The Role of Synovitis in the Physiopathology of Osteoarthritis – Effects of Chondroitin Sulphate

Synovitis and Osteoarthritis
Joints are complex structures that include: subchondral bone; cartilage surfaces, which comprise chondrocytes and the extracellular matrix; the capsule, which includes the synovial membrane; and ligaments. The joints are able to perform repetitive movements primarily due to the presence of the articular cartilage and its functional element, the extracellular matrix, which represents 95% of the volume of the cartilage. The synovial membrane – by means of fibroblast-derived type B synoviocytes – has a critical role in nourishing the chondrocytesand producing hyaluronic acid, which is necessary for the gliding ability of the joint. In addition, fibroblast-like synoviocytes (FLS) are able to synthesise and release cytokines and growth factors. Macrophagederived type A synoviocytes remove debris and degradation products from the synovial space.¹

Osteoarthritis is characterised by loss of articular cartilage in focal areas with varying degrees of osteophyte formation, subchondral bone change and synovitis.² The physiopathology of osteoarthrosis remains controversial. It has been proposed that the use of the joint applies multiple microtraumas to the articular cartilage, leading to the formation of extracellular matrix fragments and fibronectin (see Figure 1). These fragments may bind to specific membrane receptors of the chondrocyte and promote the expression of matrix metalloproteinases (MMPs), primarily MMP13, aimed at cleaving the extracellular matrix fragments. The increase in expression of MMPs is accompanied by enhanced synthesis of pro-inflammatory cytokines, essentially interleukin (IL)-1β and tumour necrosis factor (TNF)-α, which will sustain the activation of chondrocytes. Moreover, this synthesis will promote the formation of MMPs, aggrecanase, reactive oxygen intermediates, nitric oxide and lipid-derivative inflammatory mediators such as prostaglandins and leukotrienes, which will enhance the catabolic activity of the chondrocyte, causing destruction of the cartilage matrix. On the other hand, extracellular matrix fragments, IL-1β and TNF-α released into the synovial fluid will activate macrophages and mastocytes in the synovial membrane, leading to synovitis. Activation of the synovial cells will result in a further release of IL-1β, TNF-α and MMPs, which will contribute to the destruction of the cartilage matrix.^1–5

There is clinical evidence showing that osteoarthritis and synovitis are associated. Synovial abnormalities are detectable in 50% of patients with osteoarthrosis.⁶ Synovitis is reflected by several of the signs and symptoms of osteoarthritis, such as swelling and effusion, redness, pain and stiffness. ⁷ Moderate or large effusions and synovial thickening are more frequent among patients with knee pain than in those without pain, suggesting that these signs are associated with the pain of osteoarthritic knee; furthermore, the severity of knee pain is associated with synovial thickening. ⁸ In patients with osteoarthritis, changes in pain are closely associated with changes in synovitis, but not with cartilage loss. ⁹ In addition, the presence of synovitis at early stages of osteoarthritis is associated with a more rapid and destructive progression of the disease.⁶ Finally, there is evidence that a subset of patients with osteoarthritic joint disease present with synovitis and synovial hyperplasia without cartilage damage and formation of extracellular matrix fragments, suggesting that in some patients synovitis is a very early or the initial event in the development of osteoarthritis. ^10,11

Cytokines play a crucial role in the onset and progression of osteoarthritis. ¹² For instance, IL-1β and TNF-α are implicated in the early development of arthritis, and IL-1β contributes to sustain the inflammatory reaction in later stages; IL-17 and IL-18 are also pro-inflammatory cytokines in the joint. Other cytokines released in the osteoarthritic joint have a regulatory role in inflammation (IL-6 and IL-8), an inhibitory or anti-inflammatory function (IL-4, IL-10, IL-11, IL-13, interferon [IFN]-γ, and IL-1 receptor antagonist) or even an anabolic role, such as insulin-like growth factor (IGF)-1, transforming growth factor (TGF)-β, fibroblast growth factor (FGF) and bone morphogenetic protein (BMP).^13,14 The relevance of the synovial tissue in the onset and/or progression of osteoarthritis may be associated to its great capacity to release cytokines.

Synovial tissue from patients with early osteoarthritis shows activated FLS and macrophages, as well as T lymphocytes and mast cell infiltration. ^15,16 FLS release IL-1β, IL-6, IL-8, MMP1, MMP2, MMP3, MMP13, MMP1, MMP16, tissue inhibitor of metalloproteinases (TIMP)-1, receptor activator of nuclear factor-κB ligand (RANKL), TGF-β, vascular endothelial growth factor (VEGF) and FGF. RANKL contributes directly to osteoclast formation and activation at sites of bone erosion. The production of these cytokines and proteases requires the activation and nuclear translocation of nuclear factor-κB (NF-κB). ^17,18 Moreover, the activation of NF-κB increases FLS proliferation and transforms the phenotype of these cells to a highly invasive cell with great motility and ability to secrete cytokines and MMPs. ¹⁹

The synovial macrophages are an important source of IL-1β, TNF-α, IL-6, IL-12, IL-15, IL-18, granulocyte-macrophage colony-stimulating factor (GM-CSF) and macrophage inflammatory protein (MIP)-1α.1,16 Platelet-derived growth factor (PDGF), FGF, VEGF, hepatocyte growth factor (HGF) and TGF-β are also produced by synovial macrophages. ²⁰ Macrophage-derived IL-1β and TNF-α are required for the release of MMP1, 3, 9 and 13, proteins that will cleave collagen II, fibronectin, laminin, and aggrecanase. ²¹

Mononuclear T lymphocytes infiltrate the synovial membrane of osteoarthritic joints. Peri-vascular infiltration of the synovial membrane with T cells is an early phenomenon in osteoarthritis. T-cells release IL-2, IL-4, IL-10, IL-17, IL-18, IFN-γ and RANKL. The fact that most T cells express activation antigens suggests that these cells can be activated through antigen-specific immune responses. ¹⁶