Animal cells and systems

The Korean Society for Integrative Biology (한국통합생물학회)
권호 표지

Regulation of Early Steps of Chondrogenesis in the Developing Limb

  • Kang, Shin-Sung (Department of Biology, School of Biological Sciences, Kyungpook National University)
  • Published : 2008.03.31
Download PDF
⟨ Previous Next ⟩

Abstract

In the developing limb, chondrogenesis is an important prerequisite for the formation of cartilage whose template is required for bone formation. Chondrogenesis is a tightly regulated multi-step process, including mesenchymal cell recruitment/migration, prechondrogenic condensation of the mesenchymal cells, commitment to the chondrogenic lineage, and differentiation into chondrocytes. This process is controlled exquisitely by cellular interactions with the surrounding matrix and regulating factors that initiate or suppress cellular signaling pathways and transcription of specific genes in a temporal-spatial manner. Understanding the cellular and molecular mechanisms of chondrogenesis is important not only in the context of establishing basic principle of developmental biology but also in providing research direction toward preventive and/or regenerative medicine. Here, I will overview the current understanding of cellular and molecular mechanisms contributing to prechondrogenic condensation processes, the crucial steps for chondrogenesis, focusing on cell-cell and cell-matrix interactions.

Keywords

References

  1. Akiyama H, Chaboissier MC, Martin JF, Schedl A, and de Crombrugghe B (2002) 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 16: 2813-2828 https://doi.org/10.1101/gad.1017802
  2. Amalinei C, Caruntu ID, and Balan RA. (2007) Biology of metalloproteinases. Rom J Morphol Embryol 48: 323-334
  3. Aulthouse AL and Solursh M (1987) The detection of a precartilage, blastema-specific marker. Dev Biol 120: 377-384 https://doi.org/10.1016/0012-1606(87)90240-5
  4. Ballock RT, Heydemann A, Wakefield LM, Flanders KC, Roberts AB, and Sporn MB (1993) TGF-beta1 prevents hypertrophy of epiphyseal chondrocytes: Regulation of gene expression for cartilage matrix proteins and metallo-proteases. Dev Biol 158: 414-429 https://doi.org/10.1006/dbio.1993.1200
  5. Bang OS, Kim EJ, Chung JG, Lee SR, Park TK, and Kang SS (2000) Association of focal adhesion kinase with fibronectin and paxillin is required for precartilage condensation of chick mesenchymal cells. Biochem Biophys Res Commun 278: 522-529 https://doi.org/10.1006/bbrc.2000.3831
  6. Bi W, Deng JM, Zhang Z, Behringer RR, and de Crombrugghe B (1999) Sox9 is required for cartilage formation. Nat Genet 22: 85-89 https://doi.org/10.1038/8792
  7. Bord S, Horner A, Hembry RM, Reynolds JJ, and Compston JE (1997) Distribution of matrix metalloproteinases and their inhibitor, TIMP-1, in developing human osteophytic bone. J Anat 191: 39-48 https://doi.org/10.1046/j.1469-7580.1997.19110039.x
  8. Bord S, Horner A, Hembry RM, and Compston JE. (1998) Stromelysin-1 (MMP-3) and stromelysin-2 (MMP-10) expression in developing human bone: potential roles in skeletal development. Bone 23: 7-12 https://doi.org/10.1016/S8756-3282(98)00064-7
  9. Brown PD and Benya PD (1988) Alterations in chondrocyte cytoskeletal architecture during phenotypic modulation by retinoic acid and dihydrocytochalasin B-induced reexpression. J Cell Biol 106: 171-179 https://doi.org/10.1083/jcb.106.1.171
  10. Candia AF, Watabe T, Hawley SH, Onichtchouk D, Zhang Y, Derynck R, Niehrs C, and Cho KW (1997) Cellular interpretation of multiple TGF-beta signals: intracellular antagonism between activin/BVg1 and BMP-2/4 signaling mediated by Smads. Development 124: 4467-80
  11. Chetty C, Bhoopathi P, Lakka SS, and Rao JS (2007) MMP-2 siRNA induced Fas/CD95-mediated extrinsic II apoptotic pathway in the A549 lung adenocarcinoma cell line. Oncogene 26: 7675-7683 https://doi.org/10.1038/sj.onc.1210584
  12. Chimal-Monroy J and Díaz de León L (1999) Expression of Ncadherin, N-CAM, fibronectin and tenascin is stimulated by TGF-beta1, beta2, beta3 and beta5 during the formation of precartilage condensations. Int J Dev Biol 43: 59-67
  13. Contreras JE, Sánchez HA, Veliz LP, Bukauskas FF, Bennett MV, and Saez JC (2004) Role of connexin-based gap junction channels and hemichannels in ischemia-induced cell death in nervous tissue. Brain Res Brain Res Rev 47: 290-303 https://doi.org/10.1016/j.brainresrev.2004.08.002
  14. D'Angelo M, Yan Z, Nooreyazdan M, Pacifici M, Sarment DS, Billings PC, and Leboy PS (2000) MMP-13 is induced during chondrocyte hypertrophy. J Cell Biochem 77: 678-693 https://doi.org/10.1002/(SICI)1097-4644(20000615)77:4<678::AID-JCB15>3.0.CO;2-P
  15. Daniels K and Solursh M (1991) Modulation of chondrogenesis by the cytoskeleton and extracellular matrix. J Cell Sci 100 (pt 2): 249-254
  16. Daumer KM, Tufan AC, and Tuan RS (2004) Long-term in vitro analysis of limb cartilage development: involvement of Wnt signaling. J Cell Biochem 93: 526-541 https://doi.org/10.1002/jcb.20190
  17. Day TF, Guo X, Garrett-Beal L, and Yang Y (2005) Wnt/betacatenin signaling in mesenchymal progenitors controls osteoblast and chondrocyte differentiation during vertebrate skeletogenesis. Dev Cell 8: 739-750 https://doi.org/10.1016/j.devcel.2005.03.016
  18. Dealy CN, Beyer EC, and Kosher RA (1994) Expression patterns of mRNAs for the gap junction proteins connexin43 and connexin42 suggest their involvement in chick limb morphogenesis and specification of the arterial vasculature. Dev Dyn 199: 156-167 https://doi.org/10.1002/aja.1001990208
  19. DeLise AM, Fischer L, and Tuan RS (2000) Cellular interactions and signaling in cartilage development. Osteoarthritis Cartilage 8: 309-334 https://doi.org/10.1053/joca.1999.0306
  20. DeLise AM and Tuan RS (2002) Analysis of N-cadherin function in limb mesenchymal chondrogenesis in vitro. Dev Dyn 225: 195-204 https://doi.org/10.1002/dvdy.10151
  21. Djouad F, Delorme B, Maurice M, Bony C, Apparailly F, Louis- Plence P, Canovas F, Charbord P, Noel D, and Jorgensen C (2007) Microenvironmental changes during differentiation of mesenchymal stem cells towards chondrocytes. Arthritis Res Ther 9: R33 https://doi.org/10.1186/ar2153
  22. Downie SA and Newman SA (1995) Different roles for fibronectin in the generation of fore and hind limb precartilage condensations. Dev Biol 172: 519-530 https://doi.org/10.1006/dbio.1995.8068
  23. Ede DA and Shamslahidjani M (1983) Ectoderm/mesoderm recombination, dissociation and cell aggregation studies in normal and talpids mutant avian embryos. Prog Clin Biol Res 110 (Pt A): 45-55
  24. Eiberger J, Degen J, Romualdi A, Deutsch U, Willecke K, and Sohl G (2001) Connexin genes in the mouse and human genome. Cell Commun Adhes 8: 163-165 https://doi.org/10.3109/15419060109080717
  25. Fallon JF and Kelley RO (1977) Ultrastruct analysis of the apical ectodermal ridge during vertebrate limb morphogenesis. II. Gap junctions as distinctive ridge structures common to birds and mammals. J Embryol Exp Morphol 41: 223-232
  26. Fang J and Hall BK (1995) Differential expression of neural cell adhesion molecule (NCAM) during osteogenesis and secondary chondrogenesis in the embryonic chick. Int J Dev Biol 3: 519-528
  27. Filipenko NR, Attwell S, Roskelley C, and Dedhar S (2005) Integrin-linked kinase activity regulates Rac- and Cdc42- mediated actin cytoskeleton reorganization via alpha-PIX. Oncogene 24: 5837-5849 https://doi.org/10.1038/sj.onc.1208737
  28. Fischer L, Boland G, and Tuan RS (2002) Wnt-3A enhances bone morphogenetic protein-2-mediated chondrogenesis of murine C3H10T1/2 mesenchymal cells. J Biol Chem 277: 30870-30878 https://doi.org/10.1074/jbc.M109330200
  29. Frenz DA, Jaikaria NS, and Newman SA (1989) The mechanism of precartilage mesenchymal condensation: a major role for interaction of the cell surface with the amino-terminal heparin-binding domain of fibronectin. Dev Biol 136: 97-103 https://doi.org/10.1016/0012-1606(89)90133-4
  30. Gehris AL, Stringa E, Spina J, Desmond ME, Tuan RS, and Bennett VD (1997) The region encoded by the alternatively spliced exon IIIA in mesenchymal fibronectin appears essential for chondrogenesis at the level of cellular condensation. Dev Bio 190: 191-205 https://doi.org/10.1006/dbio.1997.8693
  31. Goldring MB, Tsuchimochi K, and Ijiri K (2006) The control of chondrogenesis. J Cell Biochem 97: 33-44 https://doi.org/10.1002/jcb.20652
  32. Gould SE, Upholt WB, and Kosher RA (1995) Characterization of chicken syndecan-3 as a heparan sulfate proteoglycan and its expression during embryogenesis. Dev Biol 168: 435-451
  33. Green CR, Bowles L, and Crawley A (1994) Tickle C. Expression of the connexin43 gap junctional protein in tissues at the tip of the chick limb bud is related to the epithelial-mesenchymal interactions that mediate morphogenesis. Dev Biol 161: 12-21 https://doi.org/10.1006/dbio.1994.1002
  34. Grimsrud CD, Romano PR, D'Souza M, Puzas JE, Reynolds PR, and Rosier RN (1999) BMP-6 is an autocrine stimulator of chondrocyte differentiation. J Bone Miner Res 14: 475-482 https://doi.org/10.1359/jbmr.1999.14.4.475
  35. Grundmann K, Zimmermann B, Barrach HJ, and Merker HJ (1980) Behaviour of epiphyseal mouse chondrocyte populations in monolayer culture. Morphological and immunohistochemical studies. Virchows Arch A Pathol Anat Histol 389: 167-187 https://doi.org/10.1007/BF00439484
  36. Hall BK and Miyake T (2000) All for one and one for all: condensations and the initiation of skeletal development. Bioessays 22: 138-147 https://doi.org/10.1002/(SICI)1521-1878(200002)22:2<138::AID-BIES5>3.0.CO;2-4
  37. Hausser HJ, Decking R, and Brenner RE (2004) Testican-1, an inhibitor of pro-MMP-2 activation, is expressed in cartilage. Osteoarthritis Cartilage 12: 870-877 https://doi.org/10.1016/j.joca.2004.07.008
  38. Holmbeck K, Bianco P, Caterina J, Yamada S, Kromer M, Kuznetsov SA, Mankani M, Robey PG, Poole AR, Pidoux I, Ward JM, and Birkedal-Hansen H (1999) MT1-MMPdeficient mice develop dwarfism, osteopenia, arthritis, and connective tissue disease due to inadequate collagen turnover. Cell 99: 81-92 https://doi.org/10.1016/S0092-8674(00)80064-1
  39. Huang R, Liu YG, Lin Y, Fan Y, Boynton A, Yang D, and Huang RP (2001) Enhanced apoptosis under low serum conditions in human glioblastoma cells by connexin 43 (Cx43). Mol Carcinog 32: 128-138 https://doi.org/10.1002/mc.1072
  40. Hwang NS, Varghese S, Zhang Z, and Elisseeff J (2006) Chondrogenic differentiation of human embryonic stem cellderived cells in arginine-glycine-aspartate-modified hydrogels. Tissue Eng 12: 2695-2706 https://doi.org/10.1089/ten.2006.12.2695
  41. Idowu BD, Knight MM, Bader DL, and Lee DA (2000) Confocal analysis of cytoskeletal organisation within isolated chondrocyte sub-populations cultured in agarose. Histochem J 32: 165-174 https://doi.org/10.1023/A:1004095207330
  42. Imai K, Ohta S, Matsumoto T, Fujimoto N, Sato H, Seiki M, and Okada Y (1997) Expression of membrane-type 1 matrix metalloproteinase and activation of progelatinase A in human osteoarthritic cartilage. Am J Pathol 15: 245-256
  43. Iwasaki M, Nakata K, Nakahara H, Nakase T, Kimura T, Kimata K, Caplan AI, and Ono K (1993) Transforming growth factorbeta 1 stimulates chondrogenesis and inhibits osteogenesis in high density culture of periosteum-derived cells. Endocrinology 132: 1603-1608 https://doi.org/10.1210/en.132.4.1603
  44. Jin EJ, Lee SY, Choi YA, Jung JC, Bang OS, and Kang SS (2006a) BMP-2-enhanced chondrogenesis involves p38 MAPK-mediated down-regulation of Wnt-7a pathway. Mol Cells 22: 353-359
  45. Jin EJ, Park JH, Lee SY, Chun JS, Bang OS, and Kang SS (2006b) Wnt-5a involved in TGF-b3-stmulated chondrogenic differentiation of chick wing bud mesenchymal cells. Int J Biochm Cell Biolol 238: 183-195
  46. Jin EJ, Choi YA, Park EK, Bang OS, and Kang SS (2007) MMP- 2 functions as a negative regulator of chondrogenic cell condensation via down-regulation of the FAK-integrin beta1 interaction. Dev Biol 308: 474-484 https://doi.org/10.1016/j.ydbio.2007.06.003
  47. Jin EJ, Lee SY, Jung JC, Bang OS, and Kang SS (2008) TGFbeta3 inhibits chondrogenesis of cultured chick leg bud mesenchymal cells via downregulation of connexin 43 and integrin beta4. J Cell Physiol 214: 345-353 https://doi.org/10.1002/jcp.21202
  48. Johansson N, Saarialho-Kere U, Airola K, Herva R, Nissinen L, Westermarck J, Vuorio E, Heino J, and Kahari VM (1997) Collagenase-3 (MMP-13) is expressed by hypertrophic chondrocytes, periosteal cells, and osteoblasts during human fetal bone development. Dev Dyn 208: 387-397 https://doi.org/10.1002/(SICI)1097-0177(199703)208:3<387::AID-AJA9>3.0.CO;2-E
  49. Johnson RL and Tabin CJ (1997) Molecular models for vertebrate limb development. Cell 90: 979-990 https://doi.org/10.1016/S0092-8674(00)80364-5
  50. Kalvelyte A, Imbrasaite A, Bukauskiene A, Verselis VK, and Bukauskas FF (2003) Connexins and apoptotic transformation. Biochem Pharmacol 66: 1661-1672 https://doi.org/10.1016/S0006-2952(03)00540-9
  51. Kim SJ, Cho SH, Oh CD, Kim IC, and Chun JS (2003) Retinoic acid inhibits chondrogenesis of mesenchymal cells by sustaining expression of N-cadherin and its associated proteins. J Cell Biochem 89: 837-847 https://doi.org/10.1002/jcb.10553
  52. Kingsley DM, Storm EE, Huynh TV, Copeland NG, Jenkins NA, and Lee SJ (1994) Limb alterations in brachypodism mice due to mutations in a new member of the TGF beta-superfamily. Nature 368: 639-643 https://doi.org/10.1038/368639a0
  53. Knudson CB and Knudson W (2001) Cartilage proteoglycans. Sem Cell Dev Biol 12: 69-78 https://doi.org/10.1006/scdb.2000.0243
  54. Knudson CB (2003) Hyaluronan and CD44: strategic players for cell-matrix interactions during chondrogenesis and matrix assembly. Birth Defects Res C Embryo Today 69: 174-196 https://doi.org/10.1002/bdrc.10013
  55. Krysko DV, Leybaert L, Vandenabeele P, and D'Herde K (2005) Gap junctions and the propagation of cell survival and cell death signals. Apoptosis 1: 459-469
  56. Kumar NM and Gilula NB (1996) The gap junction communication channel. Cell 84: 381-388 https://doi.org/10.1016/S0092-8674(00)81282-9
  57. Leboy PS, Sullivan TA, Nooreyazdan M, and Venezian RA (1997) Rapid chondrocyte maturation by serum-free culture with BMP-2 and ascorbic acid. J Cell Biochem 66: 394-403 https://doi.org/10.1002/(SICI)1097-4644(19970901)66:3<394::AID-JCB11>3.0.CO;2-F
  58. Leckband D and Prakasam A (2006) Mechanism and dynamics of cadherin adhesion. Annu Rev Biomed Eng 8: 259-287 https://doi.org/10.1146/annurev.bioeng.8.061505.095753
  59. Lee YA, Kang SS, Baek SH, Jung JC, Jin EJ, Tak EN, and Sonn JK (2007) Redifferentiation of dedifferentiated chondrocytes on chitosan membranes and involvement of PKCalpha and P38 MAP kinase. Mol Cells 24: 9-15
  60. Lin JH, Weigel H, Cotrina ML, Liu S, Bueno E, Hansen AJ, Hansen TW, Goldman S, and Nedergaard M (1998) Gapjunction- mediated propagation and amplification of cell injury. Nat Neurosci 1: 494-500 https://doi.org/10.1038/2210
  61. Lo SH (2006) Focal adhesions: what's new inside. Dev Biol 294: 280-291 https://doi.org/10.1016/j.ydbio.2006.03.029
  62. Lock JG, Wehrle-Haller B, and Strömblad S (2008) Cell-matrix adhesion complexes: master control machinery of cell migration. Semin Cancer Biol 18: 65-76 https://doi.org/10.1016/j.semcancer.2007.10.001
  63. Loty S, Forest N, Boulekbache H, and Sautier JM (1995) Cytochalasin D induces changes in cell shape and promotes in vitro chondrogenesis: a morphological study. Biol Cell : 149-161
  64. Makarenkova H, Becker DL, Tickle C, and Warner AE (1997) Fibroblast growth factor 4 directs gap junction expression in the mesenchyme of the vertebrate limb bud. J Cell Biol 138: 1125-1137 https://doi.org/10.1083/jcb.138.5.1125
  65. Maleski MP and Knudson CB (1996) Hyaluronan-mediated aggregation of limb bud mesenchyme and mesenchymal condensation during chondrogenesis. Exp Cell Res 225: 55-66 https://doi.org/10.1006/excr.1996.0156
  66. Mannello F, Luchetti F, Falcieri E, and Papa S (2005) Multiple roles of matrix metalloproteinases during apoptosis. Apoptosis 10:19-24 https://doi.org/10.1007/s10495-005-6058-7
  67. Mariani FV and Martin GR (2003) Deciphering skeletal patterning: clues from the limb. Nature 423: 319-325 https://doi.org/10.1038/nature01655
  68. Massague J, Andres J, Attisano L, Cheifetz S, Lopez-Casillas F, Ohtsuki M, and Wrana JL (1992) TGF-beta receptors. Mol Reprod 32: 99-104 https://doi.org/10.1002/mrd.1080320204
  69. Massague J, Hata A, and Liu F (1997) $TGF-{\beta}$ signaling through the Smad pathway. Trends Cell Biol. 7: 187-192 https://doi.org/10.1016/S0962-8924(97)01036-2
  70. Meyer RA, Cohen MF, Recalde S, Zakany J, Bell SM, Scott WJ Jr, and Lo CW (1997) Developmental regulation and asymmetric expression of the gene encoding Cx43 gap junctions in the mouse limb bud. Dev Genet 21: 290-300 https://doi.org/10.1002/(SICI)1520-6408(1997)21:4<290::AID-DVG6>3.0.CO;2-2
  71. Modarresi R, Lafond T, Roman-Blas JA, Danielson KG, Tuan RS, and Seghatoleslami MR (2005) N-cadherin mediated distribution of beta-catenin alters MAP kinase and BMP-2 signaling on chondrogenesis-related gene expression. J Cell Biochem 95: 53-63 https://doi.org/10.1002/jcb.20396
  72. Mott JD and Werb Z (2004) Regulation of matrix biology by matrix metalloproteinases. Curr Opin Cell Biol 16: 558-564 https://doi.org/10.1016/j.ceb.2004.07.010
  73. Muramatsu A, Iwai M, Morikawa T, Tanaka S, Mori T, Harada Y, and Okanoue T (2002) Influence of transfection with connexin 26 gene on malignant potential of human hepatoma cells. Carcinogenesis 23: 351-358 https://doi.org/10.1093/carcin/23.2.351
  74. Nakase T, Sohl G, Theis M, Willecke K, and Naus CC (2004) Increased apoptosis and inflammation after focal brain ischemia in mice lacking connexin43 in astrocytes. Am J Pathol. 164: 2067-2075 https://doi.org/10.1016/S0002-9440(10)63765-0
  75. Newman SA, Frenz DA, Tomasek JJ, and Rabuzzi DD (1985) Matrix-driven translocation of cells and nonliving particles. Science 228: 885-889 https://doi.org/10.1126/science.4001925
  76. Oberlender SA and Tuan RS (1994) Expression and functional involvement of N-cadherin in embryonic limb chondrogenesis. Development 120: 177-187
  77. Olsen BR, Reginato AM, and Wang W(2000) Bone development. Annu Rev Cell Dev Biol 16: 191-220 https://doi.org/10.1146/annurev.cellbio.16.1.191
  78. Onodera K, Takahashi I, Sasano Y, Bae JW, Mitani H, Kagayama M, and Mitani H (2005) Stepwise mechanical stretching inhibits chondrogenesis through cell-matrix adhesion mediated by integrins in embryonic rat limb-bud mesenchymal cells. Eur J Cell Biol 84: 45-58 https://doi.org/10.1016/j.ejcb.2004.09.004
  79. Ortega N, Behonick DJ, Colnot C, Cooper DN, and Werb Z (2005) Galectin-3 is a downstream regulator of matrix metalloproteinase-9 function during endochondral bone formation. Mol Biol Cell 16: 3028-3039 https://doi.org/10.1091/mbc.E04-12-1119
  80. Pacifici M, Koyama E, and Shibukawa Y (2006) Cellular and molecular mechanisms of synovial joint and articular cartilage formation. Ann. N Y Acad. Sci. 1068: 74-86 https://doi.org/10.1196/annals.1346.010
  81. Saez JC, Araya R, Eckardt D, Riquelme MA, and Willecke K (2003) Presence and importance of connexin43 during myogenesis. Cell Commun Adhes 10: 451-456 https://doi.org/10.1080/cac.10.4-6.451.456
  82. Sandell LJ and Adler P (1999) Developmental patterns of cartilage. Front Biosci 4: D731-742 https://doi.org/10.2741/Sandell
  83. Schwartz MA and Lewis JM (1995) Mapping in vivo associations of cytoplasmic proteins with integrin beta 1 cytoplasmic domain mutants. Mol Biol Cell 6: 151-160 https://doi.org/10.1091/mbc.6.2.151
  84. Seghatoleslami MR and Tuan RS (2002) Cell density dependent regulation of AP-1 activity is important for chondrogenic differentiation of C3H10T1/2 mesenchymal cells. J Cell Biochem 84: 237-248 https://doi.org/10.1002/jcb.10019
  85. Shi Y and Massague J (2003) Mechanisms of TGF-beta signaling from cell membrane to nucleus. Cell 113: 685-700 https://doi.org/10.1016/S0092-8674(03)00432-X
  86. Shi YB, Fu L, Hasebe T, and Ishizuya-Oka A (2007) Regulation of extracellular matrix remodeling and cell fate determination by matrix metalloproteinase stromelysin-3 during thyroid hormone-dependent post-embryonic development. Pharmacol Ther 116: 391-400 https://doi.org/10.1016/j.pharmthera.2007.07.005
  87. Shimizu H, Yokoyama S, and Asahara H (2007) Growth and differentiation of the developing limb bud from the perspective of chondrogenesis. Dev Growth Differ 49: 449-454 https://doi.org/10.1111/j.1440-169X.2007.00945.x
  88. Shum L, Hatakeyama Y, Nguyen J, Wang X, and Nuckolls GH (2003) Smad signaling in mesenchymal and chondroprogenitor cells. J Bone Joint Surg Am 3: 13-18
  89. Si-Tayeb K, Monvoisin A, Mazzocco C, Lepreux S, Decossas M, Cubel G, Taras D, Blanc JF, Robinson DR, and Rosenbaum J. (2006) Matrix metalloproteinase 3 is present in the cell nucleus and is involved in apoptosis. Am J Pathol 169: 1390-1401 https://doi.org/10.2353/ajpath.2006.060005
  90. Simon AM and Goodenough DA (1998) Diverse functions of vertebrate gap junctions. Trends Cell Biol 8: 477-483 https://doi.org/10.1016/S0962-8924(98)01372-5
  91. Somerville RP, Longpre JM, Jungers KA, Engle JM, Ross M, Evanko S, Wight TN, Leduc R, and Apte SS (2003) Characterization of ADAMTS-9 and ADAMTS-20 as a distinct ADAMTS subfamily related to Caenorhabditis elegans GON-1. J Biol Chem 278: 9503-9513 https://doi.org/10.1074/jbc.M211009200
  92. Sosinsky GE and Nicholson BJ (2005) Structural organization of gap junction channels. Biochim Biophys Acta 1711: 99-125 https://doi.org/10.1016/j.bbamem.2005.04.001
  93. Stickens D, Behonick DJ, Ortega N, Heyer B, Hartenstein B, Yu Y, Fosang AJ, Schorpp-Kistner M, Angel P, and Werb Z (2004) Altered endochondral bone development in matrix metalloproteinase 13-deficient mice. Development 131: 5883-5895 https://doi.org/10.1242/dev.01461
  94. Takahashi I, Onodera K, Sasano Y, Mizoguchi I, Bae JW, Mitani H, Kagayama M, and Mitani H (2003) Effect of stretching on gene expression of beta1 integrin and focal adhesion kinase and on chondrogenesis through cell-extracellular matrix interactions. Eur J Cell Biol 82: 182-192 https://doi.org/10.1078/0171-9335-00307
  95. Tavella S, Bellese G, Castagnola P, Martin I, Piccini D, Doliana R, Colombatti A, Cancedda R, and Tacchetti C (1997) Regulated expression of fibronectin, laminin and related integrin receptors during the early chondrocyte differentiation. J Cell Sci 110: 2261-2270
  96. Tickle C and Münsterberg A (2001) Vertebrate limb development-the early stages in chick and mouse. Curr Opin Genet Dev 11: 476-81 https://doi.org/10.1016/S0959-437X(00)00220-3
  97. Tong A, Reich A, Genin O, Pines M, and Monsonego-Ornan E (2003) Expression of chicken 75-kDa gelatinase B-like enzyme in perivascular chondrocytes suggests its role in vascularization of the growth plate. J Bone Miner Res 18: 1443-1452 https://doi.org/10.1359/jbmr.2003.18.8.1443
  98. Tuan RS (2003) Cellular signaling in developmental chondrogenesis: N-cadherin, Wnts, and BMP-2. J Bone Joint Surg Am 85: 137-141 https://doi.org/10.2106/00004623-200300002-00019
  99. Tuan RS (2004) Biology of developmental and regenerative skeletogenesis. Clin Orthop Relat Res: S105-117
  100. Tuckermann JP, Pittois K, Partridge NC, Merregaert J, and Angel P (2000) Collagenase-3 (MMP-13) and integral membrane protein 2a (Itm2a) are marker genes of chondrogenic/ osteoblastic cells in bone formation: sequential temporal, and spatial expression of Itm2a, alkaline phosphatase, MMP-13, and osteocalcin in the mouse. J Bone Miner Res 15: 1257-1265 https://doi.org/10.1359/jbmr.2000.15.7.1257
  101. Tuli R, Tuli S, Nandi S, Huang X, Manner PA, Hozack WJ, Danielson KG, Hall DJ, and Tuan RS (2003) Transforming growth factor-beta-mediated chondrogenesis of human mesenchymal progenitor cells involves N-cadherin and mitogen-activated protein kinase and Wnt signaling crosstalk. J Biol Chem 278: 41227-41236 https://doi.org/10.1074/jbc.M305312200
  102. Volk SW, Kapatkin AS, Haskins ME, Walton RM, and D'Angelo M (2003) Gelatinase activity in synovial fluid and synovium obtained from healthy and osteoarthritic joints of dogs. Am J Vet Res 64: 1225-1233 https://doi.org/10.2460/ajvr.2003.64.1225
  103. von der Mark K, Gauss V, von der Mark H, and Müller P (1977) Relationship between cell shape and type of collagen synthesised as chondrocytes lose their cartilage phenotype in culture. Nature 267:531-532 https://doi.org/10.1038/267531a0
  104. Vum TH and Werb Z (2000) Matrix metalloproteinases: effectors of development and normal physiology. Genes Dev 14: 2123-2133 https://doi.org/10.1101/gad.815400
  105. Watanabe H, de Caestecker MP, and Yamada Y (2001) Transcriptional cross-talk between Smad, ERK1/2, and p38 mitogen-activated protein kinase pathways regulates transforming growth factor-beta-induced aggrecan gene expression in chondrogenic ATDC5 cells. J Biol Chem 276: 14466-14473 https://doi.org/10.1074/jbc.M005724200
  106. White, DG., Hershey HP, Moss JJ, Daniels H, Tuan RS, and Bennett VD (2003) Functional analysis of fibronectin isoforms in chondrogenesis: full-length recombinant mesenchymal fibronectin reduces spreading and promotes condensation and chondrogenesis of limb mesenchymal cells. Differentiation 71: 251-261 https://doi.org/10.1046/j.1432-0436.2003.7104502.x
  107. Widelitz RB, Jiang TX, Murray BA, and Chuong CM (1993) Adhesion molecules in skeletogenesis: II. Neural cell adhesion molecules mediate precartilaginous mesenchymal condensations and enhance chondrogenesis. J Cell Physiol 156: 399-411 https://doi.org/10.1002/jcp.1041560224
  108. Willecke K, Thonnissen E, Rabionet R, Arbones ML, Estivill X, and Ott T (2002) Human connexin26 (GJB2) deafness mutations affect the function of gap junction channels at different levels of protein expression. Hum Genet 111: 190-197 https://doi.org/10.1007/s00439-002-0750-2
  109. Woods A, Wang G, Dupuis H, Shao Z, and Beier F (2007) Rac1 signaling stimulates N-cadherin expression, mesenchymal condensation, and chondrogenesis. J Biol Chem 282: 23500-23508 https://doi.org/10.1074/jbc.M700680200
  110. Wright E, Hargrave MR, Christiansen J, Cooper L, Kun J, Evans T, Gangadharan U, Greenfield A, and Koopman P (1995) The Sry-related gene Sox9 is expressed during chondrogenesis in mouse embryos. Nat Genet 9: 15-20 https://doi.org/10.1038/ng0195-15
  111. Wu YN, Yang Z, Hui JH, Ouyang HW, and Lee EH (2007) Cartilaginous ECM component-modification of the microbead culture system for chondrogenic differentiation of mesenchymal stem cells. Biomaterials 28: 4056-4067 https://doi.org/10.1016/j.biomaterials.2007.05.039
  112. Xu X, Li WE, Huang GY, Meyer R, Chen T, Luo Y, Thomas MP, Radice GL, and Lo CW (2001) Modulation of mouse neural crest cell motility by N-cadherin and connexin 43 gap junctions. J Cell Biol 154: 217-230 https://doi.org/10.1083/jcb.200105047
  113. Yang M, Gervasi DC, Raz A, Dehem M, Kurkinen M, and Fridman R (1996) Carbohydrate-mediated regulation of matrix metalloproteinase-2 activation in normal human fibroblasts and fibrosarcoma cells. Biochem Biophys Res Commun 228: 530-538 https://doi.org/10.1006/bbrc.1996.1694
  114. Yasui K, Kada K, Hojo M, Lee JK, Kamiya K, Toyama J, Opthof T, and Kodama I (2000) Cell-to-cell interaction prevents cell death in cultured neonatal rat ventricular myocytes. Cardiovasc Res 48: 68-76 https://doi.org/10.1016/S0008-6363(00)00145-0
  115. Yeager M and Harris AL (2007) Gap junction channel structure in the early 21st century: facts and fantasies. Curr Opin Cell Biol 19: 521-528 https://doi.org/10.1016/j.ceb.2007.09.001
  116. Yoon BS, Ovchinnikov DA, Yoshii I, Mishina Y, Behringer RR, and Lyons KM (2005) Bmpr1a and Bmpr1b have overlapping functions and are essential for chondrogenesis in vivo. Proc Natl Acad Sci USA 102: 5062-5067
  117. Yu YM, Becvar R, Yamada Y, and Reddi AH (1991) Changes in the gene expression of collagens, fibronectin, integrin and proteoglycans during matrix-induced bone morphogenesis. Biochem Biophys Res Commun 177: 427-432 https://doi.org/10.1016/0006-291X(91)92001-Z
  118. Zanetti NC and Solursh M (1984) Induction of chondrogenesis in limb mesenchymal cultures by disruption of the actin cytoskeleton. J Cell Biol 99: 115-123 https://doi.org/10.1083/jcb.99.1.115
  119. Zhang X, Ziran N, Goater JJ, Schwarz EM, Puzas JE, Rosier RN (2004) Primary murine limb bud mesenchymal cells in longterm culture complete chondrocyte differentiation: TGF-beta delays hypertrophy and PGE2 inhibits terminal differentiation. Bone 34: 809-817 https://doi.org/10.1016/j.bone.2003.12.026
  120. Zhao Q, Eberspaecher H, Lefebvre V, and De Crombrugghe B (1997) Parallel expression of Sox9 and Col2a1 in cells undergoing chondrogenesis. Dev Dyn 209: 377-386 https://doi.org/10.1002/(SICI)1097-0177(199708)209:4<377::AID-AJA5>3.0.CO;2-F
  121. Zhou Z, Apte SS, Soininen R, Cao R, Baaklini GY, Rauser RW, Wang J, Cao Y, and Tryggvason K (2000) Impaired endochondral ossification and angiogenesis in mice deficient in membrane-type matrix metalloproteinase I. Proc Natl Acad Sci USA 97: 4052-4057
  122. Zhou S, Eid K, and Glowacki J (2004) Cooperation between TGF-beta and Wnt pathways during chondrocyte and adipocyte differentiation of human marrow stromal cells. J Bone Miner Res 19: 463-470 https://doi.org/10.1359/JBMR.0301239