Osteoarthritis (OA) is the most common form of arthritis and a major cause of pain and disability in older adults (1) Often OA is referred to as degenerative joint disease “(DJD)” This is a misnomer because OA is not simply a process of wear and tear but rather abnormal remodeling of joint tissues driven by a host of inflammatory mediators within the affected joint The most common risk factors for OA include age, gender, prior joint injury, obesity, genetic predisposition, and mechanical factors, including malalignment and abnormal joint shape (2, 3) Despite the multifactorial nature of OA, the pathological changes seen in osteoarthritic joints have common features that affect the entire joint structure resulting in pain, deformity and loss of function

The pathologic changes seen in OA joints (Figures 1 and ​and2)2) include degradation of the articular cartilage, thickening of the subchondral bone, osteophyte formation, variable degrees of synovial inflammation, degeneration of ligaments and, in the knee, the menisci, and hypertrophy of the joint capsule There can also be changes in periarticular muscles, nerves, bursa, and local fat pads that may contribute to OA or the symptoms of OA The findings of pathological changes in all of the joint tissues are the impetus for considering OA as a disease of the joint as an organ resulting in “joint failure” In this review, we will summarize the key features of OA in the various joint tissues affected and provide an overview of the basic mechanisms currently thought to contribute to the pathological changes seen in these tissues






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Figure 1


Sagittal inversion recovery (A–C) and coronal fast spin echo (D–F) images illustrating the magnetic resonance imaging findings of osteoarthritis (A) reactive synovitis (thick white arrow), (B) subchondral cyst formation (white arrow), (C) bone marrow edema (thin white arrows), (D) partial thickness cartilage wear (thick black arrow), (E–F) full thickness cartilage wear (thin black arrows), subchondral sclerosis (arrowhead) and marginal osteophyte formation (double arrow) Image courtesy of Drs Hollis Potter and Catherine Hayter, Hospital for Special Surgery, New York, NY

https://onlinelibrary.wiley.com/doi/pdf/10.1002/art.34453

Osteoarthritis: A Disease of the Joint as an Organ

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(11)60243-2.pdf

Osteoarthritis: an update with relevance for clinical practice

Osteoarthritis as an inflammatory disease (osteoarthritis is not osteoarthrosis

Osteoarthritis (OA), one of the most common rheumatic disorders, is characterized by cartilage breakdown and by synovial inflammation that is directly linked to clinical symptoms such as joint swelling, synovitis and inflammatory pain The gold-standard method for detecting synovitis is histological analysis of samples obtained by biopsy, but the noninvasive imaging techniques MRI and ultrasonography might also perform well The inflammation of the synovial membrane that occurs in both the early and late phases of OA is associated with alterations in the adjacent cartilage that are similar to those seen in rheumatoid arthritis Catabolic and proinflammatory mediators such as cytokines, nitric oxide, prostaglandin E(2) and neuropeptides are produced by the inflamed synovium and alter the balance of cartilage matrix degradation and repair, leading to excess production of the proteolytic enzymes responsible for cartilage breakdown Cartilage alteration in turn amplifies synovial inflammation, creating a vicious circle As synovitis is associated with clinical symptoms and also reflects joint degradation in OA, synovium-targeted therapy could help alleviate the symptoms of the disease and perhaps also prevent structural progression

The role of synovitis in pathophysiology and clinical symptoms of osteoarthritis

Methods, systems, compositions include biocompatible polymer coated nanoceria that function as aqueous redox catalyst with enhanced activity at an acidic to moderately alkaline pH value between 1 and 8. The compositions are used as oxidizing agents for decomposition, decontamination or inactivation of organic contaminants, such as, pesticides and chemical warfare agents. Another use includes nanoceria as targetable nanocatalyst prepared by conjugating various targeting ligands to the nanoparticle coating to form a colorimetric or fluorescent probe in immunoassays and other molecule binding assays that involve the use of a molecule in solution that changes the color of the solution or emits a fluorescent signal, where localization of nanoceria to organs or tissue is assessed by treatment with an oxidation sensitive dye or other detection devices. Versatility and uses of the nanoceria compositions are controlled by pH value, choice of dye substrate and thickness of the polymer coating on the ceria nanoparticles.

/pdf/oxidase-activity-of-polymeric-coated-cerium-oxide-4shmqnmx1r.pdf

Oxidase activity of polymeric coated cerium oxide nanoparticles

Objective

To quantify the relationship between inflammation and angiogenesis in synovial tissue from patients with osteoarthritis (OA).



Methods

Hematoxylin and eosin staining and histologic grading for inflammation were performed for 104 patients who met the American College of Rheumatology criteria for OA and had undergone total joint replacement or arthroscopy. A purposive sample of synovial specimens obtained from 70 patients was used for further analysis. Vascular endothelium, endothelial cell (EC) proliferating nuclei, macrophages, and vascular endothelial growth factor (VEGF) were detected by immunohistochemical analysis. Angiogenesis (EC proliferation, EC fractional area), macrophage fractional area, and VEGF immunoreactivity were measured using computer-assisted image analysis. Double immunofluorescence histochemical analysis was used to determine the cellular localization of VEGF. Radiographic scores for joint space narrowing and osteophyte formation in the knee were also assessed.



Results

Synovial tissue samples from 32 (31%) of 104 patients with OA showed severe inflammation; thickened intimal lining and associated lymphoid aggregates were often observed. The EC fractional area, EC proliferation, and VEGF immunoreactivity all increased with increasing histologic inflammation grade and increasing macrophage fractional area. In the synovial intimal lining, VEGF immunoreactivity was localized to macrophages and increased with increasing EC fractional area and angiogenesis. No inflammation or angiogenic indices were significantly correlated with radiographic scores.



Conclusion

Inflammation and angiogenesis in the synovium are associated with OA. The angiogenic growth factor VEGF generated by the inflamed synovium may promote angiogenesis, thereby contributing to inflammation in OA.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/art.11094

Inflammation and angiogenesis in osteoarthritis.

Objectives. The osteochondral junction can be a source of pain in both RA and OA. Growth of blood vessels and nerves from the subchondral bone into articular cartilage may mediate the association between joint pathology and symptoms. We have investigated associations between angiogenesis, inflammation and neurovascular growth factor expression at the osteochondral junction in human arthritis. Methods. Osteochondral junctions from medial tibial plateaux of patients undergoing arthroplasty for RA (n = 10) or OA (n = 11), or from non-arthritic post-mortem controls (n = 11) were characterized by immunohistochemistry for CD34 and smooth muscle a-actin (blood vessels), CD68 (macrophages), CD3 (lymphocytes), proliferating cell nuclear antigen, vascular endothelial, platelet-derived and nerve growth factor (NGF). Results. Osteochondral angiogenesis was demonstrated as increased endothelial cell proliferation and vascular density in non-calcified articular cartilage, both in RA and OA. Osteochondral angiogenesis was associated with subchondral bone marrow replacement by fibrovascular tissue expressing VEGF, and with increased NGF expression within vascular channels. RA was characterized by greater lymphocyte infiltration and PDGF expression than OA, whereas chondrocyte expression of VEGF was a particular feature of OA. NGF was observed in vascular channels that contained calcitonin gene-related peptideimmunoreactive sensory nerve fibres.

Angiogenesis and nerve growth factor at the osteochondral junction in rheumatoid arthritis and osteoarthritis

Background: Normal adult articular cartilage is thought to be avascular and aneural.

Objective: To describe neurovascular structures at the osteochondral junction and in osteophytes in tibiofemoral osteoarthritis (OA) displaying a range of severity of cartilage changes.

Methods: Articular surfaces were obtained from 40 patients at total knee joint replacement surgery for tibiofemoral OA (TKR) and seven patients post mortem (PM). Antibodies directed against CD34 (vascular endothelium), protein gene product 9.5 (pan-neuronal marker), substance P and calcitonin gene-related peptide (sensory nerves) and C-flanking peptide of neuropeptide Y (sympathetic nerves) were used to localise blood vessels and nerves by immunohistochemistry. Severity of OA cartilage changes was graded histologically.

Results: TKR and PM samples displayed a range of OA cartilage changes including tidemark breaching by vascular channels. Sympathetic and sensory nerves were both present within vascular channels in the articular cartilage, in both mild and severe OA. Perivascular and free nerve fibres, and nerve trunks were observed within the subchondral bone marrow and within the marrow cavities of osteophytes. Sensory and sympathetic nerves displayed similar distributions in each region studied.

Conclusion: Vascularisation and the associated innervation of articular cartilage may contribute to tibiofemoral pain in OA across a wide range of structural disease severity.

/pdf/neurovascular-invasion-at-the-osteochondral-junction-and-in-20kf3dyppa.pdf

Neurovascular invasion at the osteochondral junction and in osteophytes in osteoarthritis

Objectives Meniscal damage is a recognised feature of knee osteoarthritis (OA), although its clinical relevance remains uncertain. This study describes vascular penetration and nerve growth in human menisci, providing a potential mechanism for the genesis of pain in knee OA.

Methods Menisci obtained post mortem were screened on the basis of high or low macroscopic tibiofemoral chondropathy as a measure of the presence and degree of OA. Forty cases (20 per group) were selected for the study of meniscal vascularity, and 16 (eight per group) for the study of meniscal innervation. Antibodies directed against α-actin and calcitonin gene-related peptide (CGRP) were used to localise blood vessels and nerves by histochemistry. Image analysis was used to compare vascular and nerve densities between groups. Data are presented as median (IQR).

Results Menisci from knees with high chondropathy displayed degeneration of collagen bundles in their outer regions, which were more vascular than the inner regions, with an abrupt decrease in vascularity at the fibrocartilage junction. Vascular densities were increased in menisci from the high compared with low chondropathy group both in the synovium (3.8% (IQR 2.6–5.2), 2.0% (IQR 1.4–2.9), p=0.002) and at the fibrocartilage junction (2.3% (IQR 1.7–3.1), 1.1% (IQR 0.8–1.9), p=0.003), with a greater density of perivascular sensory nerve profiles in the outer region (high chondropathy group, 144 nerve profiles/mm2 (IQR 134–189); low chondropathy group, 119 nerve profiles/mm2 (IQR 104–144), p=0.049).

Conclusion Tibiofemoral chondropathy is associated with altered matrix structure, increased vascular penetration, and increased sensory nerve densities in the medial meniscus. The authors suggest therefore that angiogenesis and associated sensory nerve growth in menisci may contribute to pain in knee OA.

https://ard.bmj.com/content/annrheumdis/70/3/523.full.pdf?cited-by=yes&70%2F3%2F523=

Increased vascular penetration and nerve growth in the meniscus: a potential source of pain in osteoarthritis

Osteoarthritis (OA) is the most common joint disease in the elderly population. Pathologic features include articular cartilage degradation, synovial inflammation, osteophytes, and bone marrow lesions. Pain is the main reason sufferers seek clinical assistance. Patients with end-stage OA may eventually benefit from total knee replacement (TKR) surgery.

Although joint pathology makes an important contribution to OA pain, the precise relationship between pain and structural pathology is not entirely clear (1,2). Radiographic features of OA are often weakly associated with pain, suggesting that structural, cellular, or biochemical changes that directly mediate pain may not be easily detected on radiographs. Imaging studies have indicated possible associations between pain and synovitis (3–6) or subchondral changes (6–9), but associations with histopathology have not been explored in detail. Such studies have previously been limited by age differences between OA patients and normal controls and by limited access to joint tissue from people with OA whose pain is less than that which would lead them to undergo joint replacement surgery.

Synovitis may contribute to OA knee pain. The cause of synovitis in OA is incompletely understood, but has been observed in both early (10) and late disease (11). Synovitis may mediate pain through the production of factors that sensitize or activate sensory nerves.

Recent evidence has suggested an important role of nerve growth factor (NGF) in mediating inflammatory pain through increasing nociceptor sensitivity or facilitating sensory nerve growth (12). NGF blockade was shown to improve the degree of pain from knee OA (13–15), indicating a causal link between NGF and OA pain.

NGF is elevated in a variety of rheumatic diseases, particularly in the synovial fluid of patients with inflammatory arthritis (16,17). NGF is expressed by synovial macrophages from patients with rheumatoid arthritis, spondyloarthritis, and to a lesser extent, in OA (17), as well as by synovial fibroblasts from patients with OA (18). However, the expression and cellular profile of NGF in synovial biopsy samples from people with knee OA has not been explored in detail. Synovial fibroblasts can be visualized using immunohistochemistry with antibodies directed against Hsp47, a collagen-specific molecular chaperone (19). Macrophages can be identified by the transmembrane glycoprotein CD68 (20).

Our aim in the present study was to first validate the measurement of histopathologic characteristics of knee OA by comparing samples obtained at the time of TKR surgery for OA (advanced OA) with samples collected postmortem from age-matched non-OA controls. Second, we aimed to identify histopathologic features associated with symptomatic knee OA by comparing cases with similar macroscopic chondropathy, half of whom had sought medical care for knee pain and had undergone TKR (symptomatic chondropathy) and the other half had not sought medical care for knee pain but had died of an unrelated illness (asymptomatic chondropathy). We hypothesized that symptomatic OA is mediated by specific structural and biochemical changes within the knee joint, whereas other changes may be coincidental or even protective.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/art.38778

D. Wilson

Papers

Inflammation and angiogenesis in osteoarthritis.

Angiogenesis and nerve growth factor at the osteochondral junction in rheumatoid arthritis and osteoarthritis

Neurovascular invasion at the osteochondral junction and in osteophytes in osteoarthritis

Increased vascular penetration and nerve growth in the meniscus: a potential source of pain in osteoarthritis

Structural associations of symptomatic knee osteoarthritis.