Dedifferentiation of human articular chondrocytes is associated with alterations in expression patterns of GDF-5 and its receptors
Corresponding Author
Werner Schlegel
Medical University Vienna, Department of Traumatology, Center for Joint and Cartilage Waehringer Guertel, Vienna, Austria
Medical University of Vienna, Department of Paediatrics, Waehringer Guertel, Vienna, Austria
Austrian Cluster for Tissue Regeneration, Austria
These authors contributed equally.
Correspondence to: Werner SCHLEGEL, Medical University of Vienna, Department of Traumatology, Center for Joint and Cartilage, Waehringer Guertel 18-20, A-1090 Vienna, Austria.Tel.: +43 1 40400/5964Fax: +43 1 40400/5947E-mail: [email protected]Search for more papers by this authorChristian Albrecht
Austrian Cluster for Tissue Regeneration, University of Salzburg, Department of Cell Biology, Hellbrunner Straße, Salzburg, Austria
These authors contributed equally.
Search for more papers by this authorPeter Eckl
Austrian Cluster for Tissue Regeneration, University of Salzburg, Department of Cell Biology, Hellbrunner Straße, Salzburg, Austria
Search for more papers by this authorHarald Freudenthaler
Medical University of Vienna, Department of Surgery, Waehringer Guertel, Vienna, Austria
Search for more papers by this authorAngelika Berger
Medical University Vienna, Department of Traumatology, Center for Joint and Cartilage Waehringer Guertel, Vienna, Austria
Search for more papers by this authorVilmos Vécsei
Medical University Vienna, Department of Traumatology, Center for Joint and Cartilage Waehringer Guertel, Vienna, Austria
Austrian Cluster for Tissue Regeneration, Austria
Search for more papers by this authorStefan Marlovits
Medical University Vienna, Department of Traumatology, Center for Joint and Cartilage Waehringer Guertel, Vienna, Austria
Austrian Cluster for Tissue Regeneration, Austria
Search for more papers by this authorCorresponding Author
Werner Schlegel
Medical University Vienna, Department of Traumatology, Center for Joint and Cartilage Waehringer Guertel, Vienna, Austria
Medical University of Vienna, Department of Paediatrics, Waehringer Guertel, Vienna, Austria
Austrian Cluster for Tissue Regeneration, Austria
These authors contributed equally.
Correspondence to: Werner SCHLEGEL, Medical University of Vienna, Department of Traumatology, Center for Joint and Cartilage, Waehringer Guertel 18-20, A-1090 Vienna, Austria.Tel.: +43 1 40400/5964Fax: +43 1 40400/5947E-mail: [email protected]Search for more papers by this authorChristian Albrecht
Austrian Cluster for Tissue Regeneration, University of Salzburg, Department of Cell Biology, Hellbrunner Straße, Salzburg, Austria
These authors contributed equally.
Search for more papers by this authorPeter Eckl
Austrian Cluster for Tissue Regeneration, University of Salzburg, Department of Cell Biology, Hellbrunner Straße, Salzburg, Austria
Search for more papers by this authorHarald Freudenthaler
Medical University of Vienna, Department of Surgery, Waehringer Guertel, Vienna, Austria
Search for more papers by this authorAngelika Berger
Medical University Vienna, Department of Traumatology, Center for Joint and Cartilage Waehringer Guertel, Vienna, Austria
Search for more papers by this authorVilmos Vécsei
Medical University Vienna, Department of Traumatology, Center for Joint and Cartilage Waehringer Guertel, Vienna, Austria
Austrian Cluster for Tissue Regeneration, Austria
Search for more papers by this authorStefan Marlovits
Medical University Vienna, Department of Traumatology, Center for Joint and Cartilage Waehringer Guertel, Vienna, Austria
Austrian Cluster for Tissue Regeneration, Austria
Search for more papers by this authorAbstract
Human articular chondrocytes are expanded in monolayer culture in order to obtain sufficient cells for matrix-associated cartilage transplantation. During this proliferation process, the cells change their shape as well as their expression profile. These changes resemble those that occur during embryogenesis, when the limb anlagen form the interzone that later develops the joint cleft. We analysed the expression profile of genes that are reportedly important for these changes during embryogenesis within the dedifferentiation process of adult articular chondrocytes. We found GDF-5, BMPR-Ib and connexin 43 up-regulated, as well as a down-regulation of BMPR-Ia and noggin. Connexin 32 could not be detected in either native cartilage or in dedifferentiated cells. The newly synthesized proteins were detected by immunofluorescence. There is evidence from our results that dedifferentiated chondrocytes resemble the cells from the interzone in developing synovial joints.
References
- 1 Chen D, Zhao M, Mundy GR. Bone morphogenetic proteins. Growth Factors. 2004; 22: 233–41.
- 2 Massague J. TGF-beta signal transduction. Annu Rev Biochem. 1998; 67: 753–91.
- 3 Zwijsen A, Verschueren K, Huylebroeck D. New intracellular components of bone morphogenetic protein/Smad signaling cascades. FEBS Lett. 2003; 546: 133–9.
- 4 Koenig BB, Cook JS, Wolsing DH, et al . Characterization and cloning of a receptor for BMP-2 and BMP-4 from NIH 3T3 cells. Mol Cell Biol. 1994; 14: 5961–74.
- 5 ten Dijke P, Yamashita H, Sampath TK, et al . Identification of type I receptors for osteogenic protein-1 and bone morphogenetic protein-4. J Biol Chem. 1994; 269: 16985–8.
- 6 Macias-Silva M, Hoodless PA, Tang SJ, et al . Specific activation of Smad1 signaling pathways by the BMP7 type I receptor, ALK2. J Biol Chem. 1998; 273: 25628–36.
- 7 Rosenzweig BL, Imamura T, Okadome T, et al . Cloning and characterization of a human type II receptor for bone morphogenetic proteins. Proc Natl Acad Sci USA. 1995; 92: 7632–6.
- 8 Kawabata M, Chytil A, Moses HL. Cloning of a novel type II serine/threonine kinase receptor through interaction with the type I transforming growth factor-beta receptor. J Biol Chem. 1995; 270: 5625–30.
- 9 Moustakas A, Heldin CH. From mono- to oligo-Smads: the heart of the matter in TGF-beta signal transduction. Genes Dev. 2002; 16: 1867–71.
- 10 Buxton P, Edwards C, Archer CW, et al . Growth/differentiation factor-5 (GDF-5) and skeletal development. J Bone Joint Surg Am. 2001; 83-A: S23–30.
- 11 Hatakeyama Y, Tuan RS, Shum L. Distinct functions of BMP4 and GDF5 in the regulation of chondrogenesis. J Cell Biochem. 2004; 91: 1204–17.
- 12 Polinkovsky A, et al . Mutations in CDMP1 cause autosomal dominant brachydactyly type C. Nat Genet. 1997; 17: 18–9.
- 13 Takahara M, Harada M, Guan D, et al . Developmental failure of phalanges in the absence of growth/differentiation factor 5. Bone. 2004; 35: 1069–76.
- 14 Thomas JT, Lin K, Nandedkar M, et al . A human chondrodysplasia due to a mutation in a TGF-beta superfamily member. Nat Genet. 1996; 12: 315–7.
- 15 Francis-West PH, et al . Mechanisms of GDF-5 action during skeletal development. Development. 1999; 126: 1305–15.
- 16 Nishitoh H, Ichijo H, Kimura M, et al . Identification of type I and type II serine/threonine kinase receptors for growth/differentiation factor-5. J Biol Chem. 1996; 271: 21345–52.
- 17 Archer CW, Morrison H, Pitsillides AA. Cellular aspects of the development of diarthrodial joints and articular cartilage. J Anat. 1994; 184: 447–56.
- 18 Coleman CM, Tuan RS. Functional role of growth/differentiation factor 5 in chondrogenesis of limb mesenchymal cells. Mech Dev. 2003; 120: 823–36.
- 19 Archer CW, Dowthwaite GP, Francis-West P. Development of synovial joints. Birth Defects Res C Embryo Today. 2003; 69: 144–55.
- 20 Francis-West PH, Parish J, Lee K, et al . BMP/GDF-signalling interactions during synovial joint development. Cell Tissue Res. 1999; 296: 111–9.
- 21 Craig FM, Bentley G, Archer CW. The spatial and temporal pattern of collagens I and II and keratan sulphate in the developing chick metatarsophalangeal joint. Development. 1987; 99: 383–91.
- 22 Marlovits S, Hombauer M, Tamandl D, et al . Quantitative analysis of gene expression in human articular chondrocytes in monolayer culture. Int J Mol Med. 2004; 13: 281–7.
- 23 Marlovits S, Hombauer M, Truppe M, et al . Changes in the ratio of type-I and type-II collagen expression during monolayer culture of human chondrocytes. J Bone Joint Surg Br. 2004; 86: 286–95.
- 24 Tsumaki N, Nakase T, Miyaji T, et al . Bone morphogenetic protein signals are required for cartilage formation and differently regulate joint development during skeletogenesis. J Bone Miner Res. 2002; 17: 898–906.
- 25 Allen F, Tickle C, Warner A. The role of gap junctions in patterning of the chick limb bud. Development. 1990; 108: 623–34.
- 26 Chatterjee B, Meyer RA, Loredo GA, et al . BMP regulation of the mouse connexin43 promoter in osteoblastic cells and embryos. Cell Commun Adhes. 2003; 10: 37–50.
- 27 Coleman CM, Loredo GA, Lo CW, et al . Correlation of GDF5 and connexin 43 mRNA expression during embryonic development. Anat Rec A Discov Mol Cell Evol Biol. 2003; 275: 1117–21.
Citing Literature
