Bone morphogenetic proteins promote cartilage differentiation and protect engineered artificial cartilage from fibroblast invasion and destruction.

OBJECTIVE An important role in joint and cartilage homeostasis in adults has been demonstrated recently for morphogenetic factors of the transforming growth factor beta family. Therefore, this study was undertaken to investigate the potential of bone morphogenetic proteins (BMPs) in chondrocyte differentiation using current technologies of tissue engineering. METHODS Complementary DNAs of recombinant human BMPs 2, 4, 5, 6, and 7 were transfected into primary bovine articular chondrocytes. Transgenic chondrocytes were assembled 3-dimensionally in alginate or in bioresorbable co-polymer fleeces of vicryl and polydioxanon embedded in low-melting-point agarose. Redifferentiation and formation of cartilage tissue in vitro or after subcutaneous transplantation into nude mice were assayed by semiquantitative reverse transcriptase-polymerase chain reaction, histology, and in situ hybridization, and findings were compared with those in unmodified or control-transfected primary chondrocytes. RESULTS Compared with other BMPs and control vector, BMP-7 induced a decrease in type I collagen expression in artificial cartilage, while transcription of the cartilage-specific type II collagen remained stable. In transplantation experiments, BMP-7 transgenic cartilage revealed the greatest amount of matrix synthesis, and BMP-7 was the only morphogen to suppress the infiltrative response of mouse fibroblastic cells into engineered cartilage, thereby preventing transplant destruction. CONCLUSION Cartilage differentiation and matrix maturation are promoted by BMPs in cartilage engineering. The inhibitory effect of BMP-7 on a nonspecific infiltrative response in immunocompromised nude mice further suggests that individual morphogens not only may contribute to cartilage maturation, but also may protect it from nonspecific inflammation and invasive destruction. These properties advance BMPs as promising tools for engineering of cartilaginous joint bioprostheses and as candidate biologic agents or genes for cartilage stabilization in arthritis.

[1]  H. Zeidler,et al.  The national database of the German Collaborative Arthritis Centres: I. Structure, aims, and patients , 2001, Annals of the rheumatic diseases.

[2]  M. Feldmann,et al.  Cartilage destruction and bone erosion in arthritis: the role of tumour necrosis factor α , 2000, Annals of the rheumatic diseases.

[3]  N. Zvaifler,et al.  Mesenchymal cells expressing bone morphogenetic protein receptors are present in the rheumatoid arthritis joint. , 2000, Arthritis and rheumatism.

[4]  C. Little,et al.  Mechanisms involved in cartilage proteoglycan catabolism. , 2000, Matrix biology : journal of the International Society for Matrix Biology.

[5]  J. Kreeger,et al.  Effects of human recombinant interleukin-1beta on canine articular chondrocytes in three-dimensional culture. , 2000, American journal of veterinary research.

[6]  H. Iba,et al.  Analysis of cartilage maturation using micromass cultures of primary chondrocytes , 2000, Development, growth & differentiation.

[7]  Chang-long Yu,et al.  Expression of collagen type I, II and III in loose body of osteoarthritis , 2000, Journal of orthopaedic science : official journal of the Japanese Orthopaedic Association.

[8]  L. Niswander,et al.  BMPs are required at two steps of limb chondrogenesis: formation of prechondrogenic condensations and their differentiation into chondrocytes. , 2000, Developmental biology.

[9]  P. Dieppe,et al.  The Bristol 'OA500 study': progression and impact of the disease after 8 years. , 2000, Osteoarthritis and cartilage.

[10]  J. Braun,et al.  Disability and handicap in rheumatoid arthritis and ankylosing spondylitis--results from the German rheumatological database. German Collaborative Arthritis Centers. , 2000, The Journal of rheumatology.

[11]  L. Nelles,et al.  Correlation between ALK-6 (BMPR-IB) Distribution and Responsiveness to Osteogenic Protein-1 (BMP-7) in Embryonic Mouse Bone Rudiments , 2000, Growth factors.

[12]  M. Feldmann,et al.  Defining therapeutic targets by using adenovirus: blocking NF-kappaB inhibits both inflammatory and destructive mechanisms in rheumatoid synovium but spares anti-inflammatory mediators. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[13]  C. Archer,et al.  BMP/GDF-signalling interactions during synovial joint development , 1999, Cell and Tissue Research.

[14]  M. V. D. van der Meulen,et al.  BMP-5 deficiency alters chondrocytic activity in the mouse proximal tibial growth plate. , 1999, Bone.

[15]  H Planck,et al.  Cartilage reconstruction in head and neck surgery: comparison of resorbable polymer scaffolds for tissue engineering of human septal cartilage. , 1998, Journal of biomedical materials research.

[16]  S D Gillogly,et al.  Treatment of articular cartilage defects of the knee with autologous chondrocyte implantation. , 1998, The Journal of orthopaedic and sports physical therapy.

[17]  R. Gay,et al.  Interleukin‐16, produced by synovial fibroblasts, mediates chemoattraction for CD4+ T lymphocytes in rheumatoid arthritis , 1998, European journal of immunology.

[18]  D. Grande,et al.  Expression of human bone morphogenic protein 7 in primary rabbit periosteal cells: potential utility in gene therapy for osteochondral repair , 1998, Gene Therapy.

[19]  W. B. van den Berg,et al.  Stimulation of articular cartilage repair in established arthritis by local administration of transforming growth factor-beta into murine knee joints. , 1998, Laboratory investigation; a journal of technical methods and pathology.

[20]  E. Morris,et al.  The Effect of Recombinant Human Bone Morphogenetic Protein-2 (rhBMP-2) on the Healing of Full-Thickness Defects of Articular Cartilage* , 1997, The Journal of bone and joint surgery. American volume.

[21]  K. Matsumoto,et al.  Hepatocyte growth factor facilitates cartilage repair. Full thickness articular cartilage defect studied in rabbit knees. , 1997, Acta orthopaedica Scandinavica.

[22]  S. Maeda,et al.  Expression and localization of bone morphogenetic proteins (BMPs) and BMP receptors in ossification of the ligamentum flavum. , 1997, Bone.

[23]  Y. Chernajovsky,et al.  Pathogenic lymphoid cells engineered to express TGF β1 ameliorate disease in a collagen-induced arthritis model , 1997, Gene Therapy.

[24]  R. Hewick,et al.  Recombinant human bone morphogenetic protein‐2 maintains the articular chondrocyte phenotype in long‐term culture , 1996, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[25]  E. Thonar,et al.  Recombinant human osteogenic protein 1 is a potent stimulator of the synthesis of cartilage proteoglycans and collagens by human articular chondrocytes. , 1996, Arthritis and rheumatism.

[26]  B. Hogan,et al.  Bone morphogenetic proteins: multifunctional regulators of vertebrate development. , 1996, Genes & development.

[27]  E. Hunziker,et al.  Repair of Partial-Thickness Defects in Articular Cartilage: Cell Recruitment from the Synovial Membrane* , 1996, The Journal of bone and joint surgery. American volume.

[28]  M. Sittinger,et al.  Tissue Engineering: Künstlicher Gewebeersatz aus vitalen Komponenten , 1995 .

[29]  A. Nixon,et al.  Chondrocyte-laden collagen scaffolds for resurfacing extensive articular cartilage defects. , 1995, Osteoarthritis and cartilage.

[30]  C. Ohlsson,et al.  Treatment of deep cartilage defects in the knee with autologous chondrocyte transplantation. , 1994, The New England journal of medicine.

[31]  R J Todhunter,et al.  Chondrocyte‐fibrin matrix transplants for resurfacing extensive articular cartilage defects , 1994, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[32]  C. Vacanti,et al.  Tissue-engineered morphogenesis of cartilage and bone by means of cell transplantation using synthetic biodegradable polymer matrices. , 1994, Clinics in plastic surgery.

[33]  P. Guerne,et al.  Growth factor responsiveness of human articular chondrocytes: Distinct profiles in primary chondrocytes, subcultured chondrocytes, and fibroblasts , 1994, Journal of cellular physiology.

[34]  M. E. Charness,et al.  Regulation of neural cell adhesion molecule and L1 by the transforming growth factor-beta superfamily. Selective effects of the bone morphogenetic proteins. , 1994, The Journal of biological chemistry.

[35]  T. Sato,et al.  Bone morphogenetic protein-induced muscle- and synovium-derived cartilage differentiation in vitro. , 1993, Clinical orthopaedics and related research.

[36]  R. Gay,et al.  Molecular and cellular mechanisms of joint destruction in rheumatoid arthritis: two cellular mechanisms explain joint destruction? , 1993, Annals of the rheumatic diseases.

[37]  V. Paralkar,et al.  Osteogenin and recombinant bone morphogenetic protein 2B are chemotactic for human monocytes and stimulate transforming growth factor beta 1 mRNA expression. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[38]  A. Reddi,et al.  Regulation of cartilage and bone differentiation by bone morphogenetic proteins. , 1992, Current opinion in cell biology.

[39]  F. Luyten,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. , 1992, The Journal of biological chemistry.

[40]  R Langer,et al.  Tissue engineering by cell transplantation using degradable polymer substrates. , 1991, Journal of biomechanical engineering.

[41]  G. Firestein,et al.  Cytokines in chronic inflammatory arthritis. V. Mutual antagonism between interferon-gamma and tumor necrosis factor-alpha on HLA-DR expression, proliferation, collagenase production, and granulocyte macrophage colony-stimulating factor production by rheumatoid arthritis synoviocytes. , 1990, The Journal of clinical investigation.

[42]  R. Maki,et al.  Quantitative analysis of cytokine gene expression in rheumatoid arthritis. , 1990, Journal of immunology.

[43]  F. Luyten,et al.  Stimulation of the expression of osteogenic and chondrogenic phenotypes in vitro by osteogenin. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[44]  S. de la Luna,et al.  Efficient transformation of mammalian cells with constructs containing a puromycin-resistance marker. , 1988, Gene.

[45]  P. Chomczyński,et al.  Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. , 1987, Analytical biochemistry.

[46]  B. Hoffman,et al.  A simple and very efficient method for generating cDNA libraries. , 1983, Gene.

[47]  R. Winchester,et al.  Identification of Three Major Synovial Lining Cell Populations by Monoclonal Antibodies Directed to Ia Antigens and Antigens Associated with Monocytes/Macrophages and Fibroblasts , 1983, Scandinavian journal of immunology.

[48]  P. Benya,et al.  Dedifferentiated chondrocytes reexpress the differentiated collagen phenotype when cultured in agarose gels , 1982, Cell.

[49]  E. J. Miller,et al.  Changes in type of collagen synthesized as clones of chick chondrocytes grow and eventually lose division capacity. , 1976, Proceedings of the National Academy of Sciences of the United States of America.

[50]  S. Krane.  Petulant cellular acts: destroying the ECM rather than creating it. , 2001, The Journal of clinical investigation.

[51]  D R Carter,et al.  Effects of shear stress on articular chondrocyte metabolism. , 2000, Biorheology.

[52]  M. Ochi,et al.  Beneficial effect of basic fibroblast growth factor on the repair of full-thickness defects in rabbit articular cartilage , 1999, Archives of Orthopaedic and Trauma Surgery.

[53]  M. Rudert,et al.  Synthesis of articular cartilage-like tissue in vitro , 1998, Archives of Orthopaedic and Trauma Surgery.

[54]  B. Bresnihan,et al.  Synovial tissue macrophage populations and articular damage in rheumatoid arthritis. , 1996, Arthritis and rheumatism.

[55]  R. Strieter,et al.  Cytokines in rheumatoid arthritis. , 1995, Journal of investigative medicine : the official publication of the American Federation for Clinical Research.