The role of Nkx3.2 in chondrogenesis

Roshni S. RAINBOW, Heenam KWON, Li ZENG

PDF(124 KB)
PDF(124 KB)
Front. Biol. ›› 2014, Vol. 9 ›› Issue (5) : 376-381. DOI: 10.1007/s11515-014-1321-3
REVIEW
REVIEW

The role of Nkx3.2 in chondrogenesis

Author information +
History +

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.

Keywords

Nkx3.2 / musculoskeletal development / chondrogenesis / chondrocyte hypertrophy

Cite this article

Download citation ▾
Roshni S. RAINBOW, Heenam KWON, Li ZENG. The role of Nkx3.2 in chondrogenesis. Front. Biol., 2014, 9(5): 376‒381 https://doi.org/10.1007/s11515-014-1321-3

References

[1]
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
CrossRef Pubmed Google scholar
[2]
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): 2208–2213
CrossRef Pubmed Google scholar
[3]
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
CrossRef Pubmed Google scholar
[4]
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
CrossRef Pubmed Google scholar
[5]
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
CrossRef Pubmed Google scholar
[6]
Brent A E, Tabin C J (2002). Developmental regulation of somite derivatives: muscle, cartilage and tendon. Curr Opin Genet Dev, 12(5): 548–557
CrossRef Pubmed Google scholar
[7]
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
CrossRef Pubmed Google scholar
[8]
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
CrossRef Pubmed Google scholar
[9]
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
CrossRef Pubmed Google scholar
[10]
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
CrossRef Pubmed Google scholar
[11]
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
CrossRef Pubmed Google scholar
[12]
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
CrossRef Pubmed Google scholar
[13]
Ducy P, Schinke T, Karsenty G (2000). The osteoblast: a sophisticated fibroblast under central surveillance. Science, 289(5484): 1501–1504
CrossRef Pubmed Google scholar
[14]
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
CrossRef Pubmed Google scholar
[15]
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
CrossRef Pubmed Google scholar
[16]
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
CrossRef Pubmed Google scholar
[17]
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
CrossRef Pubmed Google scholar
[18]
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
CrossRef Pubmed Google scholar
[19]
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
CrossRef Pubmed Google scholar
[20]
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
CrossRef Pubmed Google scholar
[21]
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
CrossRef Pubmed Google scholar
[22]
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
CrossRef Pubmed Google scholar
[23]
Kim Y, Nirenberg M (1989). Drosophila NK-homeobox genes. Proc Natl Acad Sci USA, 86(20): 7716–7720
CrossRef Pubmed Google scholar
[24]
Kronenberg H M (2003). Developmental regulation of the growth plate. Nature, 423(6937): 332–336
CrossRef Pubmed Google scholar
[25]
Lefebvre V, Smits P (2005). Transcriptional control of chondrocyte fate and differentiation. Birth Defects Res C Embryo Today, 75(3): 200–212
CrossRef Pubmed Google scholar
[26]
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
CrossRef Pubmed Google scholar
[27]
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
CrossRef Pubmed Google scholar
[28]
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
CrossRef Pubmed Google scholar
[29]
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
CrossRef Pubmed Google scholar
[30]
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
CrossRef Pubmed Google scholar
[31]
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
CrossRef Pubmed Google scholar
[32]
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
CrossRef Pubmed Google scholar
[33]
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
CrossRef Pubmed Google scholar
[34]
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
CrossRef Pubmed Google scholar
[35]
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
CrossRef Pubmed Google scholar
[36]
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
CrossRef Pubmed Google scholar
[37]
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
CrossRef Pubmed Google scholar
[38]
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
CrossRef Pubmed Google scholar
[39]
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
CrossRef Pubmed Google scholar
[40]
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
CrossRef Pubmed Google scholar
[41]
Tribioli C, Lufkin T (1997). Molecular cloning, chromosomal mapping and developmental expression of BAPX1, a novel human homeobox-containing gene homologous to Drosophila bagpipe. Gene, 203(2): 225–233
CrossRef Pubmed Google scholar
[42]
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
[43]
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
CrossRef Pubmed Google scholar
[44]
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
CrossRef Pubmed Google scholar
[45]
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
CrossRef Pubmed Google scholar
[46]
Yong Y, Choi S W, Choi H J, Nam H W, 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
CrossRef Pubmed Google scholar
[47]
Yoon B S, Lyons K M (2004). Multiple functions of BMPs in chondrogenesis. J Cell Biochem, 93(1): 93–103
CrossRef Pubmed Google scholar
[48]
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
CrossRef Pubmed Google scholar
[49]
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
CrossRef Pubmed Google scholar

RIGHTS & PERMISSIONS

2014 Higher Education Press and Springer-Verlag Berlin Heidelberg
PDF(124 KB)

Accesses

Citations

Detail

Sections
Recommended

/