Current Drug Targets - Volume 11, Issue 5, 2010

Osteoarthritis is among the most common pathological conditions in archeological skeletal collections and is the most frequent musculoskeletal disorder in contemporary populations [1]. Worldwide, symptomatic osteoarthritis affects 9.6% of men and 18.0% of women aged over 60 years (http://www.who.int/chp/topics/rheumatic/en/ WHO Chronic Rheumatic Conditions). As of 2005, 27 million Americans had clinical osteoarthritis [2]. It is second to heart disease as the predominant cause of functional decline in the elderly and overall costs approximately 0.7% of the US gross domestic product [3]. These may be gross underestimates as recent analyses suggest that OA in the developed world may be under-diagnosed by 90% [4]. By the year 2020, when one out of every two Americans will be over the age of 50, the Centers for Disease Control forecasts that there will be a larger increase in new cases of arthritis than of any other disease in the United States (http://www.hss.edu/ conditions_14135.asp). Given these statistics, it is surprising that a national and even global sense of urgency is lacking regarding the need for definitive disease modifying osteoarthritis therapies. The state of the public perception of osteoarthritis is not unlike that of malaria in the year 1800. Malaria at that time was the most common illness on the American frontier but considered ‘a part of life, like hard work’. Many refused to regard it as a disease [5]. Although osteoarthritis researchers recognize that the designation ‘osteoarthritis’ encompasses a common endstage of many subforms of disease with different etiologies (genetic, injury, and metabolic, among others), the predominant medical and public perception persists of osteoarthritis as a “wear-andtear” phenomenon and inevitable consequence of aging. Without a sense of urgency, how are we to arrive at the goal of discovering and validating remittive therapies for osteoarthritis and get beyond the perception that osteoarthritis is an inevitable consequence of aging? On the other hand, is a sense of urgency called for when we can't do anything about it? This ‘catch 22’ can only be overcome by deliberately and steadfastly tackling the many barriers to achieving a cure, not the least of which are barriers in the minds of osteoarthritis researchers and drug developers themselves. The papers in this edition elucidate recent science related to many tractable osteoarthritis targets for development of agents that could be delivered either systemically or intra-articularly. In addition, here I would like to draw three analogies to other chronic diseases to highlight the need for new conceptions of osteoarthritis, with the hope that this paradigm could promote the transformation of osteoarthritis into an actionable disease for which more than palliative therapies could be available. First, consider the fact that osteoarthritis is one of many distinguished silent killers that work insidiously, often over decades, to finally kill an organ. In the case of osteoarthritis, it is the joint organ. Parallels with other silent killers include the killer of bones - osteoporosis; the killer of multiple organs including the brains and kidneys - hypertension; and the killer of hearts - atherosclerotic coronary artery disease (Fig. 1). Viewed through the lens of this paradigm, osteoarthritis would seem eminently amenable to treatment given the success to date developing definitive therapy to prevent and treat these other major chronic disease entities and silent killers.

Osteoarthritis, the degeneration of the joints, is the leading source of physical disability with severely impaired quality of life due to pain and loss of joint functioning in industrialized nations. Clinically, degeneration affects mostly the large weight bearing joints of the legs like the hip or the knees, but in principle it can affect any joint of the body. Osteoarthritis represents a disease group with disease subsets that have different underlying pathophysiological mechanisms. Therefore primary osteoarthritis has to be distinguished from secondary forms of the disease, which are due to traumatic events, endocrine or metabolic disorders etc. The enormous frequency of this disease makes osteoarthritis one of the most expensive conditions in the Western world, both in terms of direct as well as indirect costs. So far, despite intensive efforts over several decades, the success of disease-modifying approaches have been rather limited and mostly restricted to analgesis and non-pharmacologic therapy (e.g. nonsteroidal anti-inflammatory agents, exercise, and physiotherapy). Joint replacement is still the unsurpassed therapy for the symptomatic relief of advanced and incapacitating OA. It is evident that there is a great need for the development of disease modifying agents in order to improve quality of life as well as to relieve the community of the enormous socio-economic burden of the disease.

Osteoarthritis (OA) is a slowly, progressive, ultimately degenerative disorder of movable joints, mainly characterized by joint pain and functional limitation and affecting all joint structures not just articular cartilage, but also the subchondral bone, ligaments, capsule, synovial membrane, and menisci. OA occurs when the equilibrium between breakdown and repair of the joint tissues becomes unbalanced. There are currently no pharmacological interventions available to patients for modifying the underlying disease (DMOADs) in relation to major drug development challenges. The current regulatory draft guidances for clinical development programs for DMOAD agents suggest radiographic joint space narrowing (JSN) as a primary endpoint. However, research efforts must continue to characterize imaging alternatives with greater sensitivity to change to enable development of new DMOADs. Past experience with DMOAD clinical trials indicate that pharmacologic agents must demonstrate pristine safety, and that consideration for special populations is important to avoid failed studies. More research is needed to determine what constitutes clinically meaningfulness for DMOAD activity in particular as it relates to OA progression. Current research pursues a variety of molecular targets including anti-catabolic agents to slow or halt OA progression and anabolic drugs to induce cartilage regrowth.

This narrative review outlines the work done in other fields with regards biomarker validation and qualification and the lessons that we may learn from this experience. Defining a universally agreed upon path for biomarker validation and qualification is urgently needed to circumvent many of the hurdles faced in OA therapeutic development irrespective of whether we are discussing biochemical markers, imaging markers or other measures. This review proposes a path that may be suitable for osteoarthritis and poses some logical next steps that will take us in this direction.

To date, no targeted treatments for osteoarthritis have been developed. Therefore the challenge for the next years is to find a treatment that may slow down the progression of the disease. Osteoarthritis of the weight-bearing joints, such as knee OA, is more a local mechanical driven disease than a generalized one. To reach a non-vascularised tissue such as the cartilage, local intra-articular administration of drugs should be considered. The purpose of this review is to evaluate the advantages of local intra-articular drug administration compared with a systemic one in patients with osteoarthritis of weight-bearing joints. New perspectives of such strategy are reviewed, including anti-cytokine therapy, gene therapy, delivery of growth factors, stem cells therapy and new lubricant agents such as lubricin. The main goal in the future will be to increase the residence time of the drug in the joint while improving its diffusion within the target tissue. One key question will be how to better define the patients likely to benefit by such an approach and when the treatment is most likely to work. Most importantly, the treatment strategy must be selected according to the pattern in an individual patient. Finally, with all intra-articular treatments, the risk/benefit ratio must be carefully evaluated.

Progressive cartilage degradation is considered a hallmark of osteoarthritis (OA), and as such, methods to inhibit this process have been extensively investigated as potential disease-modifying therapies. However, all tissues of the joint are affected by disease in OA, and it is likely that the pain and disability which are the major clinical symptoms of OA, arrise predominantly from pathology in these extra-cartilaginous structures. It is unclear therefore, whether specifically targeting inhibition of cartilage matrix breakdown will ameliorate global joint pathology and thereby affect the clinically-relevant OA-related disability. We have investigated this question by reviewing the literature and data available from studies of genetically-modified (GM) mice. A total of 79 different GM strains were identified in which OA-like cartilage erosion was analysed, 53 with increased, 18 with no change, and 8 with decreased cartilage damage. Inhibition of OA cartilage damage was afforded by mutations that either reduced chondrocyte hypertrophy or abrogated proteolysis of aggrecan and collagen II in cartilage. There was an association between increased cartilage breakdown and changes in subchondral bone, osteophytosis and synovial hyperplasia in GM mice. However, the effect of significantly inhibiting cartilage damage on pathology in other joints tissues has been less well examined. There appeared to be no diminution of osteophyte development in chondroprotected GM mice strains, but a possible reduction in subchondral bone plate changes. To date, there is no conclusive data on the effect of inhibiting cartilage breakdown on clinical signs of OA in GM mice. These studies have highlighted the tremendous advances studies of GM mice have afforded us in understanding the pathophysiology of cartilage degradation in OA. Furthermore they demonstrate the feasibility of targeting cartilage matrix destruction. However, it is evident that an important direction for ongoing research will be to determine the effect of successful protection of cartilage structural integrity on pathology in other tissues in the OA joint, and the clinical signs of the disease.

The great success of targeted biologic therapy against rheumatoid arthritis (RA) in recent years has meant that much research has been devoted to investigating the pathophysiology of osteoarthritis (OA) in the hope of defining novel therapeutic targets. In contrast to RA, with its pannus and erosions, OA has long been thought of as a degenerative disease of cartilage, with secondary bony damage and osteophytes. But in recent years, the importance of the synovium, and in particular the synovial macrophages, in OA, has been highlighted in both in vitro and in vivo studies. This review will discuss the potential of synovial macrophages and their mediators, in particular the proinflammatory cytokines tumour necrosis factor α and interleukin-1, as potential therapeutic targets in OA.

Obesity is one of the main risk factors for osteoarthritis (OA). For many years the association of obesity and OA has been simply attributed to the effects of overload on weight-bearing joints, and epidemiological surveys have shown a strict correlation between an increased body mass index and the severity of knee or hip OA, as well as some relief of pain and disability following weight loss. Instead, there is now a growing body of evidence that obesity is a complex syndrome in which an abnormal activation of neuroendocrine and pro-inflammatory pathways leads to an altered control of food intake, fat expansion and metabolic changes. Activated white adipose tissue increases the synthesis of pro-inflammatory cytokines, such as IL-6, IL-1, IL-8, TNFα, IL-18, while regulatory cytokines, such as IL-10, are decreased. Adipocytes also produce peculiar cytokines, namely adipokines, that exert multiple effects, being capable of promoting synovial inflammation, cartilage degrading enzymes, and bone matrix remodeling. Furthermore, pro-inflammatory cytokines stimulate adipocytes to synthesize neuropeptides, such as substance P and nerve growth factor, that have been shown to be critical in regulating both the appetite and cartilage homeostasis. In this scenario, where the influence of obesity on OA stems from a complex interaction of genetic, metabolic, neuroendocrine, and biomechanical factors, there may be various different potential targets for OA therapy.

In the context of OA disease, NF-κB transcription factors can be triggered by a host of stress-related stimuli including pro-inflammatory cytokines, excessive mechanical stress and ECM degradation products. Activated NF-κB regulates the expression of many cytokines and chemokines, adhesion molecules, inflammatory mediators, and several matrix degrading enzymes. NF-κB also influences the regulated accumulation and remodeling of ECM proteins and has indirect positive effects on downstream regulators of terminal chondrocyte differentiation (including β-catenin and Runx2). Although driven partly by pro-inflammatory and stress-related factors, OA pathogenesis also involves a “loss of maturational arrest” that inappropriately pushes chondrocytes towards a more differentiated, hypertrophic-like state. Growing evidence points to NF-κB signaling as not only playing a central role in the pro-inflammatory stress-related responses of chondrocytes to extra- and intra-cellular insults, but also in the control of their differentiation program. Thus unlike other signaling pathways the NF-κB activating kinases are potential therapeutic OA targets for multiple reasons. Targeted strategies to prevent unwanted NF-κB activation in this context, which do not cause side effects on other proteins or signaling pathways, need to be focused on the use of highly specific drug modalities, siRNAs or other biological inhibitors that are targeted to the activating NF-κB kinases IKKα or IKKβ or specific activating canonical NF- κB subunits. However, work remains in its infancy to evaluate the effects of efficacious, targeted NF-κB inhibitors in animal models of OA disease in vivo and to also target these strategies only to affected cartilage and joints to avoid other undesirable systemic effects.

Therapeutic alleviation of the pathophysiology of osteoarthritis (OA) is a great and unmet medical challenge. At the basic science level, significant progress has facilitated the identification of distinct pathways and targets which appear to be central to the OA-associated deterioration of articular cartilage. For example, the dysregulated activities of aggrecanases such as ADAMTS-4 and ADAMTS-5, and collagenases such as MMP-13, point to strategies for the development of selective protease inhibitors to curtail OA disease progression. Likewise, blockade of disease-associated “pro-catabolic” cytokines may offer promising opportunities in this regard. Other novel biotherapeutic approaches are also emerging, including the use of recombinant lubricin molecules for intraarticular supplementation. Expression profiling of cartilage (and other joint tissues) to identify OA-associated genes continues to yield new potential therapeutic options, including the ‘upstream’ targeting of key intracellular regulators. Moving forward into the clinic, the critical evaluation and optimization of modalities for therapeutic delivery, as well as the availability and utility of appropriate disease biomarkers and ability to determine relevant patient populations, will be other important considerations in directing the advancement of novel OA therapies.

Recent evidence from animal experiments and clinical samples points at a role for Wnt-signaling in osteoarthritis (OA) pathology. These pathways are key inducers and regulators of joint development, and are involved in formation of bone, cartilage and also synovium. Disregulation of members from this pathways has been described in OA. This makes the Wnt-family of proteins and signaling pathways an attractive target for therapy. Although knowledge is increasing rapidly it is still a challenge to decide on the best approach in targeting Wnt signaling. Activation of the canonical signaling pathway, which features intra-cellular accumulation of β-catenin, is most often implicated in recent studies in OA pathology, in experimental OA and spondyloarthritis. However, direct targeting of β-catenin is anticipated to be too hazardous, because of its importance for the maintenance of stability of articular chondrocyte phenotype and because of its proven role in carcinogenesis. A more attractive approach will be identifying the misexpression of specific Wnt-proteins or their inhibitors in various tissues that are important in OA, bone, cartilage and synovium, to point out targets for therapy. For example, recently it was shown that Wnt16 is strongly upregulated in cartilage after injury and in synovium in experimental OA, and the expression of this canonical Wnt may be responsible for OA-like changes. Alternatively, identifying more down stream Wnt signaling effector molecules, like WISP-1, for more specific therapy promises to be a safer and more efficient approach to find a treatment for this disease that heavily constrains millions of people each year.

High myopia affects approximately 2% of general population, and is a major cause of legal blindness in many developed countries. Choroidal neovascularization (CNV) is the most common vision-threatening complication of high myopia. Different therapeutic approaches have been attempted such as thermal laser photocoagulation, surgery and photodynamic therapy with verteporfin (PDT). The visual outcome of these therapies has been reported to be better than the natural history of the condition. However, the limited visual acuity improvement after PDT monotherapy and the appearance of subretinal fibrosis and chorioretinal atrophy prompted the association of other therapies. In the past few years a tremendous advance in the knowledge of the mechanisms underling CNV secondary to high myopia and age related macular degeneration has been achieved, leading to new therapeutic targets and novel drugs and combined therapies. These new therapeutic weapons have been designed to achieve a selective shut down of choroidal new vessels. Recent reviews have been published on the natural history and therapies for myopic CNV. Ohno-Matsui reported on the natural history of the condition as well as the outcome of laser photocoagulation, surgical extraction of CNV, foveal translocation and photodynamic therapy on myopic CNV in the short-term [1]. Soubrane et al. reviewed the new advances on surgery, laser photocoagulation and PDT, considering some of the potential effects of triamcinolone, pegaptanib and ranibizumab in CNV secondary to age related macular degeneration (AMD) [2]. Novack et al. reported on the pharmacological therapy of CNV in AMD [3]. The aim of this review is to summarize the recent advances in myopic CNV pathophysiology and the new therapeutic targets and drugs that are changing the clinical management of myopic CNV.

Interleukin (IL)-21, a cytokine mostly produced by activated CD4+ T cells, has been reported to play an important role in the tissue-damaging immune response in various organs. This pathogenic effect is strictly linked to the ability of IL-21 to control the functional activities of multiple immune and non-immune cells. For instance, IL-21 regulates the differentiation and function of effector CD4+ T helper cells, controls activation, proliferation, and survival of B cells and enhances the cytotoxic activity of CD8+ T cells and NK cells. IL-21 also inhibits the differentiation of inducible regulatory T cells (Tregs), while making effector CD4+ T cells resistant to the Tregs-mediated immunosuppression. Additionally, IL-21 stimulates epithelial cells and fibroblasts to make chemokines and extracellular matrix proteases, respectively. Consistently, studies from various laboratories have documented the beneficial effect of IL-21 neutralization on the progression of inflammatory diseases in mice. Here we review the present knowledge on the expression and role of IL-21 in immune-mediated pathologies.