Disease Modification In Osteoarthritis Research Articles

Disease modification and symptom relief in osteoarthritis using a mutated GCP-2/CXCL6 chemokine.

We showed that the chemokine receptor C-X-C Motif Chemokine Receptor 2 (CXCR2) is essential for cartilage homeostasis. Here, we reveal that the CXCR2 ligand granulocyte chemotactic protein 2 (GCP-2) was expressed, during embryonic development, within the prospective permanent articular cartilage, but not in the epiphyseal cartilage destined to be replaced by bone. GCP-2 expression was retained in adult articular cartilage. GCP-2 loss-of-function inhibited extracellular matrix production. GCP-2 treatment promoted chondrogenesis invitro and in human cartilage organoids implanted in nude mice invivo. To exploit the chondrogenic activity of GCP-2, we disrupted its chemotactic activity, by mutagenizing a glycosaminoglycan binding sequence, which we hypothesized to be required for the formation of a GCP-2 haptotactic gradient on endothelia. This mutated version (GCP-2-T) had reduced capacity to induce transendothelial migration invitro and invivo, without affecting downstream receptor signaling through AKT, and chondrogenic activity. Intra-articular adenoviral overexpression of GCP-2-T, but not wild-type GCP-2, reduced pain and cartilage loss in instability-induced osteoarthritis in mice. We suggest that GCP-2-T may be used for disease modification in osteoarthritis.

Recent Advances in Pharmacological Intervention of Osteoarthritis: A Biological Aspect.

Osteoarthritis (OA) is a degenerative joint disease in the musculoskeletal system with a relatively high incidence and disability rate in the elderly. It is characterized by the degradation of articular cartilage, inflammation of the synovial membrane, and abnormal structure in the periarticular and subchondral bones. Although progress has been made in uncovering the molecular mechanism, the etiology of OA is still complicated and unclear. Nevertheless, there is no treatment method that can effectively prevent or reverse the deterioration of cartilage and bone structure. In recent years, in the field of pharmacology, research focus has shifted to disease prevention and early treatment rather than disease modification in OA. Biologic agents become more and more attractive as their direct or indirect intervention effects on the initiation or development of OA. In this review, we will discuss a wide spectrum of biologic agents ranging from DNA, noncoding RNA, exosome, platelet-rich plasma (PRP), to protein. We searched for key words such as OA, DNA, gene, RNA, exosome, PRP, protein, and so on. From the pharmacological aspect, stem cell therapy is a very special technique, which is not included in this review. The literatures ranging from January 2016 to August 2021 were included and summarized. In this review, we aim to help readers have a complete and precise understanding of the current pharmacological research progress in the intervention of OA from the biological aspect and provide an indication for the future translational studies.

Disease modification in osteoarthritis; pathways to drug approval

To summarize proceedings of a workshop convened to discuss advances in disease modifying osteoarthritis (OA) drugs and regulatory challenges in bringing these drugs to market. Summary of a one day workshop held in Washington, DC in May 2019. Attendees presented data documenting the prevalence, cost and disability burden of OA; recent documentation of disease modification without concomitant clinical benefit in trials of disease modifying drugs; regulatory considerations pertinent to disease modifying therapy; and methodologic approaches to addressing these regulatory considerations. The research, pharmaceutical and regulatory communities must continue to collaborate on defining pathways for approval of disease modifying osteoarthritis drugs that document effects on clinical endpoints (such as pain, function or joint replacement) as well as on bone, cartilage and other structures.

Disease modification in OA - will we ever get there?

No drugs are currently approved that change the natural course of osteoarthritis (OA) and translate to long-term, clinically relevant benefits. Two-stage clinical trial designs for OA have now received FDA approval, but remaining challenges lie in defining suitable study populations, surrogate outcomes and pivotal long-term, clinically relevant trial endpoints.

SM04690, a WNT pathway inhibitor: anti-inflammatory and cartilage protective effects in preclinical osteoarthritis models

Purpose: Osteoarthritis (OA) is characterized by pain, swelling, and reduced function in the knee joint. Upregulated Wnt signaling drives OA through synovial inflammation, increased subchondral bone, and thinning cartilage. SM04690, a small molecule Wnt pathway inhibitor that demonstrated chondrogenesis and anti-inflammatory properties preclinically (Deshmukh et al., OAC 2017; Deshmukh et al. Arth Rheum 2016), was further evaluated to determine its potential to reduce inflammation, protect cartilage, improve joint health and modify pain in OA. Methods: Cytokine secretion (IL-6 and TNF-α) from IL-1β stimulated- and SM04690 treated-synovial fibroblasts was measured by ELISA. A single intra-articular injection of SM04690 or vehicle was evaluated in an in vivo rat knee monosodium iodoacetate (MIA) OA model. Joint inflammation was evaluated by H&E staining, inflammatory cytokines (IL-1α, IL-1β, IL-6, TNF-α and IFN-γ) by qPCR, and cartilage protection by qPCR for matrix metalloproteinases (MMPs). Histological evaluation of cartilage health was performed using OARSI score and thickness by Safranin-O staining. Pain was measured as paw withdrawal threshold using Von Frey apparatus and weight distribution using incapacitance meter and analyzed using generalized estimating equation regression accounting for repeated measurements. Results: SM04690 dose-dependently inhibited IL-1β-induced cytokine secretion in synovial fibroblasts (EC50 ∼30nM; Fig.1). In the rat MIA OA model, compared to vehicle, SM04690 injection reduced visible knee swelling, inflammatory cells, proinflammatory cytokine and MMP production (P < 0.05). SM04690 increased (P < 0.01) paw withdrawal threshold and improved (P < 0.05) weight distribution to the affected limb in treated rats, at all post-treatment timepoints, compared to vehicle. SM04690 increased Safranin-O stained cartilage thickness and decreased OARSI score (P < 0.05) compared to vehicle (Fig.2). Conclusions: In a rat MIA OA model, SM04690 injection reduced inflammation, protease production, and pain, with improved cartilage and joint health, compared to vehicle. Previously demonstrated regenerative effects in nonclinical studies1, along with anti-inflammatory properties, show SM04690 may potentially improve symptoms and provide disease modification in OA. Clinical studies are ongoing.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Targeting aging for disease modification in osteoarthritis.

Age is a key risk factor for the development of osteoarthritis and age-related changes within the joint might represent targets for therapy. The recent literature was reviewed to find studies that provide new insight into the role of aging in osteoarthritis, with a focus on the potential for disease modification. Preclinical studies using isolated cells and animal models provide evidence that two hallmarks of aging (cellular senescence and mitochondrial dysfunction) contribute to the development of osteoarthritis. Senescent cells secrete pro-inflammatory mediators and matrix degrading enzymes, and killing these cells with 'senolytic' compounds has emerged as a potential disease-modifying therapy. Mitochondrial dysfunction is associated with increased levels of reactive oxygen species (ROS) that can promote osteoarthritis by disrupting homeostatic intracellular signaling. Reducing ROS production in the mitochondria, stimulating antioxidant gene expression through Nrf2 activation, or inhibiting specific redox-sensitive signaling proteins represent additional approaches to disease modification in osteoarthritis that require further investigation. Although no human clinical trials for osteoarthritis have specifically targeted aging, preclinical studies suggest that targeting cellular senescence and/or mitochondrial dysfunction and the effects of excessive ROS may lead to novel interventions that could slow the progression of osteoarthritis.

Current status and future prospects for disease modification in osteoarthritis.

OA is a chronic, progressive and disabling joint disease, leading to a poor quality of life and an enormous social and economic burden. Current therapies for OA patients remain limited, which creates an area of huge unmet medical need. For some time, researchers have been looking for approaches that can inhibit the structural progression of OA. A variety of potential disease-modifying OA drugs have been developed, targeting cartilage, inflammatory pathways or subchondral bone. In addition, non-pharmacological therapies, including joint distraction and weight loss, draw increasing attention, with some showing disease-modifying potential. Thus we performed a comprehensive review to discuss the current status of disease-modifying therapies in OA and appraise the potentials of emerging novel agents.

Update on pharmacologic management of osteoarthritis

Purpose: Provide an overview of new approaches to the management of osteoarthritis (OA). Methods: Review of the recent literature. Results: A number of studies have recently concluded that have addressed both symptom and disease modification in OA. These studies are expanding our understanding of the mechanisms associated with pain generation and perception in OA as well as providing insight into the importance of pathways of cartilage metabolic homeostasis, respectively. Reduction of peripheral nerve input, attained by means of monoclonal inhibition of nerve growth factor (NGF), a neurotrophin capable of sensitizing peripheral nociceptors, has been demonstrated in phase 3 clinical trials to result in significant pain relief in OA, with the magnitude of the pain relief being greater than what is observed with NSAIDs in the same studies. Importantly, this approach has also been shown to be effective in low back pain and is being investigated in neuropathic pain models. Currently, the further development of this class of drugs is on hold pending a more complete understanding of their safety profile. Centrally acting compounds, specifically serotonin-norepinephrine reuptake inhibitors (SNRIs) have also been shown to provide pain modification in musculoskeletal pain conditions (OA, low back pain), adding to the armamentarium available for the management of these conditions. Novel topical agents as well as different formulations of existing opioids are also being investigated at this time. In terms of disease modification, recent trials have examined the effects of oral calcitonin on progression of structural disease as well as evaluating inhibition of the inducible nitric oxide synthase pathway, believed to be responsible for inflammatory and catabolic pathways in cartilage leading to OA. Conclusions: Inhibition of both peripheral and central pain pathways has been shown to be effective at reducing pain and improving function in people with OA. Further studies are needed to define the safety profile of therapy directed at inhibition of NGF. Disease modification remains a challenging goal, but a better understanding of the mechanism of cartilage damage has allowed new agents to be considered for study in this condition.

Pharmacologic therapy for osteoarthritis—the era of disease modification

Osteoarthritis (OA) is a prevalent and disabling condition for which few safe and effective therapeutic options are available. Current approaches are largely palliative and in an effort to mitigate the rising tide of increasing OA prevalence and disease impact, modifying the structural progression of OA has become a focus of drug development. This Review describes disease modification and discusses some of the challenges involved in the discovery and development of disease-modifying OA drugs (DMOADs). A variety of targeted agents are in mature phases of development; specific agents that are beyond preclinical development in phase II and III trials and show promise as potential DMOADs are discussed. A research agenda with respect to disease modification in OA is also provided, and some of the future challenges we face in this field are discussed.

Neues in der konservativen Therapie bei Arthrosen großer Gelenke

A large number of treatment options exist for osteoarthritis of the knee and hip. The choice of therapy depends on clinical symptomatology, preexisting risk factors (e.g. obesity), and disease stage. This review includes the novel aspects of symptomatic conservative treatment (physical medicine and drugs), especially pain management (electrotherapy), and rehabilitational aspects. Rehabilitation is essential, as osteoarthritis is a chronic condition, that requires lifelong intervention, and a causal cure has not been identified yet. New aspects of hyaluronic acid, slow-acting symptomatic drugs in osteoarthritis (chondroitin sulfate, glucosamine sulfate, and diacerein), and experimental drugs, which claim the properties of disease modification in osteoarthritis (bisphosphonates, calcitonin, and interleukin-1 antagonists), are discussed.

Prospects for disease modification in osteoarthritis

Osteoarthritis (OA) can be a progressive, disabling disease, leading to diminished quality of life, and, for over 500,000 individuals annually in the US, total joint replacement. The etiology of OA will vary among individuals, with potential roles for systemic factors (such as genetics and obesity) as well as for local biomechanical factors (such as muscle weakness, joint laxity and traumatic injury). Joint deterioration occurs over extended periods of time, and the diverse molecular mechanisms that mediate pathogenic events of early, mid and late disease are not yet fully understood. The success of biologic therapies in the treatment of rheumatoid arthritis has demonstrated that the blockade of a single dominant cytokine or regulatory molecule can prevent cartilage destruction in a complex disease, and has raised expectations that mechanism-based treatments could also be developed for patients with OA. In this review, we will address the biological mechanisms that mediate structural damage in OA and examine current targets that are candidates for disease modification. The challenges to drug development and the obstacles to disease modification strategies will also be addressed.

An update on osteoarthritis therapeutics

This review addresses recent major developments in symptomatic therapy and the principles of disease modification in osteoarthritis. It emphasizes issues that are of importance to the practicing clinician at a time when researchers in the field are trying to improve ways not only to provide symptomatic relief but also to slow disease progression. The past year has led to a reassessment of the role of cyclo-oxygenase-2 inhibitors in osteoarthritis therapy and has yielded new information on nutriceuticals such as glucosamine. The relative efficacy of intra-articular injections of agents such as corticosteroid and hyaluronic acid preparations has been assessed. In addition, reports on trials of potentially disease-modifying agents for osteoarthritis have been published. Because the therapeutic options have been reduced over the past year and the role of nutritional supplements remains unclear, the clinician is faced with a need to reassess osteoarthritis therapy. Although no practical disease-modifying agent for osteoarthritis has been identified, reports such as the recent doxycycline trial reviewed herein provide hope that continued research will soon yield a therapeutic model similar to that used in rheumatoid arthritis, for which some therapeutic agents achieve disease modification and other agents can be added as needed for symptomatic relief.

Bisphosphonates: potential therapeutic agents for disease modification in osteoarthritis.

Current treatments for osteoarthritis (OA) are mainly targeted towards providing short-term symptom relief. The focus in the development of disease-modifying drugs has been on therapies that modify cartilage directly. Recent research has highlighted the importance of subchondral bone as a target for therapeutic intervention and disease modification. At the subchondral level, affected joints have decreased bone mineral content and quality. In addition, increased bone turnover has been observed at levels similar to those in patients with osteoporosis. Consequently, the potential benefits of drugs that alter bone metabolism are being examined in this disease, in particular, the antiresorptive agents, bisphosphonates. Results from pre-clinical studies have shown promising results for these compounds. Although the mechanism of action remains unclear, comparative studies indicate that this activity may be unique to the specific structure of the bisphosphonate, rather than representative of a class effect. Clinical studies are now under way to determine the efficacy and safety of bisphosphonates which may offer new therapeutic options in the treatment of OA.

Panel Discussion II

Osteoarthritis (OA) is the most common form of arthritic disease, leading to disability and impaired quality of life and no curative treatments exist. Increasing evidence indicates that low-grade inflammation plays a pivotal role in the onset and progression of OA. In this review, we summarize emerging findings on the pathological roles of synovial macrophages, adipose tissue macrophages, and osteoclasts in OA and their potential clinical implications from cell biology to preclinical and preliminary clinical trials. The failure of synovial macrophages to transition from pro-inflammatory M1 to anti-inflammatory M2 subtypes may contribute to the initiation and maintenance of synovitis in OA. M1 macrophages promote the inflammatory microenvironment and progression of OA through interactions with synovial fibroblasts and chondrocytes, thus increasing the secretion of matrix metalloproteinases. Direct inhibition of M1 or promotion of M2 polarization may be useful therapeutic interventions. Adipose tissue macrophages present in the infrapatella fat pad (IPFP) were involved in the progression of obesity-induced OA, which contributed to changes in the integrity of the IPFP. Furthermore, macrophages and osteoclasts in the subchondral bone were involved in bone remodeling and pain through uncoupled osteoclast/osteoblast activity and increased nociceptive signaling. Growing evidence has indicated an important role for macrophage-mediated low-grade inflammation in OA. Fully understanding the link between macrophages and other cells in joints will provide new insights into OA disease modification.