Austin J Musculoskelet Disord. 2014;1(1): 1002.
Center of Experimental Orthopaedics, Saarland University Medical Center, Germany
*Corresponding author: Magali Cucchiarini, Center of Experimental Orthopaedics, Saarland University Medical Center, Kirrbergerstr. Bldg 37, D-66421 Homburg/Saar, Germany
Received: July 15, 2014; Accepted: July 16, 2014; Published: July 17, 2014
Osteoarthritis (OA) is a highly prevalent degenerative disease of the whole joint for which there is no definite cure. OA affects millions of people worldwide, becoming one of the most costly diseases of our societies, showing the urgent need for new, improved therapeutic regimens.
OA is a very complex condition with many risk factors associated with its incidence, including aging, trauma, metabolic and mechanical conditions, genetic background, and epigenetic regulation [1-6]. OA is mainly characterized by a slow, progressive, and irreversible degradation of the articular cartilage, with a loss of its major extracellular matrix (ECM) components (proteoglycans, type-II collagen) and concomitant changes in the subchondral bone, synovium, and other joint tissues (meniscus, tendons, ligaments) [3,7]. Disturbances in the cartilage homeostasis play determining roles in the pathogenesis and progression of OA. Proinflammatory cytokines (IL-1, TNF-α) and adipokines (leptin, adiponectin, resistin) locally produced by the inflamed synovium, infrapatellar fat pad, osteophytes, or by the chondrocytes themselves may all contribute to the pathophysiology of OA [1,8].
The chondrocytes, the unique cartilage-forming cells, have received particular attention for their potential implication in the progression of the disease. In normal adult cartilage, these cells are terminally differentiated, with low proliferative and metabolic activities. In early OA, instead, the chondrocytes undergo pathological changes in these activities and in their gene expression profiles, displaying transient proliferative responses and synthesis of matrixdegrading enzymes and of unnatural ECM molecules (type-X, type- III, and type-VI collagen, type-IIA procollagen, tenascin, decorin) as an attempt at repair, but further ondergoing an arrest in production of the key ECM components, a decline in responsiveness to reparative stimuli, cell senescence, and structural degeneration that can not be compensated by the invasion of regenerative cells from vascular compartment as the adult cartilage is devoid of vascularity.
Diverse pharmacological treatments and surgical interventions are available to manage the progression of OA, yet none can definitely and completely reproduce an original hyaline articular cartilage, with its natural structure and functions (gliding of the articulating surfaces in the joint, protection of the subchondral bone from mechanical stress.). This is particularly problematic for patients that are too young to undergo partial or total joint replacement.
Strategies based on the use of gene and cell therapy may offer powerful, new tools to promote the durable, effective reconstruction of an original cartilage surface in human OA [9,10]. These approaches are particularly adapted for the long term treatment of a slow, progressive disorder like OA compared with the application of recombinant factors that display very short pharmacological half-lives. Active investigation is ongoing to test the potential benefits of combining gene and cell therapy using cells relevant of the disease pathology (differentiated chondrocytes, bone cells, synoviocytes, meniscal fibrochondrocytes, tenocytes, ligament cells; progenitor cells such as from the bone marrow, adipose tissue, synovium, muscle, induced pluripotent stem cells…) and diverse candidate genes displaying metabolic, proliferative, chondroprotective, or chondroregenerative activities (growth and transcription factors, matrix-producing enzymes, signalling molecules, inhibitors of inflammation, antisense approaches) [9,10]. The choice of an adapted gene transfer system is also of the utmost importance for an effective and lasting treatment of OA by allowing for high and prolonged levels of expression of the candidate sequence due to long-term progression of this disorder. Different types of gene vehicles are available to date (classical nonviral, adenoviral, retro-/lentiviral, herpes simplex virus vectors), but those derived from the replication-defective, non-pathogenic human adeno-associated virus (AAV) recently emerged as the best suited constructs due to their low immunogenic and remarkable high efficacy to transduce all cells relevant of the OA pathogenesis for extended periods of time in vitro, but most remarkably in situ and in vivo when the cells are in their natural environment [11-38], especially in experimental models of OA in vivo [28,33,34]. Most notably, such cell- and gene-based procedures are currently tested in human clinical trials to examine the tolerability and efficacy of the treatment in patients [39,40], showing the strong value to address the question of OA therapy by molecular technologies in the affected world population.
- Goldring MB, Marcu KB. Epigenomic and microRNA-mediated regulation in cartilage development, homeostasis, and osteoarthritis. Trends Mol Med. 2012; 18: 109-118.
- van den Berg WB. Osteoarthritis year 2010 in review: pathomechanisms. Osteoarthritis Cartilage. 2011; 19: 338-341.
- Goldring MB. Chondrogenesis, chondrocyte differentiation, and articular cartilage metabolism in health and osteoarthritis. Ther Adv Musculoskelet Dis. 2012; 4: 269-285.
- Guilak F. Biomechanical factors in osteoarthritis. Best Pract Res Clin Rheumatol. 2011; 25: 815-823.
- Lotz M, Loeser RF. Effects of aging on articular cartilage homeostasis. Bone. 2012; 51: 241-248.
- Sandell LJ. Etiology of osteoarthritis: genetics and synovial joint development. Nat Rev Rheumatol. 2012; 8: 77-89.
- Loeser RF, Goldring SR, Scanzello CR, Goldring MB. Osteoarthritis: a disease of the joint as an organ. Arthritis Rheum. 2012; 64: 1697-1707.
- Goldring MB, Otero M. Inflammation in osteoarthritis. Curr Opin Rheumatol. 2011; 23: 471-478.
- Madry H, Cucchiarini M. Advances and challenges in gene-based approaches for osteoarthritis. J Gene Med. 2013; 15: 343-355.
- Orth P, Rey-Rico A2, Venkatesan JK2, Madry H3, Cucchiarini M2. Current perspectives in stem cell research for knee cartilage repair. Stem Cells Cloning. 2014; 7: 1-17.
- Arai Y, Kubo T, Fushiki S, Mazda O, Nakai H, Iwaki Y. Gene delivery to human chondrocytes by an adeno associated virus vector. J Rheumatol. 2000; 27: 979-982.
- Madry H, Cucchiarini M, Terwilliger EF, Trippel SB. Recombinant adeno-associated virus vectors efficiently and persistently transduce chondrocytes in normal and osteoarthritic human articular cartilage. Hum Gene Ther. 2003;14: 393-402.
- Madry H, Cucchiarini M, Kaul G, Kohn D, Terwilliger EF, Trippel SB. Menisci are efficiently transduced by recombinant adeno-associated virus vectors in vitro and in vivo. Am J Sports Med. 2004; 32: 1860-1865.
- Ulrich-Vinther M, Duch MR, Søballe K, O'Keefe RJ, Schwarz EM, Pedersen FS. In vivo gene delivery to articular chondrocytes mediated by an adeno-associated virus vector. J Orthop Res. 2004; 22: 726-734.
- Cucchiarini M, Madry H, Ma C, Thurn T, Zurakowski D, Menger MD. Improved tissue repair in articular cartilage defects in vivo by rAAV-mediated overexpression of human fibroblast growth factor 2. Mol Ther. 2005; 12: 229-238.
- Ulrich-Vinther M, Stengaard C, Schwarz EM, Goldring MB, Soballe K. Adeno-associated vector mediated gene transfer of transforming growth factor-beta1 to normal and osteoarthritic human chondrocytes stimulates cartilage anabolism. Eur Cell Mater. 2005;10: 40-50.
- Cucchiarini M, Thurn T, Weimer A, Kohn D, Terwilliger EF, Madry H. Restoration of the extracellular matrix in human osteoarthritic articular cartilage by overexpression of the transcription factor SOX9. Arthritis Rheum. 2007; 56: 158-167.
- Pagnotto MR, Wang Z, Karpie JC, Ferretti M, Xiao X, Chu CR. Adeno-associated viral gene transfer of transforming growth factor-beta1 to human mesenchymal stem cells improves cartilage repair. Gene Ther. 2007; 14: 804-813.
- Stender S, Murphy M, O'Brien T, Stengaard C, Ulrich-Vinther M, Søballe K. Adeno-associated viral vector transduction of human mesenchymal stem cells. Eur Cell Mater. 2007; 13: 93-99.
- Cucchiarini M, Schetting S, Terwilliger EF, Kohn D, Madry H. rAAV-mediated overexpression of FGF-2 promotes cell proliferation, survival, and alpha-SMA expression in human meniscal lesions. Gene Ther. 2009; 16: 1363-1372.
- Cucchiarini M, Terwilliger EF, Kohn D, Madry H. Remodelling of human osteoarthritic cartilage by FGF-2, alone or combined with Sox9 via rAAV gene transfer. J Cell Mol Med. 2009; 13: 2476-2488.
- Kay JD, Gouze E, Oligino TJ, Gouze JN, Watson RS, Levings PP. Intra-articular gene delivery and expression of interleukin-1Ra mediated by self-complementary adeno-associated virus. J Gene Med. 2009; 11: 605-614.
- Cucchiarini M, Ekici M, Schetting S, Kohn D, Madry H. Metabolic activities and chondrogenic differentiation of human mesenchymal stem cells following recombinant adeno-associated virus-mediated gene transfer and overexpression of fibroblast growth factor 2. Tissue Eng Part A. 2011;17: 1921-1933.
- Payne KA, Lee HH, Haleem AM, Martins C, Yuan Z, Qiao C, et al. Single intra-articular injection of adeno-associated virus results in stable and controllable in vivo transgene expression in normal rat knees. Osteoarthritis Cartilage. 2011;19: 1058-1065.
- Santangelo KS, Bertone AL. Effective reduction of the interleukin-1ß transcript in osteoarthritis-prone guinea pig chondrocytes via short hairpin RNA mediated RNA interference influences gene expression of mediators implicated in disease pathogenesis. Osteoarthritis Cartilage. 2011;19: 1449-1457.
- Ishihara A, Bartlett JS, Bertone AL. Inflammation and immune response of intra-articular serotype 2 adeno-associated virus or adenovirus vectors in a large animal model. Arthritis. 2012; 2012: 735472.
- Mason JB, Vandenberghe LH, Xiao R, Wilson JM, Richardson DW. Influence of serotype, cell type, tissue composition, and time after inoculation on gene expression in recombinant adeno-associated viral vector-transduced equine joint tissues. Am J Vet Res. 2012; 73: 1178-1185.
- Santangelo KS, Nuovo GJ, Bertone AL. In vivo reduction or blockade of interleukin-1β in primary osteoarthritis influences expression of mediators implicated in pathogenesis. Osteoarthritis Cartilage. 2012; 20: 1610-1618.
- Venkatesan JK, Ekici M, Madry H, Schmitt G, Kohn D, Cucchiarini M. SOX9 gene transfer via safe, stable, replication-defective recombinant adeno-associated virus vectors as a novel, powerful tool to enhance the chondrogenic potential of human mesenchymal stem cells. Stem Cell Res Ther. 2012; 3: 22-36.
- Weimer A, Madry H, Venkatesan JK, Schmitt G, Frisch J, Wezel A. Benefits of recombinant adeno-associated virus (rAAV)-mediated insulinlike growth factor I (IGF-I) overexpression for the long-term reconstruction of human osteoarthritic cartilage by modulation of the IGF-I axis. Mol Med. 2012; 18: 346-358.
- Cucchiarini M, Orth P, Madry H. Direct rAAV SOX9 administration for durable articular cartilage repair with delayed terminal differentiation and hypertrophy in vivo. J Mol Med (Berl). 2013; 91: 625-636.
- Goodrich LR, Phillips JN, McIlwraith CW, Foti SB, Grieger JC, Gray SJ. Optimization of scAAVIL-1ra In Vitro and In Vivo to Deliver High Levels of Therapeutic Protein for Treatment of Osteoarthritis. Mol Ther Nucleic Acids. 2013; 2: e70.
- Kyostio-Moore S, Bangari DS, Ewing P, Nambiar B, Berthelette P, Sookdeo C, et al. Local gene delivery of heme oxygenase-1 by adeno-associated virus into osteoarthritic mouse joints exhibiting synovial oxidative stress. Osteoarthritis Cartilage. 2013;21: 358-367.
- Lee HH, O'Malley MJ, Friel NA, Payne KA, Qiao C, Xiao X. Persistence, localization, and external control of transgene expression after single injection of adeno-associated virus into injured joints. Hum Gene Ther. 2013; 24: 457-466.
- Madry H, Kohn D, Cucchiarini M. Direct FGF-2 gene transfer via recombinant adeno-associated virus vectors stimulates cell proliferation, collagen production, and the repair of experimental lesions in the human ACL. Am J Sports Med. 2013; 41: 194-202.
- Venkatesan JK, Rey-Rico A, Schmitt G, Wezel A, Madry H, Cucchiarini M. rAAV-mediated overexpression of TGF- ß stably restructures human osteoarthritic articular cartilage in situ. J Transl Med. 2013; 11: 211.
- Watson RS, Broome TA, Levings PP, Rice BL, Kay JD, Smith AD. scAAV-mediated gene transfer of interleukin-1-receptor antagonist to synovium and articular cartilage in large mammalian joints. Gene Ther. 2013; 20: 670-677.
- Cucchiarini M, Madry H2. Overexpression of human IGF-I via direct rAAV-mediated gene transfer improves the early repair of articular cartilage defects in vivo. Gene Ther. 2014;.
- Evans CH, Ghivizzani SC, Robbins PD. Getting arthritis gene therapy into the clinic. Nat Rev Rheumatol. 2011; 7: 244-249.
- Ha CW, Noh MJ, Choi KB, Lee KH. Initial phase I safety of retrovirally transduced human chondrocytes expressing transforming growth factor-beta-1 in degenerative arthritis patients. Cytotherapy. 2012;14: 247-256.