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FGF signaling in the osteoprogenitor lineage non-autonomously regulates postnatal chondrocyte proliferation and skeletal growth.
Development. 2016 05 15; 143(10):1811-22.D

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+Show Affiliations

Department of Developmental Biology, Washington University School of Medicine, St Louis, MO 63110, USA.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.Departments of Orthopaedic Surgery and Medicine, Washington University School of Medicine, St Louis, MO 63110, USA.Departments of Orthopaedic Surgery and Medicine, Washington University School of Medicine, St Louis, MO 63110, USA.Department of Developmental Biology, Washington University School of Medicine, St Louis, MO 63110, USA.Departments of Orthopaedic Surgery and Medicine, Washington University School of Medicine, St Louis, MO 63110, USA.Department of Developmental Biology, Washington University School of Medicine, St Louis, MO 63110, USA dornitz@wustl.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

27052727

Citation

Karuppaiah, Kannan, et al. "FGF Signaling in the Osteoprogenitor Lineage Non-autonomously Regulates Postnatal Chondrocyte Proliferation and Skeletal Growth." Development (Cambridge, England), vol. 143, no. 10, 2016, pp. 1811-22.
Karuppaiah K, Yu K, Lim J, et al. FGF signaling in the osteoprogenitor lineage non-autonomously regulates postnatal chondrocyte proliferation and skeletal growth. Development. 2016;143(10):1811-22.
Karuppaiah, K., Yu, K., Lim, J., Chen, J., Smith, C., Long, F., & Ornitz, D. M. (2016). FGF signaling in the osteoprogenitor lineage non-autonomously regulates postnatal chondrocyte proliferation and skeletal growth. Development (Cambridge, England), 143(10), 1811-22. https://doi.org/10.1242/dev.131722
Karuppaiah K, et al. FGF Signaling in the Osteoprogenitor Lineage Non-autonomously Regulates Postnatal Chondrocyte Proliferation and Skeletal Growth. Development. 2016 05 15;143(10):1811-22. PubMed PMID: 27052727.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - FGF signaling in the osteoprogenitor lineage non-autonomously regulates postnatal chondrocyte proliferation and skeletal growth. AU - Karuppaiah,Kannan, AU - Yu,Kai, AU - Lim,Joohyun, AU - Chen,Jianquan, AU - Smith,Craig, AU - Long,Fanxin, AU - Ornitz,David M, Y1 - 2016/04/06/ PY - 2015/10/08/received PY - 2016/03/18/accepted PY - 2016/4/8/entrez PY - 2016/4/8/pubmed PY - 2017/9/2/medline KW - Chondrocyte KW - Endochondral bone formation KW - FGF signaling KW - IHH KW - Mouse KW - Osteoblast KW - PTHLH KW - Skeletal development SP - 1811 EP - 22 JF - Development (Cambridge, England) JO - Development VL - 143 IS - 10 N2 - 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. SN - 1477-9129 UR - https://www.unboundmedicine.com/medline/citation/27052727/FGF_signaling_in_the_osteoprogenitor_lineage_non_autonomously_regulates_postnatal_chondrocyte_proliferation_and_skeletal_growth_ L2 - http://dev.biologists.org/cgi/pmidlookup?view=long&pmid=27052727 DB - PRIME DP - Unbound Medicine ER -