FGF Signaling in the Osteoprogenitor Lineage Non-autonomously Regulates Postnatal Chondrocyte Proliferation and Skeletal Growth

Overview

Journal Development

Specialty Biology

Date 2016 Apr 8

PMID 27052727

Citations 37

Authors

Kannan Karuppaiah

Kai Yu

Joohyun Lim

Jianquan Chen

Craig Smith

Fanxin Long

David M Ornitz

Affiliations

Soon will be listed here.

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.

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References

Ornitz D, Marie P . FGF signaling pathways in endochondral and intramembranous bone development and human genetic disease. Genes Dev. 2002; 16(12):1446-65. DOI: 10.1101/gad.990702. View

Chen J, Tu X, Esen E, Joeng K, Lin C, Arbeit J . WNT7B promotes bone formation in part through mTORC1. PLoS Genet. 2014; 10(1):e1004145. PMC: 3907335. DOI: 10.1371/journal.pgen.1004145. View

Meyer M, Muller A, Yang J, Moik D, Ponzio G, Ornitz D . FGF receptors 1 and 2 are key regulators of keratinocyte migration in vitro and in wounded skin. J Cell Sci. 2012; 125(Pt 23):5690-701. PMC: 3575704. DOI: 10.1242/jcs.108167. View

Hilton M, Tu X, Cook J, Hu H, Long F . Ihh controls cartilage development by antagonizing Gli3, but requires additional effectors to regulate osteoblast and vascular development. Development. 2005; 132(19):4339-51. DOI: 10.1242/dev.02025. View

Kozhemyakina E, Lassar A, Zelzer E . A pathway to bone: signaling molecules and transcription factors involved in chondrocyte development and maturation. Development. 2015; 142(5):817-31. PMC: 4352987. DOI: 10.1242/dev.105536. View

Ohbayashi N, Shibayama M, Kurotaki Y, Imanishi M, Fujimori T, Itoh N . FGF18 is required for normal cell proliferation and differentiation during osteogenesis and chondrogenesis. Genes Dev. 2002; 16(7):870-9. PMC: 186331. DOI: 10.1101/gad.965702. View

Naski M, Wang Q, Xu J, Ornitz D . Graded activation of fibroblast growth factor receptor 3 by mutations causing achondroplasia and thanatophoric dysplasia. Nat Genet. 1996; 13(2):233-7. DOI: 10.1038/ng0696-233. View

Cobrinik D, Lee M, Hannon G, Mulligan G, Bronson R, Dyson N . Shared role of the pRB-related p130 and p107 proteins in limb development. Genes Dev. 1996; 10(13):1633-44. DOI: 10.1101/gad.10.13.1633. View

Dailey L, Laplantine E, Priore R, Basilico C . A network of transcriptional and signaling events is activated by FGF to induce chondrocyte growth arrest and differentiation. J Cell Biol. 2003; 161(6):1053-66. PMC: 2172997. DOI: 10.1083/jcb.200302075. View

10.

Su W, Kitagawa M, Xue N, Xie B, Garofalo S, Cho J . Activation of Stat1 by mutant fibroblast growth-factor receptor in thanatophoric dysplasia type II dwarfism. Nature. 1997; 386(6622):288-92. DOI: 10.1038/386288a0. View

11.

Smith K, Williamson T, Schwartz M, Vaccarino F . Impaired motor coordination and disrupted cerebellar architecture in Fgfr1 and Fgfr2 double knockout mice. Brain Res. 2012; 1460:12-24. PMC: 3361544. DOI: 10.1016/j.brainres.2012.04.002. View

12.

Mori Y, Saito T, Chang S, Kobayashi H, Ladel C, Guehring H . Identification of fibroblast growth factor-18 as a molecule to protect adult articular cartilage by gene expression profiling. J Biol Chem. 2014; 289(14):10192-200. PMC: 3974988. DOI: 10.1074/jbc.M113.524090. View

13.

Dy P, Wang W, Bhattaram P, Wang Q, Wang L, Ballock R . Sox9 directs hypertrophic maturation and blocks osteoblast differentiation of growth plate chondrocytes. Dev Cell. 2012; 22(3):597-609. PMC: 3306603. DOI: 10.1016/j.devcel.2011.12.024. View

14.

Koziel L, Kunath M, Kelly O, Vortkamp A . Ext1-dependent heparan sulfate regulates the range of Ihh signaling during endochondral ossification. Dev Cell. 2004; 6(6):801-13. DOI: 10.1016/j.devcel.2004.05.009. View

15.

Rodda S, McMahon A . Distinct roles for Hedgehog and canonical Wnt signaling in specification, differentiation and maintenance of osteoblast progenitors. Development. 2006; 133(16):3231-44. DOI: 10.1242/dev.02480. View

16.

Poladia D, Kish K, Kutay B, Hains D, Kegg H, Zhao H . Role of fibroblast growth factor receptors 1 and 2 in the metanephric mesenchyme. Dev Biol. 2006; 291(2):325-39. DOI: 10.1016/j.ydbio.2005.12.034. View

17.

Chau M, Forcinito P, Andrade A, Hegde A, Ahn S, Lui J . Organization of the Indian hedgehog--parathyroid hormone-related protein system in the postnatal growth plate. J Mol Endocrinol. 2011; 47(1):99-107. PMC: 8287619. DOI: 10.1530/JME-10-0177. View

18.

Hunziker E, Schenk R . Physiological mechanisms adopted by chondrocytes in regulating longitudinal bone growth in rats. J Physiol. 1989; 414:55-71. PMC: 1189130. DOI: 10.1113/jphysiol.1989.sp017676. View

19.

Chen X, Macica C, Nasiri A, Broadus A . Regulation of articular chondrocyte proliferation and differentiation by indian hedgehog and parathyroid hormone-related protein in mice. Arthritis Rheum. 2008; 58(12):3788-97. PMC: 2599803. DOI: 10.1002/art.23985. View

20.

Horton W, Hall J, Hecht J . Achondroplasia. Lancet. 2007; 370(9582):162-172. DOI: 10.1016/S0140-6736(07)61090-3. View