Skip to main content
SpringerLink
Log in

The role of Nkx3.2 in chondrogenesis

  • Review
  • Published:
Frontiers in Biology

Abstract

Transcription factor, Nkx3.2, is a member of the NK family of developmental genes and is expressed during embryogenesis in a variety of mammalian model organisms, including chicken and mouse. It was first identified in Drosophila as the Bagpipe (bap) gene, where it has been demonstrated to be essential during formation of the midgut musculature. However, mammalian homolog Nkx3.2 has been shown to play a significant role in axial and limb skeletogenesis; in particular, the human skeletal disease, spondylo-megaepiphyseal-metaphyseal dysplasia (SMMD), is associated with mutations of the Nkx3.2 gene. In this review, we highlight the role of Nkx3.2 during musculoskeletal development, with an emphasis on the factor’s role in determining chondrogenic cell fate and its subsequent role in endochondral ossification and chondrocyte survival.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Akazawa H, Komuro I, Sugitani Y, Yazaki Y, Nagai R, Noda T (2000). Targeted disruption of the homeobox transcription factor Bapx1 results in lethal skeletal dysplasia with asplenia and gastroduodenal malformation. Genes Cells, 5(6): 499–513

    Article  PubMed  CAS  Google Scholar 

  • Asayesh A, Sharpe J, Watson R P, Hecksher-Sørensen J, Hastie N D, Hill R E, Ahlgren U (2006). Spleen versus pancreas: strict control of organ interrelationship revealed by analyses of Bapx1 -/- mice. Genes Dev, 20(16): 2208–221

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Azpiazu N, Frasch M (1993). tinman and bagpipe: two homeo box genes that determine cell fates in the dorsal mesoderm of Drosophila. Genes Dev, 7(7b7B): 1325–1340

    Article  PubMed  CAS  Google Scholar 

  • Baffi M O, Slattery E, Sohn P, Moses H L, Chytil A, Serra R (2004). Conditional deletion of the TGF-beta type II receptor in Col2a expressing cells results in defects in the axial skeleton without alterations in chondrocyte differentiation or embryonic development of long bones. Dev Biol, 276(1): 124–142

    Article  PubMed  CAS  Google Scholar 

  • Bieberich C J, Fujita K, He W W, Jay G (1996). Prostate-specific and androgen-dependent expression of a novel homeobox gene. J Biol Chem, 271(50): 31779–31782

    Article  PubMed  CAS  Google Scholar 

  • Brent A E, Tabin C J (2002). Developmental regulation of somite derivatives: muscle, cartilage and tendon. Curr Opin Genet Dev, 12(5): 548–557

    Article  PubMed  CAS  Google Scholar 

  • Cairns D M, Liu R, Sen M, Canner J P, Schindeler A, Little D G, Zeng L (2012). Interplay of Nkx3.2, Sox9 and Pax3 regulates chondrogenic differentiation of muscle progenitor cells. PLoS ONE, 7(7): e39642

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Cairns D M, Sato M E, Lee P G, Lassar A B, Zeng L (2008). A gradient of Shh establishes mutually repressing somitic cell fates induced by Nkx3.2 and Pax3. Dev Biol, 323(2): 152–165

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Caron M M J, Emans P J, Cremers A, Surtel D A M, Coolsen M M E, van Rhijn L W, Welting T J M (2013). Hypertrophic differentiation during chondrogenic differentiation of progenitor cells is stimulated by BMP-2 but suppressed by BMP-7. Osteoarthritis Cartilage, 21(4): 604–613

    Article  PubMed  CAS  Google Scholar 

  • Choi S W, Jeong D U, Kim J A, Lee B, Joeng K S, Long F, Kim D W (2012). Indian Hedgehog signalling triggers Nkx3.2 protein degradation during chondrocyte maturation. Biochem J, 443(3): 789–798

    Article  PubMed  CAS  Google Scholar 

  • Church V, Yamaguchi K, Tsang P, Akita K, Logan C, Francis-West P (2005). Expression and function of Bapx1 during chick limb development. Anat Embryol (Berl), 209(6): 461–469

    Article  CAS  Google Scholar 

  • Collins C A, Olsen I, Zammit P S, Heslop L, Petrie A, Partridge T A, Morgan J E (2005). Stem cell function, self-renewal, and behavioral heterogeneity of cells from the adult muscle satellite cell niche. Cell, 122(2): 289–301

    Article  PubMed  CAS  Google Scholar 

  • Ducy P, Schinke T, Karsenty G (2000). The osteoblast: a sophisticated fibroblast under central surveillance. Science, 289(5484): 1501–1504

    Article  PubMed  CAS  Google Scholar 

  • Enomoto H, Enomoto-Iwamoto M, Iwamoto M, Nomura S, Himeno M, Kitamura Y, Kishimoto T, Komori T (2000). Cbfa1 is a positive regulatory factor in chondrocyte maturation. J Biol Chem, 275(12): 8695–8702

    Article  PubMed  CAS  Google Scholar 

  • Guo J, Chung U I, Yang D, Karsenty G, Bringhurst F R, Kronenberg H M (2006). PTH/PTHrP receptor delays chondrocyte hypertrophy via both Runx2-dependent and -independent pathways. Dev Biol, 292(1): 116–128

    Article  PubMed  CAS  Google Scholar 

  • Guo X, Mak K K, Taketo M M, Yang Y (2009). The Wnt/beta-catenin pathway interacts differentially with PTHrP signaling to control chondrocyte hypertrophy and final maturation. PLoS ONE, 4(6): e6067

    Article  PubMed  PubMed Central  Google Scholar 

  • Hellemans J, Simon M, Dheedene A, Alanay Y, Mihci E, Rifai L, Sefiani A, van Bever Y, Meradji M, Superti-Furga A, Mortier G (2009). Homozygous inactivating mutations in the NKX3-2 gene result in spondylo-megaepiphyseal-metaphyseal dysplasia. Am J Hum Genet, 85(6): 916–922

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Herbrand H, Pabst O, Hill R, Arnold H H (2002). Transcription factors Nkx3.1 and Nkx3.2 (Bapx1) play an overlapping role in sclerotomal development of the mouse. Mech Dev, 117(1–2): 217–224

    Article  PubMed  CAS  Google Scholar 

  • Kawato Y, Hirao M, Ebina K, Shi K, Hashimoto J, Honjo Y, Yoshikawa H, Myoui A (2012). Nkx3.2 promotes primary chondrogenic differentiation by upregulating Col2a1 transcription. PLoS ONE, 7(4): e34703

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Kawato Y, Hirao M, Ebina K, Tamai N, Shi K, Hashimoto J, Yoshikawa H, Myoui A (2011). Nkx3.2-induced suppression of Runx2 is a crucial mediator of hypoxia-dependent maintenance of chondrocyte phenotypes. Biochem Biophys Res Commun, 416(1–2): 205–210

    Article  PubMed  CAS  Google Scholar 

  • Kempf H, Ionescu A, Udager A M, Lassar A B (2007). Prochondrogenic signals induce a competence for Runx2 to activate hypertrophic chondrocyte gene expression. Dev Dyn, 236(7): 1954–1962

    Article  PubMed  CAS  Google Scholar 

  • Kim D W, Lassar A B (2003). Smad-dependent recruitment of a histone deacetylase/Sin3A complex modulates the bone morphogenetic protein-dependent transcriptional repressor activity of Nkx3.2. Mol Cell Biol, 23(23): 8704–8717

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Kim Y, Nirenberg M (1989). Drosophila NK-homeobox genes. Proc Natl Acad Sci USA, 86(20): 7716–7720

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Kronenberg H M (2003). Developmental regulation of the growth plate. Nature, 423(6937): 332–336

    Article  PubMed  CAS  Google Scholar 

  • Lefebvre V, Smits P (2005). Transcriptional control of chondrocyte fate and differentiation. Birth Defects Res C Embryo Today, 75(3): 200–212

    Article  PubMed  CAS  Google Scholar 

  • Lei Q, Jiao J, Xin L, Chang C J, Wang S, Gao J, Gleave M E, Witte O N, Liu X, Wu H (2006). NKX3.1 stabilizes p53, inhibits AKT activation, and blocks prostate cancer initiation caused by PTEN loss. Cancer Cell, 9(5): 367–378

    Article  PubMed  CAS  Google Scholar 

  • Lettice L, Hecksher-Sørensen J, Hill R (2001). The role of Bapx1 (Nkx3.2) in the development and evolution of the axial skeleton. J Anat, 199(Pt 1–2): 181–187

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Mackie E J, Ahmed Y A, Tatarczuch L, Chen K S, Mirams M (2008). Endochondral ossification: how cartilage is converted into bone in the developing skeleton. Int J Biochem Cell Biol, 40(1): 46–62

    Article  PubMed  CAS  Google Scholar 

  • Murtaugh L C, Zeng L, Chyung J H, Lassar A B (2001). The chick transcriptional repressor Nkx3.2 acts downstream of Shh to promote BMP-dependent axial chondrogenesis. Dev Cell, 1(3): 411–422

    Article  PubMed  CAS  Google Scholar 

  • Newman C S, Krieg P A (1999). The Xenopus bagpipe-related homeobox gene zampogna is expressed in the pharyngeal endoderm and the visceral musculature of the midgut. Dev Genes Evol, 209(2): 132–134

    Article  PubMed  CAS  Google Scholar 

  • Pacifici M, Koyama E, Iwamoto M (2005). Mechanisms of synovial joint and articular cartilage formation: recent advances, but many lingering mysteries. Birth Defects Res C Embryo Today, 75(3): 237–248

    Article  PubMed  CAS  Google Scholar 

  • Park M, Yong Y, Choi S W, Kim J H, Lee J E, Kim D W (2007). Constitutive RelA activation mediated by Nkx3.2 controls chondrocyte viability. Nat Cell Biol, 9(3): 287–298

    Article  PubMed  CAS  Google Scholar 

  • Provot S, Kempf H, Murtaugh L C, Chung U I, Kim D W, Chyung J, Kronenberg H M, Lassar A B (2006). Nkx3.2/Bapx1 acts as a negative regulator of chondrocyte maturation. Development, 133(4): 651–662

    Article  PubMed  CAS  Google Scholar 

  • Rodrigo I, Hill R E, Balling R, Münsterberg A, Imai K (2003). Pax1 and Pax9 activate Bapx1 to induce chondrogenic differentiation in the sclerotome. Development, 130(3): 473–482

    Article  PubMed  CAS  Google Scholar 

  • Schneider A, Mijalski T, Schlange T, Dai W, Overbeek P, Arnold H H, Brand T (1999). The homeobox gene NKX3.2 is a target of left-right signalling and is expressed on opposite sides in chick and mouse embryos. Curr Biol, 9(16): 911–914

    Article  PubMed  CAS  Google Scholar 

  • Shen M M, Abate-Shen C (2003). Roles of the Nkx3.1 homeobox gene in prostate organogenesis and carcinogenesis. Dev Dyn, 228(4): 767–778

    Article  PubMed  CAS  Google Scholar 

  • Simon M, Campos-Xavier A B, Mittaz-Crettol L, Valadares E R, Carvalho D, Speck-Martins C E, Nampoothiri S, Alanay Y, Mihci E, van Bever Y, Garcia-Segarra N, Cavalcanti D, Mortier G, Bonafé L, Superti-Furga A (2012). Severe neurologic manifestations from cervical spine instability in spondylo-megaepiphyseal-metaphyseal dysplasia. Am J Med Genet C Semin Med Genet, 160C(3): 230–237

    Article  PubMed  Google Scholar 

  • Takimoto A, Mohri H, Kokubu C, Hiraki Y, Shukunami C (2013). Pax1 acts as a negative regulator of chondrocyte maturation. Exp Cell Res, 319(20): 3128–3139

    Article  PubMed  CAS  Google Scholar 

  • Tanaka M, Komuro I, Inagaki H, Jenkins N A, Copeland N G, Izumo S (2000). Nkx3.1, a murine homolog of Ddrosophila bagpipe, regulates epithelial ductal branching and proliferation of the prostate and palatine glands. Dev Dyn, 219(2): 248–260

    Article  PubMed  CAS  Google Scholar 

  • Tribioli C, Frasch M, Lufkin T (1997). Bapx1: an evolutionary conserved homologue of the Drosophila bagpipe homeobox gene is expressed in splanchnic mesoderm and the embryonic skeleton. Mech Dev, 65(1–2): 145–162

    Article  PubMed  CAS  Google Scholar 

  • Tribioli C, Lufkin T (1997). Molecular cloning, chromosomal mapping and developmental expression of BAPX1, a novel human homeoboxcontaining gene homologous to Drosophila bagpipe. Gene, 203(2): 225–233

    Article  PubMed  CAS  Google Scholar 

  • Tribioli C, Lufkin T (1999). The murine Bapx1 homeobox gene plays a critical role in embryonic development of the axial skeleton and spleen. Development, 126(24): 5699–5711

    PubMed  CAS  Google Scholar 

  • Tribioli C, Lufkin T (2006). Bapx1 homeobox gene gain-of-function mice show preaxial polydactyly and activated Shh signaling in the developing limb. Dev Dyn, 235(9): 2483–2492

    Article  PubMed  CAS  Google Scholar 

  • Verzi M P, Stanfel M N, Moses K A, Kim B M, Zhang Y, Schwartz R J, Shivdasani R A, Zimmer W E (2009). Role of the homeodomain transcription factor Bapx1 in mouse distal stomach development. Gastroenterology, 136(5): 1701–1710

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Yamashita S, Andoh M, Ueno-Kudoh H, Sato T, Miyaki S, Asahara H (2009). Sox9 directly promotes Bapx1 gene expression to repress Runx2 in chondrocytes. Exp Cell Res, 315(13): 2231–2240

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Yong Y, Choi SW, Choi H J, Nam HW, Kim J A, Jeong D U, Kim D Y, Kim Y S, Kim D W (2011). Exogenous signal-independent nuclear IkappaB kinase activation triggered by Nkx3.2 enables constitutive nuclear degradation of IkappaB-alpha in chondrocytes. Mol Cell Biol, 31(14): 2802–2816

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Yoon B S, Lyons K M (2004). Multiple functions of BMPs in chondrogenesis. J Cell Biochem, 93(1): 93–103

    Article  PubMed  CAS  Google Scholar 

  • Yoshiura K I, Murray J C (1997). Sequence and chromosomal assignment of human BAPX1, a bagpipe-related gene, to 4p16.1: a candidate gene for skeletal dysplasia. Genomics, 45(2): 425–428

    Article  PubMed  CAS  Google Scholar 

  • Zeng L, Kempf H, Murtaugh L C, Sato M E, Lassar A B (2002). Shh establishes an Nkx3.2/Sox9 autoregulatory loop that is maintained by BMP signals to induce somitic chondrogenesis. Genes Dev, 16(15): 1990–2005

    Article  PubMed  CAS  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Integrative Physiology and Pathobiology, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA, 02111, USA

    Roshni S. Rainbow & Li Zeng

  2. Program in Cellular, Molecular and Developmental Biology, Sackler School of Graduate Biomedical Sciences, Tufts University, 136 Harrison Avenue, Boston, MA, 02111, USA

    Heenam Kwon & Li Zeng

  3. Department of Orthopaedics, Tufts Medical Center, 800 Washington Street, Boston, MA, 02111, USA

    Li Zeng

Authors
  1. Roshni S. Rainbow
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Heenam Kwon
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Li Zeng
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Li Zeng.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Rainbow, R.S., Kwon, H. & Zeng, L. The role of Nkx3.2 in chondrogenesis. Front. Biol. 9, 376–381 (2014). https://doi.org/10.1007/s11515-014-1321-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11515-014-1321-3

Keywords

Search

Navigation