic differentiation. Furthermore, we showed that FGFR3 hyper-activation resulted in impaired BMP signaling in chondrocytes of mouse growth plates. We also found that FGFR3 inhibited BMP-2- or constitutively activated BMPR1-induced phosphorylation of Smads through a mechanism independent of its tyrosine kinase activity. We found that FGFR3 facilitates BMPR1a to degradation through Smurf1-mediated ubiquitination pathway. We demonstrated that down-regulation of BMP signaling by BMPR1 inhibitor dorsomorphin led to the retardation of chondrogenic differentiation, which mimics the effect of FGF-2 on chondrocytes and BMP-2 treatment partially rescued the retarded growth of cultured bone rudiments from thanatophoric dysplasia type II mice. Our findings reveal that FGFR3 promotes the degradation of BMPR1a, which plays an important role in the pathogenesis of FGFR3-related skeletal dysplasia.
authors.affiliation: Center of Bone Metabolism and Repair (CBMR), Trauma Center, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing 400042, China.
authors.forename: Huabing
authors.initials: H
authors.lastname: Qi
authors.affiliation: Center of Bone Metabolism and Repair (CBMR), Trauma Center, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing 400042, China.
authors.forename: Min
authors.initials: M
authors.lastname: Jin
authors.affiliation: Center of Bone Metabolism and Repair (CBMR), Trauma Center, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing 400042, China.
authors.forename: Yaqi
authors.initials: Y
authors.lastname: Duan
authors.affiliation: Center of Bone Metabolism and Repair (CBMR), Trauma Center, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing 400042, China; State Key Laboratory of Trauma, Burns and Combined Injury, Third Military Medical University, Chongqing 400042, China.
authors.forename: Xiaolan
authors.initials: X
authors.lastname: Du
authors.affiliation: State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Medicine, Tsinghua University, Beijing 100084, China.
authors.forename: Yuanquan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Medicine, Tsinghua University, Beijing 100084, China.
authors.forename: Fangli
authors.initials: F
authors.lastname: Ren
authors.affiliation: State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Medicine, Tsinghua University, Beijing 100084, China.
authors.forename: Yinyin
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Cell Biology, New York University School of Medicine, New York, NY 10016, USA; Department of Orthopaedic Surgery, New York University School of Medicine and NYU Hospital for Joint Diseases, New York, NY 10003, USA.
authors.forename: Qingyun
authors.initials: Q
authors.lastname: Tian
authors.affiliation: Center of Bone Metabolism and Repair (CBMR), Trauma Center, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing 400042, China.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Wang
authors.affiliation: Center of Bone Metabolism and Repair (CBMR), Trauma Center, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing 400042, China.
authors.forename: Quan
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Center of Bone Metabolism and Repair (CBMR), Trauma Center, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing 400042, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Center of Bone Metabolism and Repair (CBMR), Trauma Center, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing 400042, China.
authors.forename: Yangli
authors.initials: Y
authors.lastname: Xie
authors.affiliation: Department of Cell Biology, New York University School of Medicine, New York, NY 10016, USA; Department of Orthopaedic Surgery, New York University School of Medicine and NYU Hospital for Joint Diseases, New York, NY 10003, USA.
authors.forename: Chuanju
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Xu
authors.initials: X
authors.lastname: Cao
authors.affiliation: Department of Biologic & Materials Sciences, University of Michigan School of Dentistry, Ann Arbor, MI 48109, USA.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Mishina
authors.affiliation: Department of Biochemistry, Rush University, Chicago, IL 60612, USA.
authors.forename: Di
authors.initials: D
authors.lastname: Chen
authors.affiliation: Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, 10/9N105, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Chu-xia
authors.initials: CX
authors.lastname: Deng
authors.affiliation: State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Medicine, Tsinghua University, Beijing 100084, China. Electronic address: zhijiec@tsinghua.edu.cn.
authors.forename: Zhijie
authors.initials: Z
authors.lastname: Chang
authors.affiliation: Center of Bone Metabolism and Repair (CBMR), Trauma Center, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing 400042, China; State Key Laboratory of Trauma, Burns and Combined Injury, Third Military Medical University, Chongqing 400042, China; Department of Rehabilitation Medicine, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing 400042, China. Electronic address: linchen70@163.com.
authors.forename: Lin
authors.initials: L
authors.lastname: Chen
mesh_terms: D000130:Achondroplasia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000378:metabolism / Q000494:pharmacology; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000235:genetics* / Q000378:metabolism; D002454:Cell Differentiation; D019902:Chondrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D004622:Embryo, Mammalian; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism / Q000494:pharmacology; D018507:Gene Expression Regulation, Developmental; D006132:Growth Plate / Q000166:cytology / Q000254:growth & development / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009024:Morphogenesis / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000172:deficiency / Q000235:genetics*; D015398:Signal Transduction; D051785:Smad Proteins / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination / Q000187:drug effects
chemical_list: C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D011720:Pyrazoles; D011743:Pyrimidines; D051785:Smad Proteins; D016222:Fibroblast Growth Factor 2; C516138:dorsomorphin; C492381:Smurf1 protein, mouse; D044767:Ubiquitin-Protein Ligases; C496366:Fgfr3 protein, mouse; D051498:Receptor, Fibroblast Growth Factor, Type 3; C498212:Bmpr1a protein, mouse; D052005:Bone Morphogenetic Protein Receptors, Type I
keywords: Achondroplasia; BMPR1; Chondrocyte; FGFR3; Smurf1