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Advanced Drug Delivery Reviews (v.58, #2)

Editorial Board (pp. ii).

Drug delivery in degenerative joint disease by Thomas Aigner Theme editor; Nicole Gerwin Theme editor (pp. 123-124).

Drug delivery in degenerative joint disease: Where we are and where to go? by Steven Abramson (pp. 125-127).

Drug discovery and delivery to retard the degeneration of joint tissues are challenging. Current treatment is generally inadequate. This commentary places in perspective the inadequacy characteristic of existing therapeutics and the promising developments embodied in the newer therapeutics administered via the oral or intra-auricular routes.

Keywords: Osteoarthritis; Pain management; Toxicity

Osteoarthritis: Pathobiology—targets and ways for therapeutic intervention by T. Aigner; A. Sachse; P.M. Gebhard; H.I. Roach (pp. 128-149).

Osteoarthritis is first and foremost the ongoing destruction of the articular cartilages of joints. Therefore, the extracellular matrix and the cells of the articular cartilages are the primary targets of osteoarthritis therapy. This tries to inhibit enzymatic destruction of the extracellular cartilage matrix as well as the modification of the cellular phenotype of the chondrocytes: cell degeneration and cell death are alongside anabolic activation and stabilization of the cellular phenotype of major interest. However, apart from the cartilage and its cells, other tissues of the joints are also important for the symptoms of the disease, which basically all originate outside the articular cartilage. In addition, changes in the subchondral bone as well as the synovial capsule and membrane are important at least for the progression of the disease process.All the named tissues offer different directions and ways for therapeutic intervention.

Keywords: Cartilage; Drugs; Joints; Chondrocytes; Senescence; Cartilage regeneration

Osteoarthritis by Joseph A. Buckwalter; James A. Martin (pp. 150-167).

Osteoarthritis (OA), the syndrome of joint pain and dysfunction caused by joint degeneration, affects more people than any other joint disease. In most instances joint degeneration develops in the absence of an identifiable cause, but increasing age, excessive joint loading, and joint abnormalities and insults increase the risk of OA. Articular surface contact stress that causes tissue damage and compromises that ability of chondrocytes to maintain and restore the tissue has an important role in the development of joint degeneration Current methods of attempting to restore an articular surface in osteoarthritic joints include penetrating subchondral bone, altering joint loading, osteotomies and insertion of soft tissue grafts. Dramatic advances in the prevention and treatment of OA are likely to stem from better understanding of the role of mechanical forces in the initiation and progression of joint degeneration.

Keywords: Articular cartilage; Osteoarthritis; Joint loading; Joint degeneration

Oral treatment options for degenerative joint disease—presence and future by Jürgen Steinmeyer; Yrjö T. Konttinen (pp. 168-211).

Alleviation of pain and inhibition of inflammation are the primary goals of pharmacotherapy of osteoarthritis (OA). These therapeutic goals can almost always be accomplished by the use of analgesics and nonsteroidal anti-inflammatory drugs (NSAID). One of the main problems of NSAIDs is their gastrointestinal toxicity, for which a prophylactic medication should be considered particularly amongst risk groups. Recent studies have shown that COX-2-selective and maybe also non-selective NSAIDs increase the cardiovascular risk so that their application is getting now drastically restricted. Pharmacological results published until now suggest that a clinically relevant minor analgesic and/or anti-inflammatory effect can be attained with the use of some of the SYmptomatic Slow Acting Drugs in OA (SYSADOAs). However, no clinical studies exist, which can positively confirm prevention, slowing down or reversal of any advanced joint cartilage destruction by any individual medication. Disease modifying therapy is still in its infancy; discovery and development of novel therapeutic targets and agents are an extremely difficult task, currently challenging many pharmaceutical companies and academic institutions.

Keywords: Osteoarthritis; Pharmacotherapy; Analgesics; SADOA; NSAID; MMP; COX

Biologics in development for rheumatoid arthritis: Relevance to osteoarthritis by Steven B. Abramson; Yusuf Yazici (pp. 212-225).

The osteoarthritis disease process affects not only the cartilage but also the entire joint structure, including the synovium, bone and periarticular muscles. Characteristically, abnormal biomechanical forces result in an imbalance between chondrocyte anabolic and catabolic pathways, which ultimately leads to progressive joint destruction. Within cartilage and synovium, pro-inflammatory cytokines, particularly IL-1b and TNF-a, auto-catalytically stimulate their own production and induce chondrocytes to produce additional catabolic mediators, including proteases, chemokines, nitric oxide, and prostaglandins. The success of targeted biological therapy in rheumatoid arthritis has taught that the blockade of a single dominant cytokine can lead to remarkable clinical benefit, even in complex disease. The effectiveness of biologicals in inflammatory arthritides as disease modifying agents has increased the likelihood that similar strategies can be developed to target specific molecular mechanisms in osteoarthritis (OA). However, since the clinical development program for disease-modifying OA drugs (DMOADs) is complicated by the slow progression of disease in many patients, the introduction of DMOADs will be greatly enhanced by advances in imaging and biomarkers that serve as validated surrogate endpoints for meaningful clinical outcomes.

Keywords: Osteoarthritis; Cartilage; Structure modification; Biomarkers; DMOADs; Cytokines; Biologics

Intraarticular drug delivery in osteoarthritis by Nicole Gerwin; Caroline Hops; Andrea Lucke (pp. 226-242).

Osteoarthritis (OA) is a primarily non-inflammatory, degenerative joint disease characterized by progressive loss of articular cartilage, subchondral bone sclerosis, osteophyte formation, changes in the synovial membrane, and an increased volume of synovial fluid with reduced viscosity and hence changed lubrication properties. As OA is the most common type of arthritis and a leading cause of disability, there is a largely unmet medical need for disease-modifying and symptomatic treatment. Due to the localized nature of the disease, intraarticular (IA) drug injection is an attractive treatment approach for OA. The various glucocorticoid and hyaluronic acid (HA) formulations, which are currently available on the market for IA treatment, provide only short-term pain relief or/and often do not provide adequate pain relief. The available oral drugs for symptomatic treatment also have shortcomings, most notably side effects. Therefore, there is still a large unmet need for novel OA drugs, which provide effective long-term pain relief and/or have disease-modifying properties. To achieve long-term drug exposure, different established formulations such as suspensions and hydrogels, and also novel approaches such as lipid based formulations and nano- or microparticles are currently in development. The development of novel drugs in combination with new formulations for IA treatment of OA, represents a promising approach in this challenging area of research.

Keywords: Osteoarthritis; Intraarticular; Sustained release; Hyaluronic acid; Glucocorticoid

Gene therapeutic approaches—transfer in vivo by C.H. Evans; E. Gouze; J.-N. Gouze; P.D. Robbins; S.C. Ghivizzani (pp. 243-258).

Osteoarthritis (OA) is common, debilitating, expensive, incurable and very difficult to treat. Gene transfer to the synovial linings of affected joints is a promising strategy for achieving sustained, therapeutic, intraarticular concentrations of anti-arthritic gene products. This is not reasonably possible with existing, alternative technologies. The present review summarizes progress in achieving direct, in vivo intraarticular gene delivery and expression. Numerous non-viral vectors have been evaluated for their ability to transfect the synovia of experimental animals following intraarticular injection. None have given more than low levels of temporary transgene expression and many are inflammatory. Several viral vectors, however, are very effective in this regard and successfully treat experimental models of OA. Adeno-associated virus has been used in a phase I study for the gene therapy of rheumatoid arthritis. Its use in a clinical trial for treating OA is pending.

Keywords: Synovium; Chondrocyte; Virus vectors; Gene therapy; Arthritis

Ex vivo gene therapy approaches to cartilage repair by K. Gelse; H. Schneider (pp. 259-284).

Degeneration of articular cartilage is one of the great clinical challenges that still lack a convincing therapeutic solution. Traumatically induced lesions and final stages of osteoarthritis with substantial loss of cartilage tissue require the generation of new hyaline cartilage, because significant endogenous repair does not occur. Current joint-preserving surgical approaches, however, mostly lead to fibrous repair tissue that is rapidly degraded. In experimental studies, several differentiation factors have been shown to stimulate chondrogenesis, promoting the formation of functionally acceptable cartilage-like repair tissue. Cell-mediated transfer of the respective genes may ideally combine the supply of a chondrogenic cell population with the production of such factors directly at the site of the lesion. The treatment of earlier disease stages aims both at the protection of the remaining cartilage from further degradation and a stimulation of cartilage anabolism. Various studies proved the administration of anti-catabolic or anti-inflammatory cytokines into joints affected by cartilage destruction to be beneficial. However, the clinical utility of intraarticular protein application is limited by the short half-lives of such proteins in vivo. The transfer of cells over-expressing the respective genes may provide a more sustained delivery of the therapeutic molecules and thus be the more economic option.

Keywords: Gene transfer; Differentiation factors; Cytokines; Osteoarthritis; Cartilage repair; Tissue engineering; Mesenchymal stem cells

Antisense strategies in degenerative joint diseases: Sense or nonsense? by Lars C. Huber; Oliver Distler; Renate E. Gay; Steffen Gay (pp. 285-299).

Oligodeoxynucleotides, ribozymes, and RNA interference make part of the antisense strategy, a new tool proposed to conquer cancer, viral infections, as well as cardiovascular and rheumatic diseases. The silencing effect of antisense strategies is both highly specific and potent – and only requires that the sequence of the target RNA is known. However, so far neither RNAi nor ribozymes have been approved for clinical use and only a single antisense agent is on the market.In the context of degenerative joint diseases, experimental data in the field of antisense strategies are still rare. Several studies from rheumatoid arthritis (RA), an inflammatory condition that leads to the progressive destruction of cartilage and bone within affected joints, however revealed promising results and taught us important lessons that might also be useful in therapeutic approaches for osteoarthritis (OA). To introduce these therapies in clinical practice, however, several hurdles still have to be overcome.

Keywords: Oligodeoxynucleotides; RNAi; Ribozymes; Drug design; Cartilage destruction; Osteoarthritis; Rheumatoid arthritis

Cartilage tissue engineering for degenerative joint disease by Dobrila Nesic; Robert Whiteside; Mats Brittberg; David Wendt; Ivan Martin; Pierre Mainil-Varlet (pp. 300-322).

Pain in the joint is often due to cartilage degeneration and represents a serious medical problem affecting people of all ages. Although many, mostly surgical techniques, are currently employed to treat cartilage lesions, none has given satisfactory results in the long term. Recent advances in biology and material science have brought tissue engineering to the forefront of new cartilage repair techniques. The combination of autologous cells, specifically designed scaffolds, bioreactors, mechanical stimulations and growth factors together with the knowledge that underlies the principles of cell biology offers promising avenues for cartilage tissue regeneration. The present review explores basic biology mechanisms for cartilage reconstruction and summarizes the advances in the tissue engineering approaches. Furthermore, the limits of the new methods and their potential application in the osteoarthritic conditions are discussed.

Keywords: Cartilage; Tissue engineering; Osteoarthritis; Chondrocytes; Mesenchymal stem cells; Scaffolds; Bioreactors

Pathophysiology and treatment of pain in joint disease by Hans-Georg Schaible; Martin Schmelz; Irmgard Tegeder (pp. 323-342).

Deep somatic pain originating in joints and tendons is a major therapeutic challenge. Spontaneous pain and mechanical hypersensitivity can develop as a consequence of sensitization of primary afferents directly involved in the inflammatory process, but also following sensitization of neuronal processing in the spinal cord (central sensitization) or higher centres. Inflammatory pain is linked to sensitization of sensory proteins at the nociceptive endings whereas pain originating from nerve damage (neuropathic pain) has been linked to changes in axonal ion channels producing ectopic discharge in nociceptors as a source of pain. New targets for analgesic therapy include sensory proteins at the nociceptive nerve endings such as the activating TRPV and ASIC channels, but also inhibitory opioid and cannabinoid receptors. Therapeutic targets are also found among the axonal channels that set membrane potential and modulate discharge frequency such as voltage sensitive sodium channels and various potassium channels.

Keywords: Opioids; Prostaglandin; TRPV; CB; ASIC; Sensitization; Hypersensitivity; Nociception

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Advanced Drug Delivery Reviews (v.58, #2)