The role of bone morphogenetic proteins in articular cartilage development, homeostasis and repair

A. O. Oshin; M. C. Stewart

doi:10.1160/VCOT-07-02-0018

Veterinary and Comparative Orthopaedics and Traumatology, Inhaltsverzeichnis

Vet Comp Orthop Traumatol 2007; 20(03): 151-158
DOI: 10.1160/VCOT-07-02-0018

Review Article

Schattauer GmbH

The role of bone morphogenetic proteins in articular cartilage development, homeostasis and repair

Autoren

A. O. Oshin

¹Department of Veterinary Clinical Medicine, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA
M. C. Stewart

¹Department of Veterinary Clinical Medicine, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA

Abstract

Summary

Bone morphogenetic proteins (BMPs) are members of the TGF-β superfamily of secreted ligands. BMPs regulate a diverse range of developmental processes during embryogenesis and postnatal development, and control the differentiation of several musculoskeletal tissues including bone, cartilage, tendon and ligaments. The ability of BMPs to modulate the phenotype of cells in these tissue lineages suggests that these factors could be valuable for musculoskeletal tissue regeneration. In fact, BMPs-2 and -7 are already in clinical use for bone regeneration. This review addresses the signaling mechanisms by which BMPs regulate cellular processes, the role of BMPs in articular cartilage development and joint formation, and the data that supports the use of BMPs for in vitro phenotypic support of articular chondrocyte cultures, chondrogenic differentiation of mesenchymal stem cells (MSCs) and articular cartilage repair. Given the documented importance of BMP activity for normal joint formation, articular cartilage development and maintenance, the chondrogenic activity of BMPs when applied to MSC cultures and the encouraging outcomes of several in vivo cartilage repair studies, BMP therapies hold considerable promise for effective cartilage repair and/or regeneration. Future advances in the control of BMP elution from biocompatible matrices and prolonged, dose-controlled BMP expression by genetically engineered cells should substantially improve cartilage repair strategies using BMPs and similar chondro-protective proteins.

Keywords

BMP - articular cartilage - cartilage repair

Volltext

Referenzen

References
1 Canalis E, Economides AN, Gazzerro E. Bone morphogenetic proteins, their antagonists, and the skeleton. Endocr Rev 2003; 24: 218-235.
2 Chen D, Zhao M, Mundy GR. Bone morphogenetic proteins. Growth Factors 2004; 22: 233-241.
3 Sakou T. Bone morphogenetic proteins: from basic studies to clinical approaches. Bone 1998; 22: 591-603.
4 Schlunegger MP, Grutter MG. An unusual feature revealed by the crystal structure at 2.2 A resolution of human transforming growth factor-beta 2. Nature 1992; 358: 430-434.
5 Urist MR. Bone formation by autoinduction. Science 1965; 150: 893-899.
6 Reddi AH. Bone morphogenetic proteins: an unconventional approach to isolation of first mammalian morphogens. Cytokine Growth Factor Rev 1997; 8: 11-20.
7 Kishigami S, Mishina Y. BMP signaling and early embryonic patterning. Cytokine Growth Factor Rev 2005; 16: 265-278.
8 Ashique AM, Fu K, Richman JM. Signalling via type IA and type IB bone morphogenetic protein receptors (BMPR) regulates intramembranous bone formation, chondrogenesis and feather formation in the chicken embryo. Int J Dev Biol 2002; 46: 243-253.
9 Duprez D, Bell EJ, Richardson MK. et al. Over expression of BMP-2 and BMP-4 alters the size and shape of developing skeletal elements in the chick limb. Mech Dev 1996; 57: 145-157.
10 Enomoto-Iwamoto M, Iwamoto M, Mukudai Y. et al. Bone morphogenetic protein signaling is required for maintenance of differentiated phenotype, control of proliferation, and hypertrophy in chondrocytes. J Cell Biol 1998; 140: 409-418.
11 Macias D, Ganan Y, Sampath TK. et al. Role of BMP-2 and OP-1 (BMP-7) in programmed cell death and skeletogenesis during chick limb development. Development 1997; 124: 1109-1117.
12 Pathi S, Rutenberg JB, Johnson RL. et al. Interaction of Ihh and BMP/Noggin signaling during cartilage differentiation. Dev Biol 1999; 209: 239-253.
13 Storm Storm, Kingsley DM. Joint patterning defects caused by single and double mutations inmembers of the bone morphogenetic protein (BMP) family. Development 1996; 122: 3969-3979.
14 Wolfman NM, Hattersley G, Cox K. et al. Ectopic induction of tendon and ligament in rats by growth and differentiation factors 5,6, and 7, members of the TGF-beta gene family. JClin Invest 1997; 100: 321-330.
15 Wozney JM, Rosen V. Bone morphogenetic protein and bone morphogenetic protein gene family in bone formation and repair. Clin Orthop 1998; 364: 26-37.
16 Wang EA, Rosen V, D'Alessandro JS. et al. Recombinant human bone morphogenetic protein induces bone formation. Proc Natl Acad Sci US A 1990; 87: 2220-2224.
17 Israel DI, Nove J, Kerns KM. et al. Heterodimeric bone morphogenetic proteins show enhanced activity in vitro and in vivo. Growth factors 1996; 13: 291-300.
18 Zhu W, Kim J, Cheng C. et al. Noggin regulation of bone morphogenetic protein (BMP) 2/7 heterodimer activity in vitro. Bone 2006; 39: 61-71.
19 Massague J. TGF-beta signal transduction. Annu Rev Biochem 1998; 67: 753-791.
20 Miyazono K, Kusanagi K, Inoue H. Divergence and convergence of TGF-beta/BMP signaling. J Cell Physiol 2001; 187: 265-276.
21 Zwijsen A, Verschueren K, Huylebroeck D. New intracellular components of bone morphogenetic protein/Smad signaling cascades. FEBS Lett 2003; 546: 133-139.
22 Aoki H, Fujii M, Imamura T. et al. Synergistic effects of different bone morphogenetic protein type I receptors on alkaline phosphatase induction. J Cell Sci 2001; 114: 1483-1489.
23 Gilboa L, Nohe A, Geissendorfer T. et al. Bone morphogenetic protein receptor complexes on the surface of live cells: anew oligomerizationmode for serine/threonine kinase receptors. Mol Biol Cell 2000; 11: 1023-1035.
24 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: 21345-21352.
25 Chen D, Ji X, Harris MA. et al. Differential roles for bone morphogenetic protein (BMP) receptor type IB and IA in differentiation and specification of mesenchymal precursor cells to osteoblast and adipocyte lineages. J Cell Biol 1998; 142: 295-305.
26 Rountree RB, Schoor M, Chen H. et al. BMP receptor signaling is required for postnatal maintenance of articular cartilage. PLoS Biol 2004; 2: 1815-1827.
27 Nohe A, Keating E, Knaus Petal. Signal transduction of bone morphogenetic protein receptors. Cell Signal 2004; 16: 291-299.
28 Ebisawa T, Tada K, Kitajima I. et al. Characterization of bone morphogenetic protein-6 signaling pathways in osteoblast differentiation. J Cell Sci 1999; 112: 3519-3527.
29 Liu F, Ventura F, Doody J. et al. Human type II receptor for bone morphogenic proteins (BMPs): extension of the two-kinase receptor model to the BMPs. Mol Cell Biol 1995; 15: 3479-3486.
30 Nohno T, Ishikawa T, Saito T. et al. Identification of a human type II receptor for bone morphogenetic protein-4 that forms differential heteromeric complexes with bone morphogenetic protein type I receptors. J Biol Chem 1995; 270: 22522-22526.
31 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: 7632-7636.
32 Vitt UA, Mazerbourg S, Klein C. et al. Bone morphogenetic protein receptor type II is a receptor for growth differentiation factor-9. Biol Reprod 2002; 67: 473-480.
33 Yamashita H, ten Dijke P, Huylebroeck D. et al. Osteogenic protein-1 binds to activin type II receptors and induces certain activin-like effects. J Cell Biol 1995; 130: 217-226.
34 Derynck Derynck, Feng XH. TGF-P receptor signalling. Biochim Biophys Acta 1997; 1333: F105-F150.
35 Nohe A, Hassel S, Ehrlich M. et al. The mode of bone morphogenetic protein (BMP) receptor oligomerization determines different BMP-2 signaling pathways. J Biol Chem 2002; 277: 5330-5338.
36 Wrana JL, Attisano L, Carcamo J. et al. TGF beta signals through a heteromeric protein kinase receptorcomplex. Cell 1992; 71: 1003-1014.
37 Nohe A, Hassel S, Ehrlich M. et al. The mode of bone morphogenetic protein (BMP) receptor oligomerization determines different BMP-2 signaling pathways. J Biol Chem 2002; 277: 5330-5338.
38 Heldin CH, Miyazono K, ten Dijke P. TGF-beta signalling from cell membrane to nucleus through SMAD proteins. Nature 1997; 390: 465-471.
39 de Caestecker M. The transforming growth factorbeta superfamily of receptors. Cytokine Growth Factor Rev 2004; 15: 1-11.
40 Kimura N, Matsuo R, Shibuya H. et al. BMP2-induced apoptosis is mediated by activation of the TAK1-p38 kinase pathway that is negatively regulated by Smad6. J Biol Chem 2000; 275: 17647-17652.
41 Qiao B, Padilla SR, Benya PD. Transforming growth factor (TGF)-beta-activated kinase 1 mimics and mediates TGF-beta-induced stimulation of type II collagen synthesis in chondrocytes independent of Col2a1 transcription and Smad3 signaling. J Biol Chem 2005; 280: 17562-17571.
42 Shibuya H, Iwata H, Masuyama N. et al. Role of TAK1 and TAB1 in BMP signaling in early Xenopus development. Embo J 1998; 17: 1019-1028.
43 Nakamura K, Shirai T, Morishita S. et al. p38 mitogen-activated protein kinase functionally contributes to chondrogenesis induced by growth/differentiation factor-5 in ATDC5 cells. Exp Cell Res 1999; 250: 351-363.
44 Foletta VC, Lim MA, Soosairajah J. et al. Direct signaling by the BMP type II receptor via the cytoskeletal regulator LIMK1. J Cell Biol 2003; 162: 1089-1098.
45 Balemans W, Van Hul W. Extracellular regulation of BMP signaling in vertebrates: a cocktail of modulators. Dev Biol 2002; 250: 231-250.
46 Canalis E, Economides AN, Gazzerro E. Bone morphogenetic proteins, their antagonists, and the skeleton. Endocr Rev 2003; 24: 218-235.
47 Cho Cho, Blitz IL. BMPs, Smads and metalloproteases: extracellular and intracellular modes of negative regulation. Curr Opin Genet Dev 1998; 8: 443-449.
48 Hsu DR, Economides AN, Wang X. et al. The Xenopus dorsalizing factor Gremlin identifies a novel family of secreted proteins that antagonize BMP activities. Mol Cell 1998; 1: 673-683.
49 Merino R, Rodriguez-Leon J, Macias D. et al. The BMP antagonist Gremlin regulates outgrowth, chondrogenesis and programmed cell death in the developing limb. Development 1999; 126: 5515-5522.
50 Piccolo S, Sasai Y, Lu B. et al. Dorsoventral patterning in Xenopus: inhibition of ventral signals by direct binding of chordin to BMP-4. Cell 1996; 86: 589-598.
51 Stanley E, Biben C, Kotecha S. et al. DAN is a secreted glycoprotein related to Xenopus cerberus. Mech Dev 1998; 77: 173-184.
52 Zhu L, Marvin MJ, Gardiner A. et al. Cerberus regulates left-right asymmetry of the embryonic head and heart. Curr Biol 1999; 9: 931-938.
53 Onichtchouk D, Chen Y-G, Dosch R. et al. Silencing of TGF-P signaling by the pseudoreceptor BAMBI. Nature 1999; 401: 480-485.
54 Sekiya T, Oda T, Matsuura K. et al. Transcriptional regulation of the TGF-P pseudoreceptor BAMBI by TGF-P signaling. Biochem Biophys Res Comm 2004; 320: 680-684.
55 Hanyu A, Ishidou Y, Ebisawa T. et al. The N domain of Smad7 is essential for specific inhibition of transforming growth factor-beta signaling. J Cell Biol 2001; 155: 1017-1027.
56 Imamura T, Takase M, Nishihara A. et al. Smad6 inhibits signalling by the TGF-beta superfamily. Nature 1997; 389: 622-626.
57 Hata A, Lagna G, Massague J. et al. Smad6 inhibits BMP/Smad1 signaling by specifically competing with the Smad4 tumor suppressor. Genes Dev 1998; 12: 186-197.
58 Murakami G, Watabe T. Takaoka et al. Cooperative inhibition of bone morphogenetic protein signaling by Smurf1 and inhibitory Smads. Mol Biol Cell 2003; 14: 2809-2817.
59 Capdevila J, Johnson RL. Endogenous and ectopic expression of noggin suggests a conserved mechanism for regulation of BMP function during limb and somite patterning. Dev Biol 1998; 197: 205-217.
60 Edwards CJ, Francis-West PH. Bone morphogenetic proteins in the development and healing of synovial joints. Semin Arthritis Rheum 2001; 31: 33-42.
61 Zou H, Niswander L. Requirement for BMP signaling in interdigital apoptosis and scale formation. Science 1996; 272: 738-741.
62 Dowthwaite GP, Edwards JC, Pitsillides AA. An essential role for the interaction between hyaluronan and hyaluronan binding proteins during joint development. J Histochem Cytochem 1998; 46: 641-651.
63 Edwards JC, Wilkinson LS, Jones HM. et al. The formation ofhuman synovial joint cavities: a possible role for hyaluronan and CD44 in altered interzone cohesion. JAnat 1994; 185 (Pt2) 355-367.
64 Nishida Y, Knudson CB, Eger W. et al. Osteogenic protein 1 stimulates cells-associated matrix assembly by normal human articular chondrocytes: up-regulation of hyaluronan synthase, CD44, and aggrecan. Arthritis Rheum 2000; 43: 206-214.
65 Nishida Y, Knudson CB, Knudson W. Osteogenic protein-1 inhibits matrix depletion in a hyaluronan hexasaccharide-induced model of osteoarthritis. Osteoarthritis Cartilage 2004; 12: 374-382.
66 Nishida Y, Knudson CB, Kuettner KE. et al. Osteogenic protein-1 promotes the synthesis and retention of extracellularmatrix within bovine articular cartilage and chondrocyte cultures. Osteoarthritis Cartilage 2000; 8: 127-136.
67 Storm Storm, Kingsley DM. GDF5 coordinates bone and joint formation during digit development. DevBiol 1999; 209: 11-27.
68 Merino R, Macias D, Ganan Y. et al. Expression and function of Gdf-5 during digit skeletogenesis in the embryonic chick leg bud. Dev Biol 1999; 206: 33-45.
69 Brunet LJ, McMahon JA, McMahon AP. et al. Noggin, cartilage morphogenesis, and joint formation in the mammalian skeleton. Science 1998; 280: 1455-1457.
70 Bandyopadhyay A, Tsuji K, Cox K. et al. Genetic analysis of the roles of BMP2, BMP4, and BMP7 in limb patterning and skeletogenesis. PLoS Genet 2006; 2: 2116-2130.
71 Katagiri T, Boorla S, Frendo J-L. et al. Skeletal abnormalities in doubly heterozygous Bmp4 and Bmp7 mice. Dev Genet 1998; 22: 340-348.
72 Tsuji K, Bandyopadhyay A, Harfe BD. et al. BMP2 activity, although dispensable for bone formation, is required for the initiation of fracture healing. Nature Genet 2006; 38: 1424-1429.
73 Serra R, Johnson M, Filvaroff EH. et al. Expression of a truncated, kinase-defective TGF-P type II receptor in mouse skeletal tissue promotes terminal chondrocyte differentiation and osteoarthritis. J Cell Biol 1997; 139: 541-552.
74 Yang X, Chen L, Xu X. et al. TGF-P/Smad3 signals repress chondrocyte hypertrophic differentiation and are required for maintaining articular cartilage. JCell Biol 2001; 153: 35-46.
75 Anderson HC, Hodges PT, Aguilera XM. et al. Bone morphogenetic protein (BMP) localization in developing human and rat growth plate, metaphysis, epiphysis, and articular cartilage. J Histochem Cytochem 2000; 48: 1493-1502.
76 Bobacz K, Gruber R, Soleiman A. et al. Expression of bone morphogenetic protein 6 in healthy and osteoarthritic human articular chondrocytes and stimulation of matrix synthesis in vitro. Arthritis Rheum 2003; 48: 2501-2508.
77 Chubinskaya S, Merrihew C, Cs-Szabo G. et al. Human articular chondrocytes express osteogenic protein-1. J Histochem Cytochem 2000; 48: 239-250.
78 Dell'accio F, De Bari C, El Tawil NM. et al. Activation of WNT and BMP signaling in adult human articular cartilage following mechanical injury. Arthritis Res Ther. 2006 8. R139.
79 Erlacher L, Ng CK, Ullrich R. et al. Presence of cartilage-derived morphogenetic proteins in articular cartilage and enhancement of matrix replacement in vitro. Arthritis Rheum 1998; 41: 263-273.
80 Fukui N, Zhu Y, Maloney WJ. et al. Stimulation of BMP-2 expression by pro-inflammatory cytokines IL-1 and TNF-alpha in normal and osteoarthritic chondrocytes. J Bone Joint Surg Am 2003; 85-A Suppl 3 59-66.
81 Fukui N, Ikeda Y, Toshiyuki Ohnuki T. et al. Proinflammatory cytokine tumor necrosis factor-a induces bone morphogenetic protein-2 in chondrocytes via mRNA stabilization and transcriptional up-regulation. J Biol Chem 2006; 281: 27229-27241.
82 Lories RJU, Daans M, Derese I. et al. Noggin haploinsufficiency differentially affects tissue responses in destructive and remodeling arthritis. Arthritis Rheum 2006; 54: 1736-1746.
83 Sailor LZ, Hewick RM, Morris EA. Recombinant human bone morphogenetic protein-2 maintains the articular chondrocyte phenotype in long-term culture. J Orthop Res 1996; 14: 937-945.
84 Stewart MC, Saunders KM, Burton-Wurster N. et al. Phenotypic stability of articular chondrocytes in vitro: the effects of culture models, bone morphogenetic protein 2, and serum supplementation. JBone Miner Res 2000; 15: 166-174.
85 Luyten FP, Chen P, Paralkar V. et al. Recombinant bone morphogenetic protein-4, transforming growth factor-beta 1, and activin A enhance the cartilage phenotype of articular chondrocytes in vitro. Exp Cell Res 1994; 210: 224-229.
86 Hidaka C, Quitoriano M, Warren R. et al. Enhanced matrix synthesis and in vitro formation of cartilage-like tissue by genetically modified chondrocytes expressing BMP-7. J Orthop Res 2001; 19: 751-758.
87 Flechtenmacher J, Huch K, Thonar EJ. et al. Recombinant human osteogenic protein 1 is a potent stimulator of the synthesis of cartilage proteoglycans and collagens by human articular chondrocytes. Arthritis Rheum 1996; 39: 1896-1904.
88 Grunder T, Gaissmaier C, Fritz J. et al. Bone morphogenetic protein (BMP)-2 enhances the expression of type II collagen and aggrecan in chondrocytes embedded in alginate beads. Osteoarthritis Cartilage 2004; 12: 559-567.
89 Luyten FP, Yu YM, Yanagishita M. et al. Natural bovine osteogenin and recombinant human bone morphogenetic protein-2B are equipotent in the maintenance of proteoglycans in bovine articular cartilage explant cultures. JBiolChem 1992; 267: 3691-3695.
90 Pittenger MF, Mackay AM, Beck SC. et al. Multilineage potential of adult human mesenchymal stem cells. Science 1999; 284: 143-147.
91 Otto Otto, Rao J. Tomorrow's skeleton staff: mesenchymal stem cells and the repair of bone and cartilage. Cell Prolif 2004; 37: 97-110.
92 Gregory CA, Prockop DJ, Spees JL. Non-hematopoietic bone marrow stem cells: Molecular control of expansion and differentiation. Exp Cell Res 2005; 306: 330-335.
93 Johnstone B, Hering TM, Caplan AI. et al. In vitro chondrogenesis of bone marrow-derived mesenchymal progenitor cells. Exp Cell Res 1998; 238: 265-272.
94 Mackay AM, Beck SC, Murphy JM. et al. Chondrogenic differentiation of cultured human mesenchymal stem cells from marrow. Tissue Eng 1998; 4: 415-428.
95 Yoo JU, Barthel TS, Nishimura K. et al. The chondrogenic potential of human bone-marrow-derived mesenchymal progenitor cells. J Bone Joint Surg Am 1998; 80: 1745-1757.
96 Hanada K, Solchaga LA, Caplan AI. et al. BMP-2 induction and TGF-P 1 modulation of rat periosteal cell chondrogenesis. J Cell Biochem 2001; 81: 284-294.
97 Sekiya I, Larson BL, Vuoristo JT. et al. Comparison of effect of BMP-2, -4, and -6 on in vitro cartilage formation of human adult stem cells frombone marrow stroma. Cell Tissue Res 2005; 320: 269-276.
98 Shirasawa S, Sekiya I, Sakaguchi Y. et al. In vitro chondrogenesis of human synovium-derivedmesenchymal stem cells: Optimal conditions and comparison with bone marrow-derived cells. J Cell Biochem 2006; 97: 84-97.
99 Estes BT, Wu AW, Guilak F. Potent induction of chondrocytic differentiation of human adiposederived adult stem cells by bone morphogenetic protein 6. Arthritis Rheum 2006; 54: 1222-1232.
100 Park J, Gelse K, Frank S. et al. Transgene-activated mesenchymal cells for articular cartilage repair: a comparison of primary bone marrow-, perichondrium/periosteum-and fat-derived cells. J Gene Med 2006; 8: 112-125.
101 Sakaguchi Y, Sekiya I, Yagishita K. et al. Comparison of human stem cells derived from various mesenchymal tissues: Superiority of synovium as a cell source. Arthritis Rheum 2005; 52: 2521-2529.
102 Gelse K, von der Mark K, Aigner T. et al. Articular cartilage repair by gene therapy using growth factor-producing mesenchymal cells. Arthritis Rheum 2003; 48: 430-441.
103 Grande DA, James Mason J, Evan Light E. et al. Stem cells as platforms for delivery of genes to enhance cartilage repair. J. Bone Joint Surg Am 2003; 85: 111-116.
104 Glansbeek HL, van Beuningen HM, Vitters EL. et al. Bone morphogenetic protein 2 stimulates articular cartilage proteoglycan synthesis in vivo but does not counteract interleukin-1 alpha effects on proteoglycan synthesis and content. Arthritis Rheum 1997; 40: 1020-1028.
105 van Beuningen HM, Glansbeek HL, van der Kraan PM. et al. Differential effects of local application of BMP-2 or TGF-beta 1 on both articular cartilage composition and osteophyte formation. Osteoarthritis Cartilage 1998; 6: 306-317.
106 Kuo AC, Rodrigo JJ, Reddi AH. et al. Microfracture and bone morphogenetic protein 7 (BMP-7) synergistically stimulate articular cartilage repair. Osteoarthritis Cartilage 2006; 14: 1126-1135.
107 Cook SD, Patron LP, Salkeld SL. et al. Repair of articular cartilage defects with osteogenic protein-1 (BMP-7) in dogs. J Bone Joint Surg Am 2003; 85-A Suppl 3 116-123.
108 Louwerse RT, Heyligers IC, Klein-Nulend J. et al. Use ofrecombinant human osteogenic protein-1 for the repair of subchondral defects in articular cartilage in goats. J Biomed Mater Res 2000; 49: 506-516.
109 Sellers RS, Peluso D, Morris EA. The effect of recombinant human bone morphogenetic protein-2 (rhBMP-2) on the healing of full-thickness defects of articular cartilage. J Bone Joint Surg Am 1997; 79: 1452-1463.
110 Suzuki T, Bessho K, Fujimura K. et al. Regeneration of defects in the articular cartilage in rabbit temporomandibular joints by bone morphogenetic protein-2. J Oral Maxillofacial Surg 2002; 40: 201-206.
111 Tamai N, Myoui A. Hirao et al. A new biotechnology for articular cartilage repair: subchondral implantation of a composite of interconnected porous hydroxyapatite, synthetic polymer (PLA_PEG), and bone morphogenetic protein-2 (rhBMP-2). Osteoarthritis Cartilage 2005; 13: 405-417.
112 Hidaka C, Goodrich LR, Chen CT. et al. Acceleration of cartilage repair by genetically modified chondrocytes over expressing bone morphogenetic protein-7. J Orthop Res 2006; 21: 573-583.
113 Kuroda R, Usas A, Kubo S. et al. Cartilage repair using bone morphogenetic protein 4 and musclederived stem cells. Arthritis Rheum 2006; 54: 387-389.
114 Di Cesare S, RF S, Carlson CS. et al. Regional gene therapy for full-thickness articular cartilage lesions using naked DNA with a collagen matrix. J Orthop Res 2006; 24: 1118-1127.
115 Sellers RS, Zhang R, Glasson SS. et al. Repair of articular cartilage defects one year after treatment with recombinant human bone morphogenetic protein-2 (rhBMP-2). J Bone Joint Surg Am 2000; 82: 151-160.
116 Guerne P-A, Blanco F, Kaelin A. et al. Growth factor responsiveness of human articular chondrocytes in aging and development. Arthritis Rheum 1995; 38: 960-968.
117 Hills RL, Belanger LM, Morris EA. Bone morphogenetic protein 9 is a potent anabolic factor for juvenile bovine cartilage, but not adult cartilage. J Orthop Res 2005; 23: 611-617.
118 Smith P, Shuler FD, Georgescu HI. et al. Genetic enhancement of matrix synthesis by articular chondrocytes: comparison of different growth factor genes in the presence and absence of interleukin-1. Arthritis Rheum 2000; 43: 1156-1164.