Role of gene therapy in tissue engineering procedures in rheumatology: the use of animal models

Abstract

Tissue engineering is not only the application of cells and scaffolds to generate a new tissue but should also bring into play biological principles to guide cellular behavior. A way to modify cellular behavior is genetic modification of the cells used for tissue engineering (gene therapy). In the field of rheumatic diseases, cellular modification by overexpressing anabolic factors, such as insulin-like growth factor-I or transforming growth factor β, or inhibitors of catabolic cytokines or proteolytic enzymes can protect tissues form further destruction and stimulate tissue repair. To test the effect of transgenes on tissue engineering adequate test systems have to be available. Initial testing can be done in simple in vitro systems. However, animal models are unavoidable to study the interaction between the environment and tissue engineering. Optimal models to study gene therapy in combination with tissue engineering in the field of rheumatology are not available at this moment. Arthritis models are mainly developed in small animals while high-quality tissue engineering experiments ask for a large animal model. Development of animal models that can be used for tissue engineering experiments and mimic end stage arthritic diseases is needed.

Introduction

In general tissue engineering is regarded, in a strict sense, as the application of a scaffold in combination with embedded cells to generate a new tissue or organ. However, tissue engineering in broad sense is not only application of scaffolds and cells but also the exploitation of all suitable biological principles to guide cellular behavior to produce new and healthy tissues. As a consequence of this the use of cell and gene therapy will obtain its place in the future development of tissue engineering. Application of gene therapy to control cellular behavior has a number of advantages above conventional, protein-based therapies. Advantages of genetic modification of cells in comparison with protein delivery are, amongst others, the following. The transfected, genetically modified cells will be exposed to the highest transgene concentrations, relatively little spill to the surrounding tissues will occur. Expression of the desired transgene is prolonged but not endlessly while added recombinant proteins have relatively short half-lives in vivo and often require high doses or repeated injections. Transgenes do not have to be produced in large amounts with recombinant expression technology. Transgene production can be regulated by the use of controllable or physiology-driven promoters.

In this paper we will focus on the application of gene therapy in the context of tissue engineering to provide an optimal setting for tissue regeneration and the (future) use of animal models of rheumatoid and osteoarthritis in this field.

Rheumatoid arthritis is a severe and chronic disabling joint disease of unknown etiology [1]. This disease is determined by a long-lasting inflammation of the synovial tissue in the joint and concomitant joint destruction. During the chronic arthritis inflammatory cells such as macrophages and lymphocytes invade the subsynovial tissue while the joint space is infiltrated with macrophages, lymphocytes and numerous polymorphonuclear leucocytes. The persistent arthritis results in a continuous release of catabolic cytokines and proteolytic enzymes, which results in damaged cartilage, bone and other joint structures and eventually a loss of joint function. The actual initiator of rheumatoid arthritis is still unknown but a number of important players in the pathology of this disease, such as interleukin-1 (IL-1) and tumor necrosis factor α (TNFα), have been detected. The application of cell and gene therapies in rheumatoid arthritis will be focused on the inhibition of joint inflammation, the further reduction of joint destruction and eventually repair of damaged joint tissues.

Osteoarthritis is the commonest condition to affect joints and is primarily a disease of the articular cartilage of diarthrodal joints with secondary, sometimes moderate, synovial inflammation [2]. Pathology is characterized by destruction of the articular cartilage. Like with rheumatoid arthritis, the initial cause and driving force of this disease are unknown in most cases. However, frequently aberrant biomechanical loading of the articular cartilage is involved in the initiation of this disease and a number of animal models are based on this principle. In contrast to rheumatoid arthritis, which is predominantly characterized by catabolic processes in the joint, in osteoarthritis also anabolic processes take place. During the early phase of osteoarthritis cartilage matrix molecules are synthesized at an elevated rate and other features, such as sclerosis of subchondral bone and osteophytosis, also point to a (failing) repair process in this disease. The application of cell and gene therapy in osteoarthritis is directed at the protection of cartilage from further destruction and the stimulation of the repair process in this tissue.