SOX9 gene transfer via safe, stable, replication-defective recombinant adeno-associated virus vectors as a novel, powerful tool to enhance the chondrogenic potential of human mesenchymal stem cells

Stem Cell Research and Therapy

Volumn 3, Issue 3, 2012, Pages

  Venkatesan, Jagadeesh K ^a   Ekici, Myriam ^a   Madry, Henning ^a   Schmitt, Gertrud ^a   Kohn, Dieter ^a   Cucchiarini, Magali ^a  

^a SAARLAND UNIVERSITY   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

ALKALINE PHOSPHATASE; BETA CATENIN; CELL MARKER; COLLAGEN TYPE 1; COLLAGEN TYPE 10; COLLAGEN TYPE 2; COLLAGENASE 3; LIPOPROTEIN LIPASE; OSTEOPONTIN; PARATHYROID HORMONE RELATED PROTEIN; PARVOVIRUS VECTOR; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA 2; PROTEOGLYCAN; TRANSCRIPTION FACTOR RUNX2; TRANSCRIPTION FACTOR SOX9; MMP13 PROTEIN, HUMAN; RUNX2 PROTEIN, HUMAN; SOX9 PROTEIN, HUMAN;

ADIPOGENESIS; ADULT; ARTICLE; ARTICULAR CARTILAGE; BONE DEVELOPMENT; CELL ACTIVITY; CELL DIFFERENTIATION; CELL ISOLATION; CELL LINEAGE; CELL PROLIFERATION; CELL VIABILITY; CHONDROGENESIS; CLINICAL EFFECTIVENESS; CONTROLLED STUDY; DOWN REGULATION; EMBRYO; EXTRACELLULAR MATRIX; GENE EXPRESSION REGULATION; GENE FUNCTION; GENE OVEREXPRESSION; HUMAN; HUMAN CELL; HUMAN TISSUE; HYPERTROPHY; MESENCHYMAL STEM CELL TRANSPLANTATION; NONHUMAN; PHENOTYPE; PRIORITY JOURNAL; PROTEIN EXPRESSION; VIRAL GENE DELIVERY SYSTEM; VIRUS RECOMBINANT; VIRUS REPLICATION; ADENO ASSOCIATED VIRUS; CARTILAGE CELL; CELL CULTURE; CELL SURVIVAL; CYTOLOGY; GENE TRANSFER; GENE VECTOR; GENETICS; MESENCHYMAL STEM CELL; METABOLISM; PATHOLOGY; PHYSIOLOGY; PLASMID;

ADENO-ASSOCIATED VIRUS;

ADIPOGENESIS; ALKALINE PHOSPHATASE; CARTILAGE, ARTICULAR; CELL LINEAGE; CELL PROLIFERATION; CELL SURVIVAL; CELLS, CULTURED; CHONDROCYTES; CHONDROGENESIS; CORE BINDING FACTOR ALPHA 1 SUBUNIT; DEPENDOVIRUS; GENE TRANSFER TECHNIQUES; GENETIC VECTORS; HUMANS; MATRIX METALLOPROTEINASE 13; MESENCHYMAL STEM CELLS; OSTEOGENESIS; PLASMIDS; SOX9 TRANSCRIPTION FACTOR; VIRUS REPLICATION;

EID: 84864767326     PISSN: None     EISSN: 17576512     Source Type: Journal    
DOI: 10.1186/scrt113     Document Type: Article

References (80)

1. Mesenchymal stem cells: clinical applications and biological characterization. Barry FP, Murphy JM, Int J Biochem Cell Biol 2004 36 568 584 10.1016/j.biocel.2003.11.001 15010324 (Pubitemid 38324589)
2. Mesenchymal stem cell therapy for knee osteoarthritis: preliminary report of four patients. Davatchi F, Abdollahi BS, Mohyeddin M, Shahram F, Nikbin B, Int J Rheum Dis 2011 14 211 215 10.1111/j.1756-185X.2011.01599.x 21518322
3. Safety of autologous bone marrow-derived mesenchymal stem cell transplantation for cartilage repair in 41 patients with 45 joints followed for up to 11 years and 5 months. Wakitani S, Okabe T, Horibe S, Mitsuoka T, Saito M, Koyama T, Nawata M, Tensho K, Kato H, Uematsu K, Kuroda R, Kurosaka M, Yoshiya S, Hattori K, Ohgushi H, J Tissue Eng Regen Med 2011 5 146 150 10.1002/term.299 20603892
4. Stem cells and cartilage development: complexities of a simple tissue. Hollander AP, Dickinson SC, Kafienah W, Stem Cells 2010 28 1992 1996 10.1002/stem.534 20882533
5. Repair of tissues by adult stem/progenitor cells (MSCs): controversies, myths, and changing paradigms. Prockop DJ, Mol Ther 2009 17 939 946 10.1038/mt.2009.62 19337235
6. Gene transfer and living release of transforming growth factor-beta3 for cartilage tissue engineering applications. Hao J, Yao Y, Varshney RR, Wang L, Prakash C, Li H, Wang DA, Tissue Eng Part C 2008 14 273 280 10.1089/ten.tec. 2008.0163
7. Adenoviral-mediated transfer of TGF-beta1 but not IGF-1 induces chondrogenic differentiation of human mesenchymal stem cells in pellet cultures. Kawamura K, Chu CR, Sobajima S, Robbins PD, Fu FH, Izzo NJ, Niyibizi C, Exp Hematol 2005 33 865 872 10.1016/j.exphem.2005.05.010 16038778 (Pubitemid 40982652)
8. Adeno-associated viral gene transfer of transforming growth factor-beta1 to human mesenchymal stem cells improves cartilage repair. Pagnotto MR, Wang Z, Karpie JC, Ferreti M, Xiao X, Chu CR, Gene Ther 2007 14 804 813 10.1038/sj.gt.3302938 17344902 (Pubitemid 46706060)
9. Gene-induced chondrogenesis of primary mesenchymal stem cells in vitro. Palmer GD, Steinert A, Pascher A, Gouze E, Gouze JN, Betz O, Johnstone B, Evans CH, Ghivizzani SC, Mol Ther 2005 12 219 228 10.1016/j.ymthe.2005.03.024 16043093 (Pubitemid 41025091)
10. Enhanced in vitro chondrogenesis of primary mesenchymal stem cells by combined gene transfer. Steinert AF, Palmer GD, Pilapil C, Noth U, Evans CH, Ghivizzani SC, Tissue Eng Part A 2009 15 1127 1139 10.1089/ten.tea.2007.0252 18826340
11. In vitro chondrogenesis of human bone marrow-derived mesenchymal progenitor cells in monolayer culture: activation by transfection with TGF-beta2. Wang WG, Lou SQ, Ju XD, Xia K, Xia JH, Tissue Cell 2003 35 69 77 10.1016/S0040-8166(02)00106-4 12589731 (Pubitemid 36329262)
12. Transgene-activated mesenchymal cells for articular cartilage repair: a comparison of primary bone marrow-, perichondrium/periosteum- and fat-derived cells. Park J, Gelse K, Frank S, von der Mark K, Aigner T, Schnider H, J Gene Med 2006 8 112 125 10.1002/jgm.826 16142704 (Pubitemid 43169387)
13. Hypertrophy is induced during the in vitro chondrogenic differentiation of human mesenchymal stem cells by bone morphogenetic protein-2 and bone morphogenetic protein-4 gene transfer. Steinert AF, Proffen B, Kunz M, Hendrich C, Ghivizzani SC, Noth U, Rethwilm A, Eulert J, Evans CH, Arthritis Res Ther 2009 11 148 R162 10.1186/ar2822 19799789
14. Effect of IGF-I in the chondrogenesis of bone marrow mesenchymal stem cells in the presence or absence of TGF-beta signaling. Longobardi L, O'Rear L, Aakula S, Johnstone B, Shimer K, Chytil A, Horton WA, Moses HL, Spagnoli A, J Bone Miner Res 2006 21 626 636 16598383
15. Impact of growth factors and PTHrP on early and late chondrogenic differentiation of human mesenchymal stem cells. Weiss S, Hennig T, Bock R, Steck E, Richter W, J Cell Physiol 2010 223 84 93 20049852
16. Metabolic activities and chondrogenic differentiation of human mesenchymal stem cells following recombinant adeno-associated virus-mediated gene transfer and overexpression of fibroblast growth factor 2. Cucchiarini M, Ekici M, Schetting S, Kohn D, Madry H, Tissue Eng Part A 2011 17 1921 1933 10.1089/ten.tea.2011.0018 21417714
17. Fibroblast growth factor-2 enhances proliferation and delays loss of chondrogenic potential in human adult bone-marrow-derived mesenchymal stem cells. Solchaga LA, Penick K, Goldberg VM, Caplan AI, Welter JF, Tissue Eng Part A 2010 16 1009 1019 10.1089/ten.tea.2009.0100 19842915
18. Zinc-finger protein 145, acting as an upstream regulator of SOX9, improves the differentiation potential of human mesenchymal stem cells for cartilage regeneration and repair. Liu TM, Guo XM, Tan HS, Hui JH, Lim B, Lee EH, Arthritis Rheum 2011 63 2711 2720 10.1002/art.30430 21547890
19. Stabilization of cellular properties and differentiation multipotential of human mesenchymal stem cells transduced with hTERT gene in a long-term culture. Huang G, Zheng Q, Sun J, Guo C, Yang J, Chen R, Xu Y, Wang G, Shen D, Pan Z, Jin J, Wang J, J Cell Biochem 2008 103 1256 1269 10.1002/jcb.21502 18027880 (Pubitemid 351342614)
20. Telomerase expression extends the proliferative life-span and maintains the osteogenic potential of human bone marrow stromal cells. Simonsen JL, Rosada C, Serakinci N, Justesen J, Stenderup K, Rattan SI, Jensen TG, Kassem M, Nat Biotechnol 2002 20 592 596 10.1038/nbt0602-592 12042863 (Pubitemid 34595153)
21. Enhanced treatment of articular cartilage defect of the knee by intra-articular injection of Bcl-xL-engineered mesenchymal stem cells in rabbit model. Hu B, Ren JL, Zhang JR, Ma Q, Liu YP, Mao TQ, J Tissue Eng Regen Med 2010 4 105 114 10.1002/term.212 19927304
22. Sox9 is required for cartilage formation. Bi W, Deng JM, Zhang Z, Behringer RR, de Crombrugghe B, Nat Genet 1999 22 85 89 10.1038/8792 10319868 (Pubitemid 29214811)
23. Interactions between Sox9 and beta-catenin control chondrocyte differentiation. Akiyama H, Lyons JP, Mori-Akiyama Y, Yang X, Zhang R, Zhang Z, Deng JM, Taketo MM, Nakamura T, Behringer RR, McCrea PD, de Crombrugghe B, Genes Dev 2004 18 1072 1087 10.1101/gad.1171104 15132997 (Pubitemid 38620246)
24. The combination of SOX5, SOX6, and SOX9 (the SOX trio) provides signals sufficient for induction of permanent cartilage. Ikeda T, Kamekura S, Mabuchi A, Kou I, Seki S, Takato T, Nakamura K, Kawaguchi H, Ikegawa S, Chung UI, Arthritis Rheum 2004 50 3561 3573 10.1002/art.20611 15529345 (Pubitemid 39488681)
25. SOX9 governs differentiation stage-specific gene expression in growth plate chondrocytes via direct concomitant transactivation and repression. Leung VY, Gao B, Leung KK, Melhado IG, Wynn SL, Au TY, Dung NW, Lau JY, Mak AC, Chan D, Cheah KS, PLoS Genet 2011 7 1002356 e1002371 10.1371/journal.pgen.1002356 22072985
26. Chondrogenesis enhanced by overexpression of sox9 gene in mouse bone marrow-derived mesenchymal stem cells. Tsuchiya H, Kitoh H, Sugiura F, Ishiguro N, Biochem Biophys Res Commun 2003 301 338 343 10.1016/S0006-291X(02)03026-7 12565865 (Pubitemid 36279243)
27. Pref-1 regulates mesenchymal cell commitment and differentiation through Sox9. Wang Y, Sul HS, Cell Metab 2009 9 287 302 10.1016/j.cmet.2009.01.013 19254573
28. Sox9 directs hypertrophic maturation and blocks osteoblast differentiation of growth plate chondrocytes. Dy P, Wang W, Bhattaram P, Wang Q, Wang L, Ballock RT, Lefebvre V, Dev Cell 2012 22 597 609 10.1016/j.devcel.2011. 12.024 22421045
29. Sox9 sustains chondrocyte survival and hypertrophy in part through Pik3ca-Akt pathways. Ikegami D, Akiyama H, Suzuki A, Nakamura T, Nakano T, Yoshikawa H, Tsumaki N, Development 2011 138 1507 1519 10.1242/dev.057802 21367821
30. Electroporation-mediated transfer of SOX trio genes (SOX-5, SOX-6, and SOX-9) to enhance the chondrogenesis of mesenchymal stem cells. Kim HJ, Im GI, Stem Cells Dev 2011 20 2103 2114 10.1089/scd.2010.0516 21401405
31. The promotion of cartilage defect repair using adenovirus mediated Sox9 gene transfer of rabbit bone marrow mesenchymal stem cells. Cao L, Yang F, Liu G, Yu D, Li H, Fan Q, Gan Y, Tang T, Dai K, Biomaterials 2011 32 3910 3920 10.1016/j.biomaterials.2011.02.014 21377725
32. Improving chondrogenesis: potential and limitations of SOX9 gene transfer and mechanical stimulation for cartilage tissue engineering. Kupcsik L, Stoddart MJ, Li Z, Benneker LM, Alini M, Tissue Eng Part A 2010 16 1845 1855 10.1089/ten.tea.2009.0531 20067399
33. Comparative analysis with collagen type II distinguishes cartilage oligomeric matrix protein as a primary TGFbeta-responsive gene. Li H, Haudenschild DR, Posey KL, Hecht JT, Di Cesare PE, Yik JH, Osteoarthritis Cartilage 2011 19 1246 1253 10.1016/j.joca.2011.07.011 21843649
34. Adeno-associated viral vector transduction of human mesenchymal stem cells. Stender S, Murphy M, O'Brien T, Stengaard C, Ulrich-Vinther M, Soballe K, Barry F, Eur Cell Mater 2007 13 93 99 17538898 (Pubitemid 46890463)
35. Improved tissue repair in articular cartilage defects in vivo by rAAV-mediated overexpression of human fibroblast growth factor 2. Cucchiarini M, Madry H, Ma C, Thurn T, Zurakowski D, Menger MD, Kohn D, Trippel SB, Terwilliger EF, Mol Ther 2005 12 229 238 10.1016/j.ymthe.2005.03.012 16043094 (Pubitemid 41025092)
36. Safety, tolerability, and clinical outcomes after intraarticular injection of a recombinant adeno-associated vector containing a tumor necrosis factor antagonist gene: results of a phase 1/2 study. Mease PJ, Wei N, Fudman EJ, Kivitz AJ, Schechtman J, Trapp RG, Hobbs KF, Greenwald M, Hou A, Bookbinder SA, Graham GE, Wiesenhutter CW, Willis L, Ruderman EM, Forstot JZ, Maricic MJ, Dao KH, Pritchard CH, Fiske DN, Burch FX, Prupas HM, Anklesaria P, Heald AE, J Rheumatol 2010 37 692 703 10.3899/jrheum.090817 20032102
37. Chondrogenic differentiation of mesenchymal stem cells from bone marrow: differentiation-dependent gene expression of matrix components. Barry F, Boynton RE, Liu B, Murphy JM, Exp Cell Res 2001 268 189 200 10.1006/excr.2001.5278 11478845 (Pubitemid 32744650)
38. Multilineage potential of adult human mesenchymal stem cells. Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simonetti DW, Craig S, Marshak DR, Science 1999 284 143 147 10.1126/science.284.5411.143 10102814 (Pubitemid 29282067)
39. A recombinant plasmid from which an infectious adeno-associated virus genome can be excised in vitro and its use to study viral replication. Samulski RJ, Chang LS, Shenk T, J Virol 1987 61 3096 3101 3041032 (Pubitemid 17131491)
40. Helper-free stocks of recombinant adeno-associated viruses: normal integration does not require viral gene expression. Samulski RJ, Chang LS, Shenk T, J Virol 1989 63 3822 3828 2547998 (Pubitemid 19205454)
41. rAAV-mediated overexpression of FGF-2 promotes cell proliferation, survival, and alpha-SMA expression in human meniscal lesions. Cucchiarini M, Schetting S, Terwilliger EF, Kohn D, Madry H, Gene Ther 2009 16 1363 1372 10.1038/gt.2009.91 19641531
42. Remodelling of human osteoarthritic cartilage by FGF-2, alone or combined with Sox9 via rAAV gene transfer. Cucchiarini M, Terwilliger EF, Kohn D, Madry H, J Cell Mol Med 2009 13 2476 2488 10.1111/j.1582-4934.2008.00474.x 18705695
43. Restoration of the extracellular matrix in human osteoarthritic articular cartilage by overexpression of the transcription factor SOX9. Cucchiarini M, Thurn T, Weimer A, Kohn D, Terwilliger EF, Madry H, Arthritis Rheum 2007 56 158 167 10.1002/art.22299 17195218 (Pubitemid 46106188)
44. Benefits of rAAV-mediated IGF-I overexpression for the long-term reconstruction of human osteoarthritic cartilage by modulation of the IGF-I axis. Weimer A, Madry H, Venkatesan JK, Schmitt G, Frisch J, Wezel A, Jung J, Kohn D, Terwilliger EF, Trippel SB, Cucchiarini M, Mol Med 2012 18 346 358 22160392
45. Sex reversal by loss of the C-terminal transactivation domain of human SOX9. Sudbeck P, Schmitz ML, Baeuerle PA, Scherer G, Nat Genet 1996 13 230 232 10.1038/ng0696-230 8640233 (Pubitemid 26166159)
46. Multilineage mesenchymal differentiation potential of human trabecular bone-derived cells. Noth U, Osyczka AM, Tuli R, Hickok NJ, Danielson KG, Tuan RS, J Orthop Res 2002 20 1060 1069 10.1016/S0736-0266(02)00018-9 12382974
47. Characterization of multipotential mesenchymal progenitor cells derived from human trabecular bone. Tuli R, Tuli S, Nandi S, Wang ML, Alexander PG, Haleem-Smith H, Hozack WJ, Manner PA, Danielson KG, Tuan RS, Stem Cells 2003 21 681 693 10.1634/stemcells.21-6-681 14595128 (Pubitemid 37329161)
48. The effects of Wnt inhibitors on the chondrogenesis of human mesenchymal stem cells. Im GI, Quan Z, Tissue Eng Part A 2010 16 2405 2413 10.1089/ten.tea.2009.0359 19737074
49. Functional characterization of hypertrophy in chondrogenesis of human mesenchymal stem cells. Mueller MB, Tuan RS, Arthritis Rheum 2008 58 1377 1388 10.1002/art.23370 18438858 (Pubitemid 351705927)
50. Cartilage, SOX9 and Notch signals in chondrogenesis. Hardingham TE, Oldershaw RA, Tew SR, J Anat 2006 209 469 480 10.1111/j.1469-7580.2006.00630.x 17005019 (Pubitemid 44473315)
51. Suppression of growth and tumorigenicity in the prostate tumor cell line M12 by overexpression of the transcription factor SOX9. Drivdahl R, Haugk KH, Sprenger CC, Nelson PS, Tennant MK, Plymate SR, Oncogene 2004 23 4584 4593 10.1038/sj.onc.1207603 15077158 (Pubitemid 38850406)
52. Sox9 family members negatively regulate maturation and calcification of chondrocytes through up-regulation of parathyroid hormone-related protein. Amano K, Hata K, Sugita A, Takigawa Y, Ono K, Wakabayashi M, Kogo M, Nishimura R, Yoneda T, Mol Biol Cell 2009 20 4541 4551 10.1091/mbc.E09-03-0227 19759178
53. The control of chondrogenesis. Goldring MB, Tsuchimochi K, Ijiri K, J Cell Biochem 2006 97 33 44 10.1002/jcb.20652 16215986 (Pubitemid 43050970)
54. SOX9 is a major negative regulator of cartilage vascularization, bone marrow formation and endochondral ossification. Hattori T, Muller C, Gebhard S, Bauer E, Pausch F, Schlund B, Bosl MR, Hess A, Surmann-Schmitt C, von der Mark H, de Crombrugghe B, von der Mark K, Development 2010 137 901 911 10.1242/dev.045203 20179096
55. PTHrP and skeletal development. Kronenberg HM, Ann N Y Acad Sci 2006 1068 1 13 10.1196/annals.1346.002 16831900 (Pubitemid 43824131)
56. Transcriptional control of chondrocyte fate and differentiation. Lefebvre V, Smits P, Birth Defects Res C Embryo Today 2005 75 200 221 10.1002/bdrc.20048 16187326 (Pubitemid 41456322)
57. Role of preadipocyte factor 1 in adipocyte differentiation. Wang Y, Hudak C, Sul HS, Clin Lipidol 2010 5 109 115 10.2217/clp.09.80 20414356
58. Transcriptional networks controlling chondrocyte proliferation and differentiation during endochondral ossification. Wuelling M, Vortkamp A, Pediatr Nephrol 2010 25 625 631 10.1007/s00467-009-1368-6 19949815
59. Osteo-chondroprogenitor cells are derived from Sox9 expressing precursors. Akiyama H, Kim JE, Nakashima K, Balmes G, Iwai N, Deng JM, Zhang Z, Martin JF, Behringer RR, Nakamura T, de Crombrugghe B, Proc Natl Acad Sci USA 2005 102 14665 14670 10.1073/pnas.0504750102 16203988 (Pubitemid 41457113)
60. Runx2/Cbfa1 stimulation by retinoic acid is potentiated by BMP2 signaling through interaction with Smad1 on the collagen X promoter in chondrocytes. Drissi MH, Li X, Sheu TJ, Zuscik MJ, Schwarz EM, Puzas JE, Rosier RN, O'Keefe RJ, J Cell Biochem 2003 90 1287 1298 10.1002/jcb.10677 14635200 (Pubitemid 37485062)
61. Cbfa1 is a positive regulatory factor in chondrocyte maturation. Enomoto H, Enomoto-Iwamoto M, Iwamoto M, Nomura S, Himeno M, Kitamura Y, Kishimoto T, Komori T, J Biol Chem 2000 275 8695 8702 10.1074/jbc.275.12.8695 10722711 (Pubitemid 30180221)
62. Collagenase 3 is a target of Cbfa1, a transcription factor of the runt gene family involved in bone formation. Jimenez MJ, Balbin M, Lopez JM, Alvarez J, Komori T, Lopez-Otin C, Mol Cell Biol 1999 19 4431 4442 10330183 (Pubitemid 29242017)
63. Sox9 directly promotes Bapx1 gene expression to repress Runx2 in chondrocytes. Yamashita S, Andoh M, Ueno-Kudoh H, Sato T, Miyaki S, Asahara H, Exp Cell Res 2009 315 2231 2240 10.1016/j.yexcr.2009.03.008 19306868
64. Dominance of SOX9 function over RUNX2 during skeletogenesis. Zhou G, Zheng Q, Engin F, Munivez E, Chen Y, Sebald E, Krakow D, Lee B, Proc Natl Acad Sci USA 2006 103 19004 19009 10.1073/pnas.0605170103 17142326 (Pubitemid 350002818)
65. Canonical Wnt/beta-catenin signaling prevents osteoblasts from differentiating into chondrocytes. Hill TP, Spater D, Taketo MM, Birchmeier W, Hartmann C, Dev Cell 2005 8 727 738 10.1016/j.devcel.2005.02.013 15866163 (Pubitemid 40585295)
66. Indian hedgehog couples chondrogenesis to osteogenesis in endochondral bone development. Chung UI, Schipani E, McMahon AP, Kronenberg HM, J Clin Invest 2001 107 295 304 10.1172/JCI11706 11160153 (Pubitemid 32157961)
67. The chondrogenic transcription factor Sox9 is a target of signaling by the parathyroid hormone-related peptide in the growth plate of endochondral bones. Huang W, Chung UI, Kronenberg HM, de Crombrugghe B, Proc Natl Acad Sci USA 2001 98 160 165 10.1073/pnas.011393998 11120880 (Pubitemid 32095880)
68. PTHrP promotes chondrogenesis and suppresses hypertrophy from both bone marrow-derived and adipose tissue-derived MSCs. Kim YJ, Kim HJ, Im GI, Biochem Biophys Res Commun 2008 373 104 108 10.1016/j.bbrc.2008.05.183 18554504
69. Parathyroid hormone-related peptide (PTHrP) inhibits Runx2 expression through the PKA signaling pathway. Li TF, Dong Y, Ionescu AM, Rosier RN, Zuscik MJ, Schwarz EM, O'Keefe RJ, Drissi H, Exp Cell Res 2004 299 128 136 10.1016/j.yexcr.2004.05.025 15302580 (Pubitemid 39078388)
70. Regulation of rate of cartilage differentiation by Indian hedgehog and PTH-related protein. Vortkamp A, Lee K, Lanske B, Segre GV, Kronenberg HM, Tabin CJ, Science 1996 273 613 622 10.1126/science.273.5275.613 8662546 (Pubitemid 26262108)
71. PTHrP overexpression partially inhibits a mechanical strain-induced arthritic phenotype in chondrocytes. Wang D, Taboas JM, Tuan RS, Osteoarthritis Cartilage 2011 19 213 221 10.1016/j.joca.2010.11.003 21087676
72. Targeted overexpression of parathyroid hormone-related peptide in chondrocytes causes chondrodysplasia and delayed endochondral bone formation. Weir EC, Philbrick WM, Amling M, Neff LA, Baron R, Broadus AE, Proc Natl Acad Sci USA 1996 93 10240 10245 10.1073/pnas.93.19.10240 8816783 (Pubitemid 26314606)
73. Sox9 inhibits Wnt signaling by promoting beta-catenin phosphorylation in the nucleus. Topol L, Chen W, Song H, Day TF, Yang Y, J Biol Chem 2009 284 3323 3333 19047045
74. Sox5 and Sox6 are needed to develop and maintain source, columnar, and hypertrophic chondrocytes in the cartilage growth plate. Smits P, Dy P, Mitra S, Lefebvre V, J Cell Biol 2004 164 747 758 10.1083/jcb.200312045 14993235 (Pubitemid 38282958)
75. Use of genetically modified muscle and fat grafts to repair defects in bone and cartilage. Evans CH, Liu FJ, Glatt V, Hoyland JA, Kirker-Head C, Walsh A, Betz O, Wells JW, Betz V, Porter RM, Saad FA, Gerstenfeld LC, Einhorn TA, Harris MB, Vrahas MS, Eur Cell Mater 2009 18 96 111 20073015
76. Genetic modification of chondrocytes with insulin-like growth factor-1 enhances cartilage healing in an equine model. Goodrich LR, Hidaka C, Robbins PD, Evans CH, Nixon AJ, J Bone Joint Surg Br 2007 89 672 685 17540757 (Pubitemid 46958780)
77. Articular cartilage repair by genetically modified bone marrow aspirate in sheep. Ivkovic A, Pascher A, Hudetz D, Maticic D, Jelic M, Dickinson S, Loparic M, Haspl M, Windhager R, Pecina M, Gene 2010 17 779 789
78. Cartilage repair using bone morphogenetic protein 4 and muscle-derived stem cells. Kuroda R, Usas A, Kubo S, Corsi K, Peng H, Rose T, Cummins J, Fu FH, Huard J, Arthritis Rheum 2006 54 433 442 10.1002/art.21632 16447218 (Pubitemid 43228617)
79. Direct delayed human adenoviral BMP-2 or BMP-6 gene therapy for bone and cartilage regeneration in a pony osteochondral model. Menendez MI, Clark DJ, Carlton M, Flanigan DC, Jia G, Sammet S, Weisbrode SE, Knopp MV, Bertone AL, Osteoarthritis Cartilage 2011 19 1066 1075 10.1016/j.joca.2011.05.007 21683796
80. IL-1ra/IGF-1 gene therapy modulates repair of microfractured chondral defects. Morisset S, Frisbie DD, Robbins PD, Nixon AJ, McIlwraith CW, Clin Orthop Relat Res 2007 462 221 228 17534189 (Pubitemid 47367867)