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Osteoarthritis is the most common chronic joint disease characterized by progressive damage to the joints, leading to pain and loss of function. There is currently no cure or disease-modifying therapy for osteoarthritis. Hence, the increasing disease prevalence linked with ageing and obesity represents a substantial socio-economic burden. Intra-articular therapy by injection of drugs into affected joints can optimize local drug bioavailability, while reducing risks of systemic toxicity, a concern in an ageing patient population. In this review, we investigate the current landscape of intra-articular drug therapies for osteoarthritis, including established approaches and those in clinical development. We performed a literature review using PubMed, complemented with a search for clinical trials using the ClinicalTrials.gov repository. Additionally, conference abstracts and presentations were identified and systematic snowballing was applied. Identified drugs were divided into several groups by main mechanism of action, and include drugs that reduce inflammation (anti-inflammatory), drugs aiming to prevent or reverse structural damage (structure modifying), drugs that aim to reduce the pain, and other drugs with a specific target. Most studies have been performed for osteoarthritis of the knee, a joint that is easily accessible for intra-articular treatments. Optimal therapy would provide symptomatic relief, while preventing further damage to the joint. The field of intra-articular drug therapies for osteoarthritis is rapidly evolving with clear challenges identified: definition of relevant outcome measures, optimization of clinical trial set-ups, and dealing with placebo responses. While many uncertainties persist, it appears that the innovation in drug development and improved clinical trial set-up may finally deliver successful therapies for this important disease.

Osteoarthritis is a chronic degenerative disorder of the joint and represents one of the most common diseases worldwide. Its prevalence and severity are increasing owing to aging of the population, but treatment options remain largely limited to painkillers and anti-inflammatory drugs, which only provide symptomatic relief. In the late stages of the disease, surgical interventions are often necessary to partially restore joint function. Although the focus of osteoarthritis research has been originally on the articular cartilage, novel findings are now pointing to osteoarthritis as a disease of the whole joint, in which failure of different joint components can occur. In this Review, we summarize recent progress in the field, including data from novel ‘omics’ technologies and from a number of preclinical and clinical trials. We describe different in vitro and in vivo systems that can be used to study molecules, pathways and cells that are involved in osteoarthritis. We illustrate that a comprehensive and multisystem approach is necessary to understand the complexity and heterogeneity of the disease and to better guide the development of novel therapeutic strategies for osteoarthritis.

Ankylosing spondylitis (AS) is a chronic inflammatory disorder of unknown aetiology. Unlike other systemic autoimmune diseases, in AS, the innate immune system has a dominant role characterized by aberrant activity of innate and innate-like immune cells, including γδ T cells, group 3 innate lymphoid cells, neutrophils, mucosal-associated invariant T cells and mast cells, at sites predisposed to the disease. The intestine is involved in disease manifestations, as it is at the forefront of the interaction between the mucosal-associated immune cells and the intestinal microbiota. Similarly, biomechanical factors, such as entheseal micro-trauma, might also be involved in the pathogenesis of the articular manifestation of AS, and sentinel immune cells located in the entheses could provide links between local damage, genetic predisposition and the development of chronic inflammation. Although these elements might support the autoinflammatory nature of AS, studies demonstrating the presence of autoantibodies (such as anti-CD74, anti-sclerostin and anti-noggin antibodies) and evidence of activation and clonal expansion of T cell populations support an autoimmune component to the disease. This Review presents the evidence for autoinflammation and the evidence for autoimmunity in AS and, by discussing the pathophysiological factors associated with each, aims to reconcile the two hypotheses.Ankylosing spondylitis (AS) is a chronic inflammatory disease with hallmarks of both autoimmune and autoinflammatory pathology. In this Review, the authors examine the evidence for both disease processes and aim to reconcile the two.

Osteoarthritis is the most prevalent and crippling joint disease, and lacks curative treatment, as the underlying molecular basis is unclear. Here, we show that DOT1L, an enzyme involved in histone methylation, is a master protector of cartilage health. Loss of DOT1L disrupts the molecular signature of healthy chondrocytes in vitro and causes osteoarthritis in mice. Mechanistically, the protective function of DOT1L is attributable to inhibition of Wnt signalling, a pathway that when hyper-activated can lead to joint disease. Unexpectedly, DOT1L suppresses Wnt signalling by inhibiting the activity of sirtuin-1 (SIRT1), an important regulator of gene transcription. Inhibition of SIRT1 protects against osteoarthritis triggered by loss of DOT1L activity. Modulating the DOT1L network might therefore be a therapeutic approach to protect the cartilage against osteoarthritis. DOT1L is one of the few genes linked to osteoarthritis by human GWAS. Here the authors show that DOT1L-dependent histone methylation protects homeostasis of articular chondrocytes by SIRT1-dependent inhibition of canonical WNT signalling, and that inhibition of DOT1L can drive osteoarthritic disease in mice.

Mechanical loading is an important factor in musculoskeletal health and disease. Tendons and ligaments require physiological levels of mechanical loading to develop and maintain their tissue architecture, a process that is achieved at the cellular level through mechanotransduction-mediated fine tuning of the extracellular matrix by tendon and ligament stromal cells. Pathological levels of force represent a biological (mechanical) stress that elicits an immune system-mediated tissue repair pathway in tendons and ligaments. The biomechanics and mechanobiology of tendons and ligaments form the basis for understanding how such tissues sense and respond to mechanical force, and the anatomical extent of several mechanical stress-related disorders in tendons and ligaments overlaps with that of chronic inflammatory arthritis in joints. The role of mechanical stress in ‘overuse’ injuries, such as tendinopathy, has long been known, but mechanical stress is now also emerging as a possible trigger for some forms of chronic inflammatory arthritis, including spondyloarthritis and rheumatoid arthritis. Thus, seemingly diverse diseases of the musculoskeletal system might have similar mechanisms of immunopathogenesis owing to conserved responses to mechanical stress.Mechanical loading is an important factor in the development of tendon and ligament disorders. In this Review, the authors discuss the evidence for the known role of mechanical loading in tendinopathy and its potential role in inflammatory arthritis.

Key Points Entheses are predominantly extra-articularly localized structures that represent a key target of musculoskeletal inflammation in diseases such as psoriatic arthritis (PsA) and spondyloarthritis (SpA) Entheses contain a specific immune microenvironment, which is activated by a combination of factors that include mechanical stress, genetic susceptibility and microbial-triggered immune activation Enthesitis arises from robust activation of prostaglandin E2 and the IL-23–IL-17 axis, leading to the influx of innate immune cells and homing of inflammation into the entheses, which is followed by mesenchymal tissue responses and new bone formation Clinical and imaging instruments have been developed that enable the reliable detection and monitoring of enthesitis in patients with PsA and SpA Inhibition of the key effector cytokines of enthesitis — IL-17, IL-23 and TNF — has shown to be effective in supporting the resolution of enthesitis in PsA and SpA This article provides an overview of the pathophysiology of enthesitis, from induction and inflammation to tissue proliferation and bone formation. Building on these pathophysiological concepts, the clinical presentation, assessment and treatment of enthesitis are also discussed. Entheses are the insertion sites of tendons and ligaments to the bone surface and are essential structures for locomotion. Inflammation of the entheses (enthesitis) is a key feature of psoriatic arthritis and spondyloarthritis. To date, our conceptual understanding of enthesitis remains limited. This Review provides an insight into the pathophysiology of enthesitis, addressing the role of biomechanics, prostaglandin E2-mediated vasodilation and the activation of innate immune cells in the initiation phase of enthesitis, as well as the role of entheseal IL-23-responsive cells that augment inflammation by producing pro-inflammatory mediators such as IL-17A, IL-22 and TNF. In addition, the molecular steps that translate inflammation into resident tissue responses, resulting in new bone formation, are discussed. The second part of the article summarizes the clinical features of enthesitis, and the role of clinical and imaging instruments in detecting enthesitis are discussed together with their challenges and limitations. Finally, the Review summarizes the current treatment possibilities for enthesitis based on the aforementioned pathophysiological concepts, focusing on the role of cytokine-blocking agents.

Targeted therapies for chronic joint diseases are now able to control many of the disease symptoms—the research focus has now shifted towards the structural damage that occurs in skeletal tissues. Lories provides a timely update on the current knowledge in osteoimmunology, with a discussion of the role of tissue repair and remodeling in chronic arthritis such as ankylosing spondylitis and rheumatoid arthritis. The introduction of targeted therapies has dramatically changed the prognosis of patients with chronic joint diseases such as rheumatoid arthritis (RA) and ankylosing spondylitis (AS). As control of inflammation, and hence of symptoms of disease, is increasingly achieved, more attention is given towards the long-term consequences of these disorders, to the structural damage in the skeletal tissues and to the resulting disability. In AS, bone remodeling with new cartilage and bone formation leading to ankylosis is a striking feature. Clinically successful TNF antagonists do not inhibit radiographic progression of disease. New insights into the molecules involved in ankylosis (such as bone morphogenetic proteins and Wnts) have suggested that the classical paradigm linking inflammation and ankylosis can be challenged, and new concepts of disease onset and progression, with a focus on cell stress and damage, are rapidly evolving. In RA, inhibition of Wnt signaling and defective osteoblast function have been associated with lack of repair. As restoration of tissue integrity and homeostasis is the ultimate goal of therapy, these findings suggest new roads for therapeutic intervention. For patients with AS or RA, such strategies will be critically dependent on further research that defines individual risk factors and need for interventions. Key Points Ankylosing spondylitis (AS) is characterized by extensive cartilage and bone formation, which leads to ankylosis in the sacroiliac joints and the spine Ankylosis and ongoing inflammation both contribute to reduced mobility and increased disability in patients with AS Radiographic progression of disease in AS (characterized by ankylosis) varies greatly between patients In rheumatoid arthritis (RA), suppression of osteoblast activity interferes with healing of erosions; why this inhibition persists even after clinical control of the disease has been achieved is unclear The osteoimmunology research agenda in AS and RA is rapidly evolving, providing new insights into disease onset and the reason why symptoms manifest in the joint or spine

Objectives Spondyloarthritides (SpA) are characterised by both peripheral and axial arthritis. The hallmarks of peripheral SpA are the development of enthesitis, most typically of the Achilles tendon and plantar fascia, and new bone formation. This study was undertaken to unravel the mechanisms leading towards enthesitis and new bone formation in preclinical models of SpA. Results First, we demonstrated that TNFΔARE mice show typical inflammatory features highly reminiscent of SpA. The first signs of inflammation were found at the entheses. Importantly, enthesitis occurred equally in the presence or absence of mature T and B cells, underscoring the importance of stromal cells. Hind limb unloading in TNFΔARE mice significantly suppressed inflammation of the Achilles tendon compared with weight bearing controls. Erk1/2 signalling plays a crucial role in mechanotransduction-associated inflammation. Furthermore, new bone formation is strongly promoted at entheseal sites by biomechanical stress and correlates with the degree of inflammation. Conclusions These findings provide a formal proof of the concept that mechanical strain drives both entheseal inflammation and new bone formation in SpA.

Key Points Wnt signalling is essential for joint health: loss of and excessive activation of the canonical signalling pathway are both deleterious for articular cartilage In cartilage, Wnt ligands have distinct effects on the activation of downstream cascades; Wnt16 seems to be a partial agonist that protects against excessive cascade activation Ligand–receptor, ligand–antagonist and receptor–antagonist interactions, as well as the establishment of concentration gradients by cell surface and extracellular matrix molecules, all contribute to the regulation of Wnt pathway activation Intracellularly, β-catenin forms complexes with the T cell factor and lymphoid enhancer-binding factor family of transcription factors, and the composition of these complexes determines the resulting transcriptional response Histone modifications further regulate the activity of canonical Wnt signalling in cartilage; DOT1L limits excessive activation of Wnt signalling and protects the cartilage against osteoarthritis Increasing insights into specific mechanisms that regulate Wnt signalling in the joint such as histone modification might reveal unexpected opportunities in achieving tissue-specific effects and developing targeted therapies In this Review, the role of canonical Wnt signalling in articular cartilage is discussed, along with the regulatory mechanisms that exist to fine-tune Wnt signalling and the rationale for developing drugs that modulate Wnt signalling for the treatment of joint diseases such as osteoarthritis. Wnt signalling pathways have key roles in joint development, homeostasis and disease, particularly in osteoarthritis. New data is starting to reveal the importance of tightly regulating canonical Wnt signalling pathway activation to maintain homeostasis and health in articular cartilage. In addition to the presence of different Wnt antagonists that limit pathway activation in articular cartilage, the reciprocal crosstalk between the canonical and non-canonical cascades and competitive antagonism between different Wnt ligands seem to be critical in restraining excessive Wnt pathway activation. Changes in transcriptional complex assembly upon Wnt pathway activation, epigenetic modulation of target gene transcription, in particular through histone modifications, and complex interactions between the Wnt signalling pathway and other signalling pathways, are also instrumental in adjusting Wnt signalling. In this Review, the cellular and molecular mechanisms involved in fine-tuning canonical Wnt signalling in the joint are updated, with a focus on the articular cartilage. The interventions for preventing or treating osteoarthritis are also discussed, which should aim to limit disease-associated excessive canonical Wnt activity to avoid joint damage.

Osteoarthritis (OA) is a disease of the whole joint, at the centre of which lies the interface between cartilage and bone. Altered transfer of mechanical stress across this boundary is thought to result from, and to exacerbate, OA, but molecular crosstalk was presumed to be minimal. Accumulating data challenge this assumption, and this Review explores the biology and pathology of the bone–cartilage functional unit. Osteoarthritis (OA) refers to a group of mechanically-induced joint disorders to which both genetic and acquired factors contribute. Current pathophysiological concepts focus on OA as a disease of the whole joint. Within these models, the functional unit formed by the articular cartilage and the subchondral bone seems to be of particular interest. Cartilage and bone receive and dissipate the stress associated with movement and loading, and are therefore continuously challenged biomechanically. Recent data support the view that cartilage and bone can communicate over the calcified tissue barrier; vessels reach out from bone into the cartilage zone, patches of uncalcified cartilage are in contact with bone, and microcracks and fissures further facilitate transfer of molecules. Several molecular signaling pathways such as bone morphogenetic proteins and Wnts are hypothesized to have a role in OA and can activate cellular and molecular processes in both cartilage and bone cells. In addition, intracellular activation of different kinase cascades seems to be involved in the molecular crosstalk between cartilage and bone cells. Further research is required to integrate these different elements into a comprehensive approach that will increase our understanding of the disease processes in OA, and that could lead to the development of specific therapeutics or treatment strategies. Key Points Osteoarthritis (OA) is a disease of the whole joint, to which changes in cartilage, bone, bone marrow, synovium, menisci, ligaments and neural tissue contribute Subchondral bone changes, with increased metabolism and sclerosis, are often the first detectable alterations in the OA process Increased subchondral remodeling might lead to decreased local mineralization Molecular crosstalk between the cartilage and bone is possible, and it increases with progression of OA Identifying risk factors for disease and halting disease progression are the main clinical challenges in OA