Advances in drug delivery for articular cartilage.

The complex structure of articular cartilage, the connective tissue lining diarthrodial joints, enables this tissue to dissipate compressive loads but also appears to hinder its repair ability. At best, both natural and surgical repair attempts replace the highly ordered extracellular matrix of native articular cartilage with fibrous repair tissue of inferior mechanical properties. Numerous bioactive molecules closely regulate the cellular processes in healthy and degenerative articular cartilage. Accordingly, this review outlines the roles of important signaling molecules in cartilage tissue. In addition, drug delivery strategies, aimed at utilizing these bioactive agents to prevent inflammation, to regulate extracellular matrix metabolism, and to control cellular activities, are discussed. As scientists gain further insight into the complex signaling cascades of articular cartilage, continued refinement of drug delivery systems is necessary to develop effective clinical therapies for articular cartilage repair.

[1]  M. Sakuda,et al.  Stimulation of cartilage‐matrix proteoglycan synthesis by morphologically transformed chondrocytes grown in the presence of fibroblast growth factor and transforming growth factor‐beta , 1989, Journal of cellular physiology.

[2]  F. Silver,et al.  Cartilage wound healing. An overview. , 1995, Otolaryngologic clinics of North America.

[3]  E. Thonar,et al.  The superficial layer of human articular cartilage is more susceptible to interleukin-1-induced damage than the deeper layers. , 1996, Arthritis and rheumatism.

[4]  G. P. Harper,et al.  A synthetic peptide metalloproteinase inhibitor, but not Timp, prevents the breakdown of proteoglycan within articular cartilagein vitro , 1992, Agents and Actions.

[5]  M. Takigawa,et al.  Nitric oxide mediates interleukin-1-induced gene expression of matrix metalloproteinases and basic fibroblast growth factor in cultured rabbit articular chondrocytes. , 1998, Journal of biochemistry.

[6]  W. Border,et al.  Transforming Growth Factor β in Tissue Fibrosis , 1994 .

[7]  K. Athanasiou,et al.  Ex vivo synthesis of articular cartilage. , 2000, Biomaterials.

[8]  R. Abagyan,et al.  TNF-alpha convertase enzyme from human arthritis-affected cartilage: isolation of cDNA by differential display, expression of the active enzyme, and regulation of TNF-alpha. , 1998, Journal of immunology.

[9]  H. Häuselmann.  Mechanisms of cartilage destruction and novel nonsurgical therapeutic strategies to retard cartilage injury in rheumatoid arthritis. , 1997, Current opinion in rheumatology.

[10]  B. Boyan,et al.  Bone and cartilage tissue engineering. , 1999, Clinics in plastic surgery.

[11]  D. Xie,et al.  Fibronectin fragments alter matrix protein synthesis in cartilage tissue cultured in vitro. , 1993, Archives of biochemistry and biophysics.

[12]  W. B. van den Berg,et al.  Transforming growth factor-beta 1 stimulates articular chondrocyte proteoglycan synthesis and induces osteophyte formation in the murine knee joint. , 1994, Laboratory investigation; a journal of technical methods and pathology.

[13]  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.

[14]  Y Ikada,et al.  Effect of basic fibroblast growth factor on cartilage regeneration in chondrocyte-seeded collage scaffold ns , 2003 .

[15]  C. Wirth,et al.  Techniques of cartilage growth enhancement: a review of the literature. , 1996, Arthroscopy : the journal of arthroscopic & related surgery : official publication of the Arthroscopy Association of North America and the International Arthroscopy Association.

[16]  F. Luyten,et al.  Recombinant bone morphogenetic protein-4, transforming growth factor-beta 1, and activin A enhance the cartilage phenotype of articular chondrocytes in vitro. , 1994, Experimental cell research.

[17]  J. Puzas,et al.  Transforming growth factor beta: an autocrine regulator of chondrocytes. , 1989, Connective tissue research.

[18]  J. Wozney,et al.  Potential of porous poly-D,L-lactide-co-glycolide particles as a carrier for recombinant human bone morphogenetic protein-2 during osteoinduction in vivo. , 1999, Journal of biomedical materials research.

[19]  G. Campion,et al.  Dose-range and dose-frequency study of recombinant human interleukin-1 receptor antagonist in patients with rheumatoid arthritis. The IL-1Ra Arthritis Study Group. , 1996, Arthritis and rheumatism.

[20]  R. Day,et al.  Nonsteroidal antiinflammatory drugs--differences and similarities. , 1991, The New England journal of medicine.

[21]  S. Weisbrode,et al.  Use of an Isolated Joint Model to Detect Early Changes Induced by Intra-Articular Injection of Paclitaxel-Impregnated Polymeric Microspheres , 2001, Journal of investigative surgery : the official journal of the Academy of Surgical Research.

[22]  M. Nimni.  Polypeptide growth factors: targeted delivery systems. , 1997, Biomaterials.

[23]  G. Loredo,et al.  Regulation of glycosaminoglycan metabolism by bone morphogenetic protein-2 in equine cartilage explant cultures. , 1996, American journal of veterinary research.

[24]  T. Minas.  The role of cartilage repair techniques, including chondrocyte transplantation, in focal chondral knee damage. , 1999, Instructional course lectures.

[25]  K J Gooch,et al.  IGF-I and mechanical environment interact to modulate engineered cartilage development. , 2001, Biochemical and biophysical research communications.

[26]  A. Caplan,et al.  Osteochondrogenic potential of marrow mesenchymal progenitor cells exposed to TGF‐β1 or PDGF‐BB as assayed in vivo and in vitro , 1996, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[27]  L. Pottenger,et al.  Effects of basic fibroblast growth factor, transforming growth factor‐β1, insulin‐like growth factor‐1, and insulin on human osteoarthritic articular cartilage explants , 1995, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[28]  D. W. Jackson,et al.  Tissue engineering principles in orthopaedic surgery. , 1999, Clinical orthopaedics and related research.

[29]  E. Hunziker,et al.  Structural Barrier Principle for Growth Factor-Based Articular Cartilage Repair , 2001, Clinical orthopaedics and related research.

[30]  A. Mikos,et al.  Controlled release of an osteogenic peptide from injectable biodegradable polymeric composites. , 2002, Journal of controlled release : official journal of the Controlled Release Society.

[31]  R. O’Keefe,et al.  Autocrine regulation of articular cartilage. , 1998, Instructional course lectures.

[32]  K. Ono,et al.  Transforming growth factor-beta 1 stimulates chondrogenesis and inhibits osteogenesis in high density culture of periosteum-derived cells. , 1993, Endocrinology.

[33]  R. Coutts,et al.  Effects of growth factors on cartilage repair. , 1997, Instructional course lectures.

[34]  M E Bolander,et al.  Transforming growth factor-beta and the initiation of chondrogenesis and osteogenesis in the rat femur , 1990, The Journal of cell biology.

[35]  O. Johnell,et al.  Effect of transforming growth factor‐β and platelet‐derived growth factor‐BB on articular cartilage in rats , 1996, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[36]  J. Graycar,et al.  Cartilage-inducing factor-B is a unique protein structurally and functionally related to transforming growth factor-beta. , 1987, The Journal of biological chemistry.

[37]  P. Segarini,et al.  Modulation of chondroblast phenotype by transforming growth factor-beta. , 1988, Pathology and immunopathology research.

[38]  G. Homandberg,et al.  Association of proteoglycan degradation with catabolic cytokine and stromelysin release from cartilage cultured with fibronectin fragments. , 1996, Archives of biochemistry and biophysics.

[39]  J. Mort,et al.  Modulation of the catabolic effects of interleukin‐1β on human articular chondrocytes by transforming growth factor‐β , 1996 .

[40]  J. Buckwalter,et al.  Effects of fibronectin on articular cartilage chondrocyte proteoglycan synthesis and response to insulin‐like growth factor‐I , 1998, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[41]  K. Hillan,et al.  Pathways by which interleukin 17 induces articular cartilage breakdown in vitro and in vivo. , 2001, Cytokine.

[42]  E B Hunziker,et al.  Articular cartilage repair: are the intrinsic biological constraints undermining this process insuperable? , 1999, Osteoarthritis and cartilage.

[43]  R. Iozzo,et al.  A Composite Element Binding the Vitamin D Receptor and the Retinoic X Receptor α Mediates the Transforming Growth Factor-β Inhibition of Decorin Gene Expression in Articular Chondrocytes* , 2001, The Journal of Biological Chemistry.

[44]  J. Puzas,et al.  Synergistic effect of transforming growth factor β and fibroblast growth factor on DNA synthesis in chick growth plate chondrocytes , 1990, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[45]  E A Morris,et al.  Isolation, characterization, and chondrogenic potential of human bone marrow‐derived multipotential stromal cells , 2000, Journal of cellular physiology.

[46]  P. Guerne,et al.  IL-6 production by human articular chondrocytes. Modulation of its synthesis by cytokines, growth factors, and hormones in vitro. , 1990, Journal of immunology.

[47]  R. Loeser,et al.  Chondrocyte integrin expression and function. , 2000, Biorheology.

[48]  C. Kaps,et al.  Porcine mesenchymal stem cells , 2002, Cell and Tissue Research.

[49]  S. Lamberts,et al.  Contrasting modulation by transforming growth factor-beta-1 of insulin-like growth factor-I production in osteoblasts and chondrocytes. , 1990, Endocrinology.

[50]  J. Bijlsma,et al.  ROLE OF TNFα, IN RELATION TO IL-1 AND IL-6 IN THE PROTEOGLYCAN TURNOVER OF HUMAN ARTICULAR CARTILAGE , 1991 .

[51]  T. I. Morales.  Transforming growth factor-beta 1 stimulates synthesis of proteoglycan aggregates in calf articular cartilage organ cultures. , 1991, Archives of biochemistry and biophysics.

[52]  B. Clarke.  Dynamics of Bone and Cartilage Metabolism , 2000 .

[53]  J. Buckwalter,et al.  Damage control mechanisms in articular cartilage: the role of the insulin-like growth factor I axis. , 2000, The Iowa orthopaedic journal.

[54]  Albert C. Chen,et al.  Differential effects of bFGF and IGF-I on matrix metabolism in calf and adult bovine cartilage explants. , 1994, Archives of biochemistry and biophysics.

[55]  Napoleone Ferrara,et al.  VEGF couples hypertrophic cartilage remodeling, ossification and angiogenesis during endochondral bone formation , 1999, Nature Medicine.

[56]  J A Martin,et al.  The role of chondrocyte-matrix interactions in maintaining and repairing articular cartilage. , 2000, Biorheology.

[57]  W. Horton,et al.  In vivo cartilage formation from growth factor modulated articular chondrocytes. , 1998, Clinical orthopaedics and related research.

[58]  W. B. van den Berg,et al.  Growth factors and cartilage repair. , 2001, Clinical orthopaedics and related research.

[59]  J. McPherson,et al.  Cartilage-inducing factor-A. Apparent identity to transforming growth factor-beta. , 1986, The Journal of biological chemistry.

[60]  R. Heller,et al.  Cytokine Control of Interstitial Collagenase and Collagenase-3 Gene Expression in Human Chondrocytes* , 1996, The Journal of Biological Chemistry.

[61]  H. Minehara,et al.  Growth Factor Expression in the Osteophytes of the Human Femoral Head in Osteoarthritis , 2000, Clinical orthopaedics and related research.

[62]  I. Sekiya,et al.  BMP-6 enhances chondrogenesis in a subpopulation of human marrow stromal cells. , 2001, Biochemical and biophysical research communications.

[63]  M. Lotz,et al.  IL-18 is produced by articular chondrocytes and induces proinflammatory and catabolic responses. , 1999, Journal of immunology.

[64]  J. Pelletier,et al.  Excess of metalloproteases over tissue inhibitor of metalloprotease may contribute to cartilage degradation in osteoarthritis and rheumatoid arthritis. , 1994, Laboratory investigation; a journal of technical methods and pathology.

[65]  Y. Nagai,et al.  The role of IL-4 and IL-6 in IL-1-dependent cartilage matrix degradation. , 1995, British journal of rheumatology.

[66]  F. Luyten,et al.  Insulin-like growth factors maintain steady-state metabolism of proteoglycans in bovine articular cartilage explants. , 1988, Archives of biochemistry and biophysics.

[67]  M. Heberer,et al.  Specific growth factors during the expansion and redifferentiation of adult human articular chondrocytes enhance chondrogenesis and cartilaginous tissue formation in vitro , 2001, Journal of cellular biochemistry.

[68]  M. Sporn,et al.  Transforming growth factor-beta: biological function and chemical structure. , 1986, Science.

[69]  R. O’Keefe,et al.  Effects of transforming growth factor‐β1 and fibroblast growth factor on DNA synthesis in growth plate chondrocytes are enhanced by insulin‐like growth factor‐I , 1994 .

[70]  E. Hunziker,et al.  Differential effects of insulin-like growth factor I and growth hormone on developmental stages of rat growth plate chondrocytes in vivo. , 1994, The Journal of clinical investigation.

[71]  R. Stockwell.  Biology of cartilage cells , 1979 .

[72]  Thomas Häupl,et al.  Bone morphogenetic proteins promote cartilage differentiation and protect engineered artificial cartilage from fibroblast invasion and destruction. , 2002, Arthritis and rheumatism.

[73]  G. Homandberg,et al.  High concentrations of fibronectin fragments cause short-term catabolic effects in cartilage tissue while lower concentrations cause continuous anabolic effects. , 1994, Archives of biochemistry and biophysics.

[74]  T. Hardingham,et al.  Effects of catabolic and anabolic cytokines on proteoglycan biosynthesis in young, old and osteoarthritic canine cartilage. , 1990, Biochemical Society transactions.

[75]  T. Park,et al.  Temperature-responsive and degradable hyaluronic acid/Pluronic composite hydrogels for controlled release of human growth hormone. , 2002, Journal of controlled release : official journal of the Controlled Release Society.

[76]  W. B. van den Berg,et al.  Bone morphogenetic protein 2 stimulates articular cartilage proteoglycan synthesis in vivo but does not counteract interleukin-1alpha effects on proteoglycan synthesis and content. , 1997, Arthritis and rheumatism.

[77]  Y. Sugioka,et al.  Basic fibroblast growth factor stimulates articular cartilage enlargement in young rats in vivo , 1996, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[78]  L. Bonewald,et al.  Growth plate chondrocytes store latent transforming growth factor (TGF)‐β1 in their matrix through latent TGF‐β1 binding protein‐1 , 1998 .

[79]  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.

[80]  Kyriacos A. Athanasiou,et al.  Biodegradable Implants for the Treatment of Osteochondral Defects in a Goat Model , 1997 .

[81]  P. Cuevas,et al.  Basic fibroblast growth factor (FGF) promotes cartilage repair in vivo. , 1988, Biochemical and biophysical research communications.

[82]  K. Miyazono,et al.  Transforming growth factor-beta 1, -beta 2, and -beta 3 secreted by a human glioblastoma cell line. Identification of small and different forms of large latent complexes. , 1992, The Journal of biological chemistry.

[83]  K. Miyazono,et al.  Role of the latent TGF-beta binding protein in the activation of latent TGF-beta by co-cultures of endothelial and smooth muscle cells , 1993, The Journal of cell biology.

[84]  R. Wait,et al.  Basic FGF mediates an immediate response of articular cartilage to mechanical injury , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[85]  C. Conover,et al.  Factors regulating insulin-like growth factor-binding protein-3 binding, processing, and potentiation of insulin-like growth factor action. , 1996, Endocrinology.

[86]  P. Roughley,et al.  Matrix metalloproteinases cleave at two distinct sites on human cartilage link protein. , 1993, The Biochemical journal.

[87]  A. Rowan,et al.  TRANSFORMING GROWTH FACTOR-β1 BLOCKS THE RELEASE OF COLLAGEN FRAGMENTS FROM BOVINE NASAL CARTILAGE STIMULATED BY ONCOSTATIN M IN COMBINATION WITH IL-1α , 2000 .

[88]  J. Sieper,et al.  Regulation of Expression of Cytokines and Growth Factors in Osteoarthritic Cartilage Explants , 2001, Clinical Rheumatology.

[89]  Y. Kawashima,et al.  Prolonged Anti-Inflammatory Action of DL-Lactide/Glycolide Copolymer Nanospheres Containing Betamethasone Sodium Phosphate for an Intra-Articular Delivery System in Antigen-Induced Arthritic Rabbit , 2002, Pharmaceutical Research.

[90]  T. I. Morales.  The role and content of endogenous insulin-like growth factor-binding proteins in bovine articular cartilage. , 1997, Archives of biochemistry and biophysics.

[91]  Robert Langer,et al.  Controlled‐release of IGF‐I and TGF‐β1 in a photopolymerizing hydrogel for cartilage tissue engineering , 2001, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[92]  Denis Vivien,et al.  Differential effects of transforming growth factor‐β and epidermal growth factor on the cell cycle of cultured rabbit articular chondrocytes , 1990, Journal of cellular physiology.

[93]  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.

[94]  X. Ronot,et al.  Growth-promoting effects of acidic and basic fibroblast growth factor on rabbit articular chondrocytes aging in culture. , 1989, Experimental cell research.

[95]  T. Hardingham,et al.  Effect of interleukin-1 and insulin like growth factor-1 on the release of proteoglycan components and hyaluronan from pig articular cartilage in explant culture. , 1991, Matrix.

[96]  W. B. van den Berg,et al.  Differential effects of local application of BMP-2 or TGF-beta 1 on both articular cartilage composition and osteophyte formation. , 1998, Osteoarthritis and cartilage.

[97]  B. Swoboda,et al.  Vascular endothelial growth factor in articular cartilage of healthy and osteoarthritic human knee joints , 2001, Annals of the rheumatic diseases.

[98]  E. Hunziker,et al.  Chondrogenesis in Cartilage Repair is Induced by Members of the Transforming Growth Factor-Beta Superfamily , 2001, Clinical orthopaedics and related research.

[99]  A. Rowan,et al.  Modulation of the expression of matrix metalloproteinase and tissue inhibitors of metalloproteinases by TGF-beta1 and IGF-1 in primary human articular and bovine nasal chondrocytes stimulated with TNF-alpha. , 2001, Cytokine.

[100]  A. Mikos,et al.  Controlled release of transforming growth factor β1 from biodegradable polymer microparticles , 2000 .

[101]  M. Takigawa,et al.  Nitric oxide mediates interleukin-1-induced matrix degradation and basic fibroblast growth factor release in cultured rabbit articular chondrocytes: a possible mechanism of pathological neovascularization in arthritis. , 1996, Endocrinology.

[102]  A. Hollander,et al.  Effects of growth factors and interleukin-1 alpha on proteoglycan and type II collagen turnover in bovine nasal and articular chondrocyte pellet cultures. , 1996, Endocrinology.

[103]  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.

[104]  L. Joosten,et al.  Role of interleukin-1, tumor necrosis factor alpha, and interleukin-6 in cartilage proteoglycan metabolism and destruction. Effect of in situ blocking in murine antigen- and zymosan-induced arthritis. , 1995, Arthritis and rheumatism.