Indian hedgehog signaling regulates proliferation and differentiation of chondrocytes and is essential for bone formation

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St-Jacques, Benoit¹; Hammerschmidt, Matthias²; McMahon, Andrew P.³

Indian hedgehog signaling regulates proliferation and differentiation of chondrocytes and is essential for bone formation

Genes Dev. August 15, 1999;13(16):2072-2086

©1999 Cold Spring Harbor Laboratory Press

Affiliations

¹Ontogeny, Inc., Cambridge, Massachusetts 02138 USA

²Spemann-Laboratories, Max-Plank-Institut für Immunobiologie, Frieburg, Germany

³Harvard University, Department of Molecular and Cellular Biology, Cambridge, Massachusetts 02138 USA
Abstract and keywords

The mechanisms that control cell proliferation and cell differentiation during morphogenesis of the endochondral skeleton of vertebrates are poorly understood. Indian hedgehog (Ihh) signaling from prehypertrophic chondrocytes has been implicated in the control of chondrocyte maturation by way of feedback control of a second secreted factor parathyroid hormone-related peptide (PTHrP) at the articular surfaces. Analysis of an Ihh null mutant suggests a more extensive role for Ihh in skeletal development. Mutants display markedly reduced chondrocyte proliferation, maturation of chondrocytes at inappropriate position, and a failure of osteoblast development in endochondral bones. Together, the results suggest a model in which Ihh coordinates diverse aspects of skeletal morphogenesis through PTHrP-dependent and independent processes.

Keywords: Signaling; Drosophila; cell proliferation; differentiation; chondrocytes; skeletal morphogenesis
Links

PubMed: 10465785

WoS: 000082364400003
History

Received: 1999-05-21

Accepted: 1999-07-7

Cited Works (4)

Year	Entry
1997	Otto F, Thornell AP, Crompton T, Denzel A, Gilmour KC, Rosewell IR, Stamp GW, Beddington RS, Mundlos S, Olsen BR, Selby PB, Owen MJ. Cbfa1, a candidate gene for cleidocranial dysplasia syndrome, is essential for osteoblast differentiation and bone development. Cell. May 30, 1997;89(5):765-771.
1997	Ducy P, Zhang R, Geoffroy V, Ridall AL, Karsent G. Osf2/Cbfa1: a transcriptional activator of osteoblast differentiation. Cell. May 30, 1997;89(5):747-754.
1996	Vortkamp A, Lee K, Lanske B, Segre GV, Kronenberg HM, Tabi CJ. Regulation of rate of cartilage differentiation by Indian hedgehog and PTH-related protein. Science. August 2, 1996;273(5275):613-622.
1997	Komori T, Yagi H, Nomura S, Yamaguchi A, Sasaki K, Deguchi K, Shimizu Y, Bronson RT, Gao Y-H, Inada M, Sato M, Okamoto R, Kitamura Y, Yoshiki S, Kishimoto T. Targeted disruption of Cbfa1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts. Cell. May 30, 1997;89(5):755-764.

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Year	Entry
2020	Nakamichi R, Kurimoto R, Tabata Y, Asahara H. Transcriptional, epigenetic and microRNA regulation of growth plate. Bone. August 2020;137:115434.
2020	Lukač N, Katavić V, Novak S, Šućur A, Filipović M, Kalajzić I, Grčević D, Kovačić N. What do we know about bone morphogenetic proteins and osteochondroprogenitors in inflammatory conditions? Bone. August 2020;137:115403.
2020	Guo Q, Guo Q, Xiao Y, Li C, Huang Y, Luo X. Regulation of bone marrow mesenchymal stem cell fate by long non-coding RNA. Bone. December 2020;141:115617.
2021	Hensley AP, McAlinden A. The role of microRNAs in bone development. Bone. February 2021;143:115760.
2002	Nakashima K, Zhou X, Kunkel G, Zhang Z, Deng JM, Behringer RR, de Crombrugghe B. The novel zinc finger-containing transcription factor osterix is required for osteoblast differentiation and bone formation. Cell. January 11, 2002;108(1):17-29.
2002	Karsenty G, Wagner EF. Reaching a genetic and molecular understanding of skeletal development. Dev Cell. April 2002;2(4):389-406.
2005	Hill TP, Später D, Taketo MM, Birchmeier W, Hartmann C. Canonical Wnt/β-catenin signaling prevents osteoblasts from differentiating into chondrocytes. Dev Cell. May 2005;8(5):727-738.
2005	Day TF, Guo X, Garrett-Beal L, Yang Y. Wnt/β-catenin signaling in mesenchymal progenitors controls osteoblast and chondrocyte differentiation during vertebrate skeletogenesis. Dev Cell. May 2005;8(5):739-750.
2010	Maes C, Kobayashi T, Selig MK, Torrekens S, Roth SI, Mackem S, Carmeliet G, Kronenberg HM. Osteoblast precursors, but not mature osteoblasts, move into developing and fractured bones along with invading blood vessels. Dev Cell. August 17, 2010;19(2):329-344.
2006	Rodda SJ, McMahon AP. Distinct roles for Hedgehog and canonical Wnt signaling in specification, differentiation and maintenance of osteoblast progenitors. Development. August 15, 2006;133(16):3231-3244.
2002	Akiyama H, Chaboissier M-C, Martin JF, Schedl A, de Crombrugghe B. The transcription factor Sox9 has essential roles in successive steps of the chondrocyte differentiation pathway and is required for expression of Sox5 and Sox6. Genes Dev. November 1, 2002;16(21):2813-2828.
2008	Mackie EJ, Ahmed YA, Tatarczuch L, Chen K-S, Mirams M. Endochondral ossification: how cartilage is converted into bone in the developing skeleton. Int J Biochem Cell Biol. January 2008;40(1):46-62.
2022	Zhang L, Fu X, Ni L, Liu C, Zheng Y, You H, Li M, Xiu C, Zhang L, Gong T, Luo N, Zhang Z, He G, Hu S, Yang H, Chen D, Chen J. Hedgehog signaling controls bone homeostasis by regulating osteogenic/adipogenic fate of skeletal stem/progenitor cells in mice. J Bone Miner Res. March 2022;37(3):559-576.
2022	Coveney CR, Samvelyan HJ, Miotla-Zarebska J, Carnegie J, Chang E, Corrin CJ, Coveney T, Stott B, Parisi I, Duarte C, Vincent TL, Staines KA, Wann AKT. Ciliary IFT88 protects coordinated adolescent growth plate ossification from disruptive physiological mechanical forces. J Bone Miner Res. June 2022;37(6):1081-1096.
2022	Rux D, Helbig K, Han B, Cortese C, Koyama E, Han L, Pacifici M. Primary cilia direct murine articular cartilage tidemark patterning through hedgehog signaling and ambulatory load. J Bone Miner Res. June 2022;37(6):1097-1116.
2017	Shi Y, He G, Lee W-C, McKenzie JA, Silva MJ, Long F. Gli1 identifies osteogenic progenitors for bone formation and fracture repair. Nat Commun. December 11, 2017;8:2043.
2012	Long F. Building strong bones: molecular regulation of the osteoblast lineage. Nat Rev Mol Cell Biol. January 2012;13(1):27-38.
2003	Kronenberg HM. Developmental regulation of the growth plate. Nature. May 15, 2003;423(6937):332-336.
2018	Mizuhashi K, Ono W, Matsushita Y, Sakagami N, Takahashi A, Saunders TL, Nagasawa T, Kronenberg HM, Ono N. Resting zone of the growth plate houses a unique class of skeletal stem cells. Nature. November 8, 2018;563(7730):254-258.
2020	Qin X, Jiang Q, Nagano K, Moriishi T, Miyazaki T, Komori H, Ito K, von der Mark K, Sakane C, Kaneko H, Komori T. Runx2 is essential for the transdifferentiation of chondrocytes into osteoblasts. PLoS Genet. November 2020;16(11):e1009169.
2007	Jiang J. The Role of Cellular Interactions in Osteochondral Graft Design and the Maintenance of a Stable Osteochondral Interface [PhD thesis]. Columbia University; 2007.
2003	Chan GK. Delineation of Regulatory Factors and Mechanisms That Govern the Differentiation of Mesenchymal Cells to the Osteoblastic Lineage [PhD thesis]. McGill University; June 2003.
2009	Landman AS. Pocket Protein Family Function in Mesenchymal Tissue Development and Tumorigenesis [PhD thesis]. Cambridge, MA: Massachusetts Institute of Technology; September 2009.
2009	Miller ES. The Role of E2f4 in Cell Cycle Exit and Bone Development [PhD thesis]. Cambridge, MA: Massachusetts Institute of Technology; June 2009.
2005	Squire ME. Bone’s Response to Unloading, as Defined by Altered Gene Expression, Cellular Activity, and Architecture, is Modulated by Genetics and Gender [PhD thesis]. Stony Brook, NY: Stony Brook University; August 2005.
2007	Nowlan NC. Mechanoregulation of Bone Formation: From Embryogenesis to Evolution [PhD thesis]. Trinity College Dublin; October 2007.
2012	Statman LY. Mechanosensitive Β-Catenin Signaling Modulates Mesenchymal Stem Cell Chondrogenesis [PhD thesis]. San Francisco, University of California; 2012.
2021	Rivera KO. Localized Neurotrophin Delivery Via Microparticles for Enhanced Bone Fracture Repair [PhD thesis]. San Francisco, University of California; 2021.
2021	Leek CC. The Role of Fibroblast Growth Factor Signaling During Superstructure Development and in Muscle-Bone Crosstalk [PhD thesis]. University of Delaware; 2021.
2001	Smith-Adaline EA. Influence of Mechanical Stimulation on Strain Environment and Patterns of Gene Expression During Fracture Healing [PhD thesis]. University of Michigan; 2001.
2007	McDonald MM. The Role of the Osteoclast During Endochondral Ossification in a Rat Fracture Model [PhD thesis]. University of Technology Sydney (UTS); May 2007.
2014	Schwartz AG. Ihh Signaling and Muscle Forces Are Required for Enthesis Development [PhD thesis]. St. Louis, MO: Washington University in St. Louis; May 2014.
2017	Boyle J. Accurate Determination and Application of Local Strain for Studying Tissues With Gradients in Mechanical Properties [PhD thesis]. St. Louis, MO: Washington University in St. Louis; December 2017.