Steven R. Goldring

Osteoarthritis: A Disease of the Joint as an Organ

Richard F. Loeser, MD*, Department of Internal Medicine, Section of Molecular Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA Steven R. Goldring, MD, Chief Scientific Officer and Richard L. Menschel Chair, The Hospital for Special Surgery and Department of Medicine, Weill Cornell Medical College, New York, New York, USA Carla R. Scanzello, MD, PhD, and Department of Internal Medicine, Section of Rheumatology, Rush Medical College, Chicago, IL, USA Mary B. Goldring, PhD The Hospital for Special Surgery and Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, New York, USA

The role of synovitis in osteoarthritis pathogenesis

Research into the pathophysiology of osteoarthritis (OA) has focused on cartilage and peri-articular bone, but there is increasing recognition that OA affects all of the joint tissues, including the synovium (SM). Under normal physiological conditions the synovial lining consists of a thin layer of cells with phenotypic features of macrophages and fibroblasts. These cells and the underlying vascularized connective tissue stroma form a complex structure that is an important source of synovial fluid (SF) components that are essential for normal cartilage and joint function. The histological changes observed in the SM in OA generally include features indicative of an inflammatory synovitis; specifically they encompass a range of abnormalities, such as synovial lining hyperplasia, infiltration of macrophages and lymphocytes, neoangiogenesis and fibrosis. The pattern of synovial reaction varies with disease duration and associated metabolic and structural changes in other joint tissues. Imaging modalities including magnetic resonance (MRI) and ultrasound (US) have proved useful in detecting and quantifying synovial abnormalities, but individual studies have varied in their methods of evaluation. Despite these differences, most studies have concluded that the presence of synovitis in OA is associated with more severe pain and joint dysfunction. In addition, synovitis may be predictive of faster rates of cartilage loss in certain patient populations. Recent studies have provided insights into the pathogenic mechanisms underlying the development of synovitis in OA. Available evidence suggests that the inflammatory process involves engagement of Toll-like receptors and activation of the complement cascade by degradation products of extracellular matrices of cartilage and other joint tissues. The ensuing synovial reaction can lead to synthesis and release of a wide variety of cytokines and chemokines. Some of these inflammatory mediators are detected in joint tissues and SF in OA and have catabolic effects on chondrocytes. These inflammatory mediators represent potential targets for therapeutic interventions designed to reduce both symptoms and structural joint damage in OA. This article is part of a Special Issue entitled Osteoarthritis.

Proteomic Analysis of Synovial Fluid From the Osteoarthritic Knee: Comparison With Transcriptome Analyses of Joint Tissues

OBJECTIVEnThe pathophysiology of the most common joint disease, osteoarthritis (OA), remains poorly understood. Since synovial fluid (SF) bathes joint cartilage and synovium, we reasoned that a comparative analysis of its protein constituents in health and OA could identify pathways involved in joint damage. We undertook this study to perform a proteomic analysis of knee SF from OA patients and control subjects and to compare the results to microarray expression data from cartilage and synovium.nnnMETHODSnAge-matched knee SF samples from 10 control subjects, 10 patients with early-stage OA, and 10 patients with late-stage OA were compared using 2-dimensional difference-in-gel electrophoresis and mass spectrometry (MS). MS with a multiplexed peptide selected reaction monitoring assay was used to confirm differential expression of a subset of proteins in an independent OA patient cohort. Proteomic results were analyzed by Ingenuity Pathways Analysis and compared to published synovial tissue and cartilage messenger RNA profiles.nnnRESULTSnSixty-six proteins were differentially present in healthy and OA SF. Three major pathways were identified among these proteins: the acute-phase response signaling pathway, the complement pathway, and the coagulation pathway. Differential expression of 5 proteins was confirmed by selected reaction monitoring assay. A focused analysis of transcripts corresponding to the differentially present proteins indicated that both synovial and cartilage tissues may contribute to the OA SF proteome.nnnCONCLUSIONnProteins involved in the acute-phase response signaling pathway, the complement pathway, and the coagulation pathway are differentially regulated in SF from OA patients, suggesting that they contribute to joint damage. Validation of these pathways and their utility as biomarkers or therapeutic targets in OA is warranted.

The Role of Bone in Osteoarthritis Pathogenesis

This article focuses on the specific skeletal features of osteoarthritis and the putative mechanisms involved in their pathogenesis. In addition, the relationship of these changes to the alterations in articular cartilage and the other tissues comprising the diarthrodial joint are reviewed.

Bone remodelling in inflammatory arthritis

The inflammatory arthropathies that include rheumatoid arthritis, the seronegative spondyloarthropathies and systemic lupus erythematosus are characterised by marked alterations in the architecture and structural integrity of peri-articular bone; however, the pattern and natural history of the skeletal changes differs in these conditions. In part, this can be attributed to differences in the primary anatomical site of the inflammation, but also there is evidence that there are differences in the biological properties and products produced by inflammatory tissues. This review will focus on recent advances in the understanding of the cellular and molecular mechanisms that contribute to the differential pattern of articular bone remodelling in these prototypical inflammatory forms of arthritis.

Early knee osteoarthritis

Concepts regarding osteoarthritis, the most common joint disease, have dramatically changed in the past decade thanks to the development of new imaging techniques and the widespread use of arthroscopy that permits direct visualisation of intra-articular tissues and structure. MRI and ultrasound allow the early detection of pre-radiographic structural changes not only in the peri-articular bone but also in the cartilage, menisci, synovial membrane, ligaments and fat pad. The significance of MRI findings such as cartilage defects, bone marrow lesions, synovial inflammation/effusions and meniscal tears in patients without radiographic signs of osteoarthritis is not fully understood. Nevertheless, early joint tissue changes are associated with symptoms and, in some cases, with progression of disease. In this short review, we discuss the emerging concept of early osteoarthritis localised to the knee based on recently updated knowledge. We highlight the need for a new definition of early osteoarthritis that will permit the identification of patients at high risk of osteoarthritis progression and to initiate early treatment interventions.

Osteoimmunology and bone homeostasis: relevance to spondyloarthritis.

The seronegative spondyloarthopathies (SpA) share certain common articular and peri-articular features that differ from rheumatoid arthritis (RA) and other forms of inflammatory arthritis. These include the tendency of the SpAs to involve the axial skeleton in addition to the diarthrodial joints, and the prominent involvement of the extra-articular entheses (sites of ligamentous and tendon insertion), which are not common sites of primary pathology in RA and other inflammatory arthropathies. The differential anatomic sites of bone pathology in the SpAs in comparison to the other forms of arthritis suggest that the underlying pathogenic processes and cellular and molecular mechanisms that account for the peri-articular bone pathology involve different underlying disease mechanisms. This review will highlight the molecular and cellular processes that are involved in the pathogenesis of the skeletal pathology in the SpAs, and provide evidence that many of the factors involved in regulation of bone cell function exhibit potent immune-regulatory activity, providing support for the general concept of osteoimmunology.

Inflammatory signaling induced bone loss

A broad spectrum of inflammatory disorders have the capacity to target the skeleton and to de-regulate the processes of physiological bone remodeling. This review will focus on the systemic inflammatory rheumatologic disorders, which target articular and peri-articular bone tissues. Many of these disorders also affect extra-articular tissues and organs, and in addition, have the capacity to produce systemic bone loss and increased risk of osteoporotic fractures. Attention will focus on rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and the seronegative spondyloarthropathies (SpAs), which include ankylosing spondylitis (AS), reactive arthritis (formerly designated as Reiters syndrome), the arthritis of inflammatory bowel disease, juvenile onset spondyloarthropathy and psoriatic arthritis. The discussion will principally focus on RA, which is a prototypical model of an inflammatory disorder that de-regulates bone remodeling, but also will review the other forms of inflammatory joint disease to highlight the differential effects of inflammation on bone remodeling in these conditions. This article is part of a Special Issue entitled Muscle Bone Interactions.

The osteocyte: key player in regulating bone turnover.

Osteocytes are the most abundant cell type in bone and are distributed throughout the mineralised bone matrix forming an interconnected network that ideally positions them to sense and to respond to local biomechanical and systemic stimuli to regulate bone remodelling and adaptation. The adaptive process is dependent on the coordinated activity of osteoclasts and osteoblasts that form a so called bone multicellular unit that remodels cortical and trabecular bone through a process of osteoclast-mediated bone resorption, followed by a phase of bone formation mediated by osteoblasts. Osteocytes mediate their effects on bone remodelling via both cell–cell interactions with osteoclasts and osteoblasts, but also via signaling through the release of soluble mediators. The remodelling process provides a mechanism for adapting the skeleton to local biomechanical factors and systemic hormonal influences and for replacing bone that has undergone damage from repetitive mechanical loading.

10 – The Role of the Immune System in the Bone Loss of Inflammatory Arthritis

Publisher Summary The rheumatic diseases include a broad spectrum of disorders that share a propensity to affect the anatomic components of the joints and the adjacent peri-articular tissues. The diarthrodial joints are the most commonly affected sites. These joints join two opposing bone surfaces, which are covered by hyaline cartilage. The purpose of the hyaline cartilage is to provide an articulating surface that facilitates joint motion. Diarthrodial joints are encased in a highly specialized lining membrane termed the synovium, which separates the joint cavity from the underlying connective tissues. This membrane consists of a mixed population of cells expressing phenotypic features of fibroblasts and macrophages. It provides a barrier that permits trafficking of nutrients from the underlying vasculature to the cells of the articular cartilage, and is also the source of products that interact with the cartilage and contribute to the unique “low friction” properties of the cartilage surfaces. In patients with rheumatoid arthritis (RA), a prototypical form of inflammatory arthritis, the synovium is the site of the initial inflammatory process. It is important to note that in the rheumatic diseases, which are associated with inflammatory arthritis, the underlying disturbance in immune regulation that is responsible for the localized joint pathology may target extra-articular organs and tissues and these features may dominate the clinical picture. This chapter will not address the non-articular manifestation of these disorders, but it is relevant to note that involvement of organs, such as the kidneys, may profoundly affect skeletal tissue remodeling.