title: FGF signaling in the osteoprogenitor lineage non-autonomously regulates postnatal chondrocyte proliferation and skeletal growth.
abstract: Fibroblast growth factor (FGF) signaling is important for skeletal development; however, cell-specific functions, redundancy and feedback mechanisms regulating bone growth are poorly understood. FGF receptors 1 and 2 (Fgfr1 and Fgfr2) are both expressed in the osteoprogenitor lineage. Double conditional knockout mice, in which both receptors were inactivated using an osteoprogenitor-specific Cre driver, appeared normal at birth; however, these mice showed severe postnatal growth defects that include an ∼50% reduction in body weight and bone mass, and impaired longitudinal bone growth. Histological analysis showed reduced cortical and trabecular bone, suggesting cell-autonomous functions of FGF signaling during postnatal bone formation. Surprisingly, the double conditional knockout mice also showed growth plate defects and an arrest in chondrocyte proliferation. We provide genetic evidence of a non-cell-autonomous feedback pathway regulating Fgf9, Fgf18 and Pthlh expression, which led to increased expression and signaling of Fgfr3 in growth plate chondrocytes and suppression of chondrocyte proliferation. These observations show that FGF signaling in the osteoprogenitor lineage is obligately coupled to chondrocyte proliferation and the regulation of longitudinal bone growth.
authors.affiliation: Department of Developmental Biology, Washington University School of Medicine, St Louis, MO 63110, USA.
authors.forename: Kannan
authors.initials: K
authors.lastname: Karuppaiah
authors.affiliation: Department of Developmental Biology, Washington University School of Medicine, St Louis, MO 63110, USA Division of Craniofacial Medicine, Department of Pediatrics, University of Washington and Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, Seattle, WA 98101, USA.
authors.forename: Kai
authors.initials: K
authors.lastname: Yu
authors.affiliation: Departments of Orthopaedic Surgery and Medicine, Washington University School of Medicine, St Louis, MO 63110, USA.
authors.forename: Joohyun
authors.initials: J
authors.lastname: Lim
authors.affiliation: Departments of Orthopaedic Surgery and Medicine, Washington University School of Medicine, St Louis, MO 63110, USA.
authors.forename: Jianquan
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Developmental Biology, Washington University School of Medicine, St Louis, MO 63110, USA.
authors.forename: Craig
authors.initials: C
authors.lastname: Smith
authors.affiliation: Departments of Orthopaedic Surgery and Medicine, Washington University School of Medicine, St Louis, MO 63110, USA.
authors.forename: Fanxin
authors.initials: F
authors.lastname: Long
authors.affiliation: Department of Developmental Biology, Washington University School of Medicine, St Louis, MO 63110, USA dornitz@wustl.edu.
authors.forename: David M
authors.identifier: 0000-0003-1592-7629
authors.initials: DM
authors.lastname: Ornitz
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001846:Bone Development / Q000187:drug effects; D019070:Cell Lineage / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019902:Chondrocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D006132:Growth Plate / Q000187:drug effects / Q000378:metabolism; D019426:Integrases / Q000378:metabolism; D018345:Mice, Knockout; D008954:Models, Biological; D010011:Osteocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D044162:Parathyroid Hormone-Related Protein / Q000008:administration & dosage / Q000494:pharmacology; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000378:metabolism; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000076182:Sp7 Transcription Factor; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D044162:Parathyroid Hormone-Related Protein; D000076182:Sp7 Transcription Factor; C479466:Sp7 protein, mouse; D014157:Transcription Factors; D005346:Fibroblast Growth Factors; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051497:Receptor, Fibroblast Growth Factor, Type 2; C045073:Cre recombinase; D019426:Integrases
keywords: Chondrocyte; Endochondral bone formation; FGF signaling; IHH; Mouse; Osteoblast; PTHLH; Skeletal development