Col10a1 gene expression and chondrocyte hypertrophy during skeletal development and disease

Abstract

The type X collagen gene, COL10A1, is specifically expressed by hypertrophic chondrocytes during endochondral ossification. Endochondral ossification is a well-coordinated process that involves a cartilage intermediate and leads to formation of most of the skeleton in vertebrates during skeletogenesis. Chondrocyte hypertrophy is a critical stage of endochondral ossification linking both bone and cartilage development. Given its specific association with chondrocyte hypertrophy, type X collagen plays essential roles in endochondral ossification. It was previously shown that transgenic mice with mutant type X collagen develop variable skeleton-hematopoietic abnormalities indicating defective endochondral ossification, while mutations and abnormal expression of human COL10A1 cause abnormal chondrocyte hypertrophy that has been seen in many skeletal disorders, including skeletal chondrodysplasia and osteoarthritis. In this review, we summarized the skeletal chondrodysplasia with COL10A1 gene mutation that shows growth plate defect. We also reviewed recent studies that correlate the type X collagen gene expression and chondrocyte hypertrophy with osteoarthritis. Due to its significant clinical relevance, the type X collagen gene regulation has been extensively studied over the past two decades. Here, we focus on recent progress characterizing the cis-enhancer elements and their binding factors that together confer hypertrophic chondrocyte-specific murine type X collagen gene (Col10a1) expression. Based on literature review and our own studies, we surmise that there are multiple factors that contribute to hypertrophic chondrocyte-specific Col10a1 expression. These factors include both transactivators (such as Runx2, MEF2C etc.) and repressors (such as AP1, NFATc1, Sox9 etc.), while other co-factors or epigenetic control of Col10a1 expression may not be excluded.

Key words： Col10a1 gene expression; cis-enhancer; transcription factors; AP1 and Runx2; chondrocyte hypertrophy; skeletal development and diseases

Acknowledgments

The studies were supported by the Arthritis Foundation Arthritis Investigator Award (Q.Z.) and the NSFC grant (31271399, Q.Z., J.G., Y.L.).

References

1 AdamsS L, PallanteK M, NiuZ, CohenA J, LuJ, LeBoyP S (2003). Stimulation of type-X collagen gene transcription by retinoids occurs in part through the BMP signaling pathway. J Bone Joint Surg Am, 85-A(Suppl 3): 29–33

PMID

2 ArnoldM A, KimY, CzubrytM P, PhanD, McAnallyJ, QiX, SheltonJ M, RichardsonJ A, Bassel-DubyR, OlsonE N (2007). MEF2C transcription factor controls chondrocyte hypertrophy and bone development. Dev Cell, 12(3): 377–389

PMID

3 BatemanJ F, FreddiS, McNeilR, ThompsonE, HermannsP, SavarirayanR, LamandéS R (2004). Identification of four novel COL10A1 missense mutations in schmid metaphyseal chondrodysplasia: further evidence that collagen X NC1 mutations impair trimer assembly. Hum Mutat, 23(4): 396

PMID

4 BatemanJ F, FreddiS, NattrassG, SavarirayanR (2003). Tissue-specific RNA surveillance? Nonsense-mediated mRNA decay causes collagen X haploinsufficiency in Schmid metaphyseal chondrodysplasia cartilage. Hum Mol Genet, 12(3): 217–225

PMID

5 BatemanJ F, WilsonR, FreddiS, LamandéS R, SavarirayanR (2005). Mutations of COL10A1 in Schmid metaphyseal chondrodysplasia. Hum Mutat, 25(6): 525–534

PMID

6 BeierF, VornehmS, PöschlE, von der MarkK, LammiM J (1997). Localization of silencer and enhancer elements in the human type X collagen gene. J Cell Biochem, 66(2): 210–218

PMID

7 ChambersD, YoungD A, HowardC, ThomasJ T, BoamD S, GrantM E, WallisG A, Boot-HandfordR P (2002). An enhancer complex confers both high-level and cell-specific expression of the human type X collagen gene. FEBS Lett, 531(3): 505–508

PMID

8 ChanD, ColeW G, RogersJ G, BatemanJ F (1995). Type X collagen multimer assembly in vitro is prevented by a Gly618 to Val mutation in the alpha 1(X) NC1 domain resulting in Schmid metaphyseal chondrodysplasia. J Biol Chem, 270(9): 4558–4562

PMID

9 ChangH J, YangM J, YangY H, HouM F, HsuehE J, LinS R (2009). MMP13 is potentially a new tumor marker for breast cancer diagnosis. Oncol Rep, 22(5): 1119–1127

PMID

10 ChapmanK B, PrendesM J, SternbergH, KiddJ L, FunkW D, WagnerJ, WestM D (2012). COL10A1 expression is elevated in diverse solid tumor types and is associated with tumor vasculature. Future Oncol, 8(8): 1031–1040

PMID

11 D’AlonzoR C, SelvamuruganN, KarsentyG, PartridgeN C (2002). Physical interaction of the activator protein-1 factors c-Fos and c-Jun with Cbfa1 for collagenase-3 promoter activation. J Biol Chem, 277(1): 816–822

PMID

12 DesmedtC, MajjajS, KheddoumiN, SinghalS K, Haibe-KainsB, El OuriaghliF, ChaboteauxC, MichielsS, LallemandF, JourneF, DuvillierH, LoiS, QuackenbushJ, DekoninckS, BlanpainC, LagneauxL, HouhouN, DelorenziM, LarsimontD, PiccartM, SotiriouC (2012). Characterization and clinical evaluation of CD10⁺ stroma cells in the breast cancer microenvironment. Clin Cancer Res, 18(4): 1004–1014

PMID

13 DongY, DrissiH, ChenM, ChenD, ZuscikM J, SchwarzE M, O’KeefeR J (2005). Wnt-mediated regulation of chondrocyte maturation: modulation by TGF-beta. J Cell Biochem, 95(5): 1057–1068

PMID

14 DongY F, SoungY, SchwarzE M, O’KeefeR J, DrissiH (2006). Wnt induction of chondrocyte hypertrophy through the Runx2 transcription factor. J Cell Physiol, 208(1): 77–86

PMID

15 DouradoG, LuValleP (1998). Proximal DNA elements mediate repressor activity conferred by the distal portion of the chicken collagen X promoter. J Cell Biochem, 70(4): 507–516

PMID

15 DrissiM H, LiX, SheuT J, ZuscikM J, SchwarzE M, PuzasJ E, RosierR N, O’KeefeR J (2003). Runx2/Cbfa1 stimulation by retinoic acid is potentiated by BMP2 signaling through interaction with Smad1 on the collagen X promoter in chondrocytes. J Cell Biochem, 90(6): 1287–1298

PMID

104 DrissiH, ZuscikM, RosierR, O’KeefeR (2005). Transcriptional regulation of chondrocyte maturation: potential involvement of transcription factors in OA pathogenesis. Mol Aspects Med, 26(3): 169–179

PMID

17 DyP, WangW, BhattaramP, WangQ, WangL, BallockR T, LefebvreV (2012). Sox9 directs hypertrophic maturation and blocks osteoblast differentiation of growth plate chondrocytes. Dev Cell, 22(3): 597–609

PMID

18 EerolaI, SalminenH, LammiP, LammiM, von der MarkK, VuorioE, SäämänenA M (1998). Type X collagen, a natural component of mouse articular cartilage: association with growth, aging, and osteoarthritis. Arthritis Rheum, 41(7): 1287–1295

PMID

19 EferlR, HoebertzA, SchillingA F, RathM, KarrethF, KennerL, AmlingM, WagnerE F (2004). The Fos-related antigen Fra-1 is an activator of bone matrix formation. EMBO J, 23(14): 2789–2799

PMID

20 EferlR, WagnerE F (2003). AP-1: a double-edged sword in tumorigenesis. Nat Rev Cancer, 3(11): 859–868

PMID

21 FangJ, HallB K (1997). Chondrogenic cell differentiation from membrane bone periostea. Anat Embryol (Berl), 196(5): 349–362 (Review)

PMID

22 GebhardS, PöschlE, RiemerS, BauerE, HattoriT, EberspaecherH, ZhangZ, LefebvreV, de CrombruggheB, von der MarkK (2004). A highly conserved enhancer in mammalian type X collagen genes drives high levels of tissue-specific expression in hypertrophic cartilage in vitro and in vivo. Matrix Biol, 23(5): 309–322

PMID

23 GoldringM B, TsuchimochiK, IjiriK (2006). The control of chondrogenesis. J Cell Biochem, 97(1): 33–44

PMID

24 GomezS, Lopez-CeperoJ M, SilvestriniG, BonucciE (1996). Matrix vesicles and focal proteoglycan aggregates are the nucleation sites revealed by the lanthanum incubation method: a correlated study on the hypertrophic zone of the rat epiphyseal cartilage. Calcif Tissue Int, 58(4): 273–282

PMID

25 GregoryC A, ZabelB, GrantM E, Boot-HandfordR P, WallisG A (2000). Equal expression of typ X collagen mRNA fom mutant and wild type COL10A1 alleles in growth plate cartilage from a patient with metaphyseal chondrodysplasia type Schmid. J Med Genet, 37(8): 627–629

PMID

26 GrskovicI, KutschA, FrieC, GromaG, StermannJ, Schlötzer-SchrehardtU, NiehoffA, MossS E, RosenbaumS, PöschlE, ChmielewskiM, RapplG, AbkenH, BatemanJ F, CheahK S, PaulssonM, BrachvogelB (2012). Depletion of annexin A5, annexin A6, and collagen X causes no gross changes in matrix vesicle-mediated mineralization, but lack of collagen X affects hematopoiesis and the Th1/Th2 response. J Bone Miner Res, 27(11): 2399–2412

PMID

27 HattoriT, MüllerC, GebhardS, BauerE, PauschF, SchlundB, BöslM R, HessA, Surmann-SchmittC, von der MarkH, de CrombruggheB, von der MarkK (2010). SOX9 is a major negative regulator of cartilage vascularization, bone marrow formation and endochondral ossification. Development, 137(6): 901–911

PMID

28 HessJ, AngelP, Schorpp-KistnerM (2004). AP-1 subunits: quarrel and harmony among siblings. J Cell Sci, 117(Pt 25): 5965–5973

PMID

29 HessJ, HartensteinB, TeurichS, SchmidtD, Schorpp-KistnerM, AngelP (2003). Defective endochondral ossification in mice with strongly compromised expression of JunB. J Cell Sci, 116(Pt 22): 4587–4596

PMID

30 HessJ, PorteD, MunzC, AngelP (2001). AP-1 and Cbfa/runt physically interact and regulate parathyroid hormone-dependent MMP13 expression in osteoblasts through a new osteoblast-specific element 2/AP-1 composite element. J Biol Chem, 276(23): 20029–20038

PMID

31 HigashikawaA, SaitoT, IkedaT, KamekuraS, KawamuraN, KanA, OshimaY, OhbaS, OgataN, TakeshitaK, NakamuraK, ChungU I, KawaguchiH (2009). Identification of the core element responsive to runt-related transcription factor 2 in the promoter of human type X collagen gene. Arthritis Rheum, 60(1): 166–178

PMID

32 HinoiE, BialekP, ChenY T, RachedM T, GronerY, BehringerR R, OrnitzD M, KarsentyG (2006). Runx2 inhibits chondrocyte proliferation and hypertrophy through its expression in the perichondrium. Genes Dev, 20(21): 2937–2942

PMID

33 HoM S, TsangK Y, LoR L, SusicM, MäkitieO, ChanT W, NgV C, SillenceD O, Boot-HandfordR P, GibsonG, CheungK M, ColeW G, CheahK S, ChanD (2007). COL10A1 nonsense and frame-shift mutations have a gain-of-function effect on the growth plate in human and mouse metaphyseal chondrodysplasia type Schmid. Hum Mol Genet, 16(10): 1201–1215

PMID

34 HovhannisyanH, ZhangY, HassanM Q, WuH, GlackinC, LianJ B, SteinJ L, MontecinoM, SteinG S, van WijnenA J (2013). Genomic occupancy of HLH, AP1 and Runx2 motifs within a nuclease sensitive site of the Runx2 gene. J Cell Physiol, 228(2): 313–321

PMID

35 IjiriK, ZerbiniL F, PengH, CorreaR G, LuB, WalshN, ZhaoY, TaniguchiN, HuangX L, OtuH, WangH, WangJ F, KomiyaS, DucyP, RahmanM U, FlavellR A, GravalleseE M, OettgenP, LibermannT A, GoldringM B (2005). A novel role for GADD45beta as a mediator of MMP-13 gene expression during chondrocyte terminal differentiation. J Biol Chem, 280(46): 38544–38555

PMID

36 IkegawaS, NakamuraK, NaganoA, HagaN, NakamuraY (1997). Mutations in the N-terminal globular domain of the type X collagen gene (COL10A1) in patients with Schmid metaphyseal chondrodysplasia. Hum Mutat, 9(2): 131–135

PMID

37 IkegawaS, NishimuraG, NagaiT, HasegawaT, OhashiH, NakamuraY (1998). Mutation of the type X collagen gene (COL10A1) causes spondylometaphyseal dysplasia. Am J Hum Genet, 63(6): 1659–1662

PMID

38 ImabuchiR, OhmiyaY, KwonH J, OnoderaS, KitamuraN, KurokawaT, GongJ P, YasudaK (2011). Gene expression profile of the cartilage tissue spontaneously regenerated in vivo by using a novel double-network gel: comparisons with the normal articular cartilage. BMC Musculoskelet Disord, 12(1): 213

PMID

39 InadaM, YasuiT, NomuraS, MiyakeS, DeguchiK, HimenoM, SatoM, YamagiwaH, KimuraT, YasuiN, OchiT, EndoN, KitamuraY, KishimotoT, KomoriT (1999). Maturational disturbance of chondrocytes in Cbfa1-deficient mice. Dev Dyn, 214(4): 279–290

PMID

40 JacenkoO, LuValleP A, OlsenB R (1993). Spondylometaphyseal dysplasia in mice carrying a dominant negative mutation in a matrix protein specific for cartilage-to-bone transition. Nature, 365(6441): 56–61

PMID

41 JochumW, DavidJ P, ElliottC, WutzA, PlenkH Jr, MatsuoK, WagnerE F (2000). Increased bone formation and osteosclerosis in mice overexpressing the transcription factor Fra-1. Nat Med, 6(9): 980–984

PMID

42 JochumW, PasseguéE, WagnerE F (2001). AP-1 in mouse development and tumorigenesis. Oncogene, 20(19): 2401–2412

PMID

43 KamekuraS, KawasakiY, HoshiK, ShimoakaT, ChikudaH, MaruyamaZ, KomoriT, SatoS, TakedaS, KarsentyG, NakamuraK, ChungU I, KawaguchiH (2006). Contribution of runt-related transcription factor 2 to the pathogenesis of osteoarthritis in mice after induction of knee joint instability. Arthritis Rheum, 54(8): 2462–2470

PMID

44 KarrethF, HoebertzA, ScheuchH, EferlR, WagnerE F (2004). The AP1 transcription factor Fra2 is required for efficient cartilage development. Development, 131(22): 5717–5725

PMID

45 KawaguchiH (2008). Endochondral ossification signals in cartilage degradation during osteoarthritis progression in experimental mouse models. Mol Cells, 25(1): 1–6

PMID

46 KennerL, HoebertzA, BeilF T, KeonN, KarrethF, EferlR, ScheuchH, SzremskaA, AmlingM, Schorpp-KistnerM, AngelP, WagnerE F (2004). Mice lacking JunB are osteopenic due to cell-autonomous osteoblast and osteoclast defects. J Cell Biol, 164(4): 613–623

PMID

47 KimI S, OttoF, ZabelB, MundlosS (1999). Regulation of chondrocyte differentiation by Cbfa1. Mech Dev, 80(2): 159–170

PMID

48 KomoriT, YagiH, NomuraS, YamaguchiA, SasakiK, DeguchiK, ShimizuY, BronsonR T, GaoY H, InadaM, SatoM, OkamotoR, KitamuraY, YoshikiS, KishimotoT (1997). Targeted disruption of Cbfa1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts. Cell, 89(5): 755–764

PMID

49 KronenbergH M (2003). Developmental regulation of the growth plate. Nature, 423(6937): 332–336

PMID

50 KungL H, RajparM H, BriggsM D, Boot-HandfordR P (2012). Hypertrophic chondrocytes have a limited capacity to cope with increases in endoplasmic reticulum stresswithout triggering the unfolded protein response. J Histochem Cytochem, 60(10): 734–48

51 KwanK M, PangM K, ZhouS, CowanS K, KongR Y, PfordteT, OlsenB R, SillenceD O, TamP P, CheahK S (1997). Abnormal compartmentalization of cartilage matrix components in mice lacking collagen X: implications for function. J Cell Biol, 136(2): 459–471

PMID

52 LeeB, ThirunavukkarasuK, ZhouL, PastoreL, BaldiniA, HechtJ, GeoffroyV, DucyP, KarsentyG (1997). Missense mutations abolishing DNA binding of the osteoblast-specific transcription factor OSF2/CBFA1 in cleidocranial dysplasia. Nat Genet, 16(3): 307–310

PMID

53 LeungV Y, GaoB, LeungK K, MelhadoI G, WynnS L, AuT Y, DungN W, LauJ Y, MakA C, ChanD, CheahK S (2011). SOX9 governs differentiation stage-specific gene expression in growth plate chondrocytes via direct concomitant transactivation and repression. PLoS Genet, 7(11): e1002356

PMID

54 LiF, LuY, DingM, NapieralaD, AbbassiS, ChenY, DuanX, WangS, LeeB, ZhengQ (2011). Runx2 contributes to murine Col10a1 gene regulation through direct interaction with its cis-enhancer. J Bone Miner Res, 26(12): 2899–2910

PMID

55 LinsenmayerT F, ChenQ A, GibneyE, GordonM K, MarchantJ K, MayneR, SchmidT M (1991). Collagen types IX and X in the developing chick tibiotarsus: analyses of mRNAs and proteins. Development, 111(1): 191–196

PMID

56 LinsenmayerT F, FitchJ M, GrossJ, MayneR (1985). Are collagen fibrils in the developing avian cornea composed of two different collagen types? Evidence from monoclonal antibody studies. Ann N Y Acad Sci, 460(1 Biology, Chem): 232–245

PMID

57 LongF, LinsenmayerT F (1995). Tissue-specific regulation of the type X collagen gene. Analyses by in vivo footprinting and transfection with a proximal promoter region. J Biol Chem, 270(52): 31310–31314

PMID

58 MackieE J, AhmedY A, TatarczuchL, ChenK S, MiramsM (2008). Endochondral ossification: how cartilage is converted into bone in the developing skeleton. Int J Biochem Cell Biol, 40(1): 46–62

PMID

59 MacLeanH E, KimJ I, GlimcherM J, WangJ, KronenbergH M, GlimcherL H (2003). Absence of transcription factor c-maf causes abnormal terminal differentiation of hypertrophic chondrocytes during endochondral bone development. Dev Biol, 262(1): 51–63

PMID

60 MageeC, NurminskayaM, FavermanL, GaleraP, LinsenmayerT F (2005). SP3/SP1 transcription activity regulates specific expression of collagen type X in hypertrophic chondrocytes. J Biol Chem, 280(27): 25331–25338

PMID

61 MäkitieO, SusicM, ColeW G (2010). Early-onset metaphyseal chondrodysplasia type Schmid associated with a COL10A1 frame-shift mutation and impaired trimerization of wild-type α1(X) protein chains. J Orthop Res, 28(11): 1497–1501

PMID

62 MäkitieO, SusicM, WardL, BarclayC, GlorieuxF H, ColeW G (2005). Schmid type of metaphyseal chondrodysplasia and COL10A1 mutations—findings in 10 patients. Am J Med Genet A, 137A(3): 241–248

PMID

63 MarksD S, GregoryC A, WallisG A, BrassA, KadlerK E, Boot-HandfordR P (1999). Metaphyseal chondrodysplasia type Schmid mutations are predicted to occur in two distinct three-dimensional clusters within type X collagen NC1 domains that retain the ability to trimerize. J Biol Chem, 274(6): 3632–3641

PMID

64 MaruyamaT, MiyamotoY, YamamotoG, YamadaA, YoshimuraK, SuzawaT, TakamiM, AkiyamaT, HoshinoM, IwasaF, IkumiN, TachikawaT, MishimaK, BabaK, KamijoR (2013). Downregulation of carbonic anhydrase IX promotes Col10a1 expression in chondrocytes. PLoS ONE, 8(2): e56984

PMID

65 MatsuiY, YasuiN, KawabataH, OzonoK, NakataK, MizushimaT, TsumakiN, KataokaE, FujitaY, OchiT (2000). A novel type X collagen gene mutation (G595R) associated with Schmid-type metaphyseal chondrodysplasia. J Hum Genet, 45(2): 105–108

PMID

66 McIntoshI, AbbottM H, FrancomanoC A (1995). Concentration of mutations causing Schmid metaphyseal chondrodysplasia in the C-terminal noncollagenous domain of type X collagen. Hum Mutat, 5(2): 121–125

PMID

67 MyšičkováA, VingronM (2012). Detection of interacting transcription factors in human tissues using predicted DNA binding affinity. BMC Genomics, 13(13 Suppl 1): S2

PMID

68 NaefF, HuelskenJ (2005). Cell-type-specific transcriptomics in chimeric models using transcriptome-based masks. Nucleic Acids Res, 33(13): e111

PMID

69 OttoF, ThornellA P, CromptonT, DenzelA, GilmourK C, RosewellI R, StampG W, BeddingtonR S, MundlosS, OlsenB R, SelbyP B, OwenM J (1997). Cbfa1, a candidate gene for cleidocranial dysplasia syndrome, is essential for osteoblast differentiation and bone development. Cell, 89(5): 765–771

PMID

70 PapachristouD, PirttiniemiP, KantomaaT, AgnantisN, BasdraE K (2006). Fos- and Jun-related transcription factors are involved in the signal transduction pathway of mechanical loading in condylar chondrocytes. Eur J Orthod, 28(1): 20–26

PMID

71 PenolazziL, LisignoliG, LambertiniE, TorreggianiE, ManferdiniC, LolliA, VecchiatiniR, CiardoF, GabusiE, FacchiniA, GambariR, PivaR (2011). Transcription factor decoy against NFATc1 in human primary osteoblasts. Int J Mol Med, 28(2): 199–206

PMID

72 PulligO, WeselohG, RonnebergerD, KäkönenS, SwobodaB (2000). Chondrocyte differentiation in human osteoarthritis: expression of osteocalcin in normal and osteoarthritic cartilage and bone. Calcif Tissue Int, 67(3): 230–240

PMID

73 RajparM H, McDermottB, KungL, EardleyR, KnowlesL, HeeranM, ThorntonD J, WilsonR, BatemanJ F, PoulsomR, ArvanP, KadlerK E, BriggsM D, Boot-HandfordR P (2009). Targeted induction of endoplasmic reticulum stress induces cartilage pathology. PLoS Genet, 5(10): e1000691

PMID

74 RiemerS, GebhardS, BeierF, PöschlE, von der MarkK (2002). Role of c-fos in the regulation of type X collagen gene expression by PTH and PTHrP: Localization of a PTH/PTHrPresponsive region in the human COL10A1 enhancer. J Cell Biochem, 86: 688–699

75 SaharD E, LongakerM T, QuartoN (2005). Sox9 neural crest determinant gene controls patterning and closure of the posterior frontal cranial suture. Dev Biol, 280(2): 344–361

PMID

76 SaitoT, FukaiA, MabuchiA, IkedaT, YanoF, OhbaS, NishidaN, AkuneT, YoshimuraN, NakagawaT, NakamuraK, TokunagaK, ChungU I, KawaguchiH (2010). Transcriptional regulation of endochondral ossification by HIF-2alpha during skeletal growth and osteoarthritis development. Nat Med, 16(6): 678–686

PMID

77 SakimuraR, TanakaK, YamamotoS, MatsunobuT, LiX, HanadaM, OkadaT, NakamuraT, LiY, IwamotoY (2007). The effects of histone deacetylase inhibitors on the induction of differentiation in chondrosarcoma cells. Clin Cancer Res, 13(1): 275–282

PMID

78 SawaiH, IdaA, NakataY, KoyamaK (1998). Novel missense mutation resulting in the substitution of tyrosine by cysteine at codon 597 of the type X collagen gene associated with Schmid metaphyseal chondrodysplasia. J Hum Genet, 43(4): 259–261

PMID

79 SchipaniE, ProvotS (2003). PTHrP, PTH, and the PTH/PTHrP receptor in endochondral bone development. Birth Defects Res C Embryo Today, 69(4): 352–362

PMID

80 ShenG (2005). The role of type X collagen in facilitating and regulating endochondral ossification of articular cartilage. Orthod Craniofac Res, 8(1): 11–17

PMID

81 SimõesB, ConceiçãoN, ViegasC S, PintoJ P, GavaiaP J, HurstL D, KelshR N, CancelaM L (2006). Identification of a promoter element within the zebrafish colXalpha1 gene responsive to runx2 isoforms Osf2/Cbfa1 and til-1 but not to pebp2alphaA2. Calcif Tissue Int, 79(4): 230–244

PMID

82 StratakisC A, OrbanZ, BurnsA L, VotteroA, MitsiadesC S, MarxS J, AbbassiV, ChrousosG P (1996). Dideoxyfingerprinting (ddF) analysis of the type X collagen gene (COL10A1) and identification of a novel mutation (S671P) in a kindred with Schmid metaphyseal chondrodysplasia. Biochem Mol Med, 59(2): 112–117

PMID

83 TakedaS, BonnamyJ P, OwenM J, DucyP, KarsentyG (2001). Continuous expression of Cbfa1 in nonhypertrophic chondrocytes uncovers its ability to induce hypertrophic chondrocyte differentiation and partially rescues Cbfa1-deficient mice. Genes Dev, 15(4): 467–481

PMID

84 TanJ T, KremerF, FreddiS, BellK M, BakerN L, LamandéS R, BatemanJ F (2008). Competency for nonsense-mediated reduction in collagen X mRNA is specified by the 3′ UTR and corresponds to the position of mutations in Schmid metaphyseal chondrodysplasia. Am J Hum Genet, 82(3): 786–793

PMID

85 ThomasD P, SuntersA, GentryA, GrigoriadisA E (2000). Inhibition of chondrocyte differentiation in vitro by constitutive and inducible overexpression of the c-fos proto-oncogene. J Cell Sci, 113(Pt 3): 439–450

PMID

86 Thomas-ChollierM, HuftonA, HeinigM, O’KeeffeS, MasriN E, RoiderH G, MankeT, VingronM (2011). Transcription factor binding predictions using TRAP for the analysis of ChIP-seq data and regulatory SNPs. Nat Protoc, 6(12): 1860–1869

PMID

87 TsuchimochiK, OteroM, DragomirC L, PlumbD A, ZerbiniL F, LibermannT A, MarcuK B, KomiyaS, IjiriK, GoldringM B (2010). GADD45beta enhances Col10a1 transcription via the MTK1/MKK3/6/p38 axis and activation of C/EBPbeta-TAD4 in terminally differentiating chondrocytes. J Biol Chem, 285(11): 8395–8407

PMID

88 van der KraanP M, van den BergW B (2012). Chondrocyte hypertrophy and osteoarthritis: role in initiation and progression of cartilage degeneration? Osteoarthritis Cartilage, 20(3): 223–232

PMID

89 von der MarkK, FrischholzS, AignerT, BeierF, BelkeJ, ErdmannS, BurkhardtH (1995). Upregulation of type X collagen expression in osteoarthritic cartilage. Acta Orthop Scand Suppl, 266: 125–129

PMID

90 von der MarkK, KirschT, NerlichA, KussA, WeselohG, GlückertK, StössH (1992). Type X collagen synthesis in human osteoarthritic cartilage. Indication of chondrocyte hypertrophy. Arthritis Rheum, 35(7): 806–811

PMID

91 VonkL A, KragtenA H, DhertW J, SarisD B, CreemersL B (2014). Overexpression of hsa-miR-148a promotes cartilage production and inhibits cartilage degradation by osteoarthritic chondrocytes. Osteoarthritis Cartilage, 22(1): 145–153

PMID

92 WagnerE F (2002). Functions of AP1 (Fos/Jun) in bone development. Ann Rheum Dis, 61(61 Suppl 2): ii40–ii42

PMID

93 WallisG A, RashB, SykesB, BonaventureJ, MaroteauxP, ZabelB, Wynne-DaviesR, GrantM E, Boot-HandfordR P (1996). Mutations within the gene encoding the alpha 1 (X) chain of type X collagen (COL10A1) cause metaphyseal chondrodysplasia type Schmid but not several other forms of metaphyseal chondrodysplasia. J Med Genet, 33(6): 450–457

PMID

94 WarmanM L, AbbottM, ApteS S, HefferonT, McIntoshI, CohnD H, HechtJ T, OlsenB R, FrancomanoC A (1993). A type X collagen mutation causes Schmid metaphyseal chondrodysplasia. Nat Genet, 5(1): 79–82

PMID

95 WilsonR, FreddiS, ChanD, CheahK S, BatemanJ F (2005). Misfolding of collagen X chains harboring Schmid metaphyseal chondrodysplasia mutations results in aberrant disulfide bond formation, intracellular retention, and activation of the unfolded protein response. J Biol Chem, 280(16): 15544–15552

PMID

96 WoelfleJ V, BrennerR E, ZabelB, ReichelH, NelitzM (2011). Schmid-type metaphyseal chondrodysplasia as the result of a collagen type X defect due to a novel COL10A1 nonsense mutation: A case report of a novel COL10A1 mutation. J Orthop Sci, 16(2): 245–249

PMID

97 ZanottiS, CanalisE (2013). Notch suppresses nuclear factor of activated T cells (NFAT) transactivation and Nfatc1 expression in chondrocytes. Endocrinology, 154(2): 762–772

PMID

98 ZhengQ, KellerB, ZhouG, NapieralaD, ChenY, ZabelB, ParkerA E, LeeB (2009). Localization of the cis-enhancer element for mouse type X collagen expression in hypertrophic chondrocytes in vivo. J Bone Miner Res, 24(6): 1022–1032

PMID

99 ZhengQ, SebaldE, ZhouG, ChenY, WilcoxW, LeeB, KrakowD (2005). Dysregulation of chondrogenesis in human cleidocranial dysplasia. Am J Hum Genet, 77(2): 305–312

PMID

100 ZhengQ, ZhouG, MorelloR, ChenY, Garcia-RojasX, LeeB (2003). Type X collagen gene regulation by Runx2 contributes directly to its hypertrophic chondrocyte-specific expression in vivo. J Cell Biol, 162(5): 833–842

PMID

101 ZhouG, ZhengQ, EnginF, MunivezE, ChenY, SebaldE, KrakowD, LeeB (2006). Dominance of SOX9 function over RUNX2 during skeletogenesis. Proc Natl Acad Sci USA, 103(50): 19004–19009

PMID

102 ZhuY, LiL, ZhouL, MeiH, JinK, LiuK, XuW, TangJ, YangY, ZhaoR, HeX (2011). A novel mutation leading to elongation of the deduced α1(X) chain results in Metaphyseal Chondrodysplasia type Schmid. Clin Chim Acta, 412(13–14): 1266–1269

PMID

103 ZimmermannP, BoeufS, DickhutA, BoehmerS, OlekS, RichterW (2008). Correlation of COL10A1 induction during chondrogenesis of mesenchymal stem cells with demethylation of two CpG sites in the COL10A1 promoter. Arthritis Rheum, 58(9): 2743–2753

PMID