Osteoarthritis, angiogenesis and inflammation

C. S. Bonnet and D. A. Walsh

Academic Rheumatology, University of Nottingham, Nottingham City Hospital, Nottingham, UK.

Correspondence to: D. A. Walsh, Academic Rheumatology, University of Nottingham, Clinical Sciences Building, Nottingham City Hospital, Hucknall Road, Nottingham NG5 1PB, UK. E-mail: David.Walsh{at}nottingham.ac.uk


    Abstract
 Top
 Abstract
 Introduction
 Synovitis in osteoarthritis
 Chronic synovitis
 Angiogenesis and inflammation
 Angiogenesis in the bone...
 Angiogenesis and the sensory...
 Therapeutic implications
 Conclusion
 References
 
Angiogenesis and inflammation are closely integrated processes in osteoarthritis (OA) and may affect disease progression and pain. Inflammation can stimulate angiogenesis, and angiogenesis can facilitate inflammation. Angiogenesis can also promote chondrocyte hypertrophy and endochondral ossification, contributing to radiographic changes in the joint. Inflammation sensitizes nerves, leading to increased pain. Innervation can also accompany vascularization of the articular cartilage, where compressive forces and hypoxia may stimulate these new nerves, causing pain even after inflammation has subsided. Inhibition of inflammation and angiogenesis may provide effective therapeutics for the treatment of OA by improving symptoms and retarding joint damage. This review aims to summarize (i) the evidence that angiogenesis and inflammation play an important role in the pathophysiology of OA and (ii) possible directions for future research into therapeutics that could effectively treat this disease.

KEY WORDS: Osteoarthritis, Synovitis, Angiogenesis, Innervation, Osteophyte, Macrophage, Chondrocalcinosis


    Introduction
 Top
 Abstract
 Introduction
 Synovitis in osteoarthritis
 Chronic synovitis
 Angiogenesis and inflammation
 Angiogenesis in the bone...
 Angiogenesis and the sensory...
 Therapeutic implications
 Conclusion
 References
 
Osteoarthritis (OA) is a group of chronic, painful, disabling conditions affecting synovial joints. The phenomenon of OA may be defined clinically, radiologically or pathologically; however, its aetiology remains poorly understood. As with other complex clinical syndromes, there is often a lack of concordance between the various components that we recognize as OA; for example, there is usually only a weak association between radiological features and pain. OA may be classified according to presumed aetiological factors, as in post-traumatic OA. It can be classified according to the distribution of joints affected; for example, into nodal, knee or hip joint arthritis. Furthermore, OA can be classified according to the presence or absence of associated features, such as chondrocalcinosis. Recent genetic and epidemiological analyses provide further support for these classifications, whilst further emphasizing heterogeneity within the diagnosis.

OA is commonly described as a non-inflammatory disease in order to distinguish it from ‘inflammatory arthritis’, such as rheumatoid arthritis (RA) or the seronegative spondyloarthropathies. Despite this, inflammation is increasingly recognized as contributing to the symptoms and progression of OA [1, 2]. Morning and inactivity stiffness are common symptoms in patients with the disease, and acute inflammatory flares, characterized by local warmth, tenderness and effusion, are not uncommon. Non-steroidal anti-inflammatory drugs alleviate symptoms of OA and may be more effective than simple analgesics, such as paracetamol [3]. Intra-articular injection of corticosteroids similarly may alleviate both pain and stiffness, not only during acute flares but also as maintenance therapy. Serological or histological evidence of synovitis is commonly found in OA, even though OA has not been consistently associated with specific immune responses.

Pain, the predominant symptom in OA, is multidimensional in its nature and mediated through a variety of factors. The presence or absence of synovitis may be an independent predictor of OA symptoms. The pain experience results from interactions between inflammation and other features of disease, including radiological severity [4], innervation of articular structures [5, 6], central and peripheral sensitization [7] and psychological factors [8]. The precise contribution of inflammation to pain in OA may vary from time to time and from patient to patient. It is currently unclear whether inflammation is a feature of all patients with OA at some stage of their disease, or whether synovitis itself defines one or more disease subgroups.

Inflammation may be both a primary event in OA and secondary to other aspects of the disease, such as biochemical changes within the cartilage. Recent studies indicate that histological and serological evidence of synovitis is an early feature in OA and not restricted to patients with end-stage disease undergoing joint replacement surgery [2, 9, 10]. Synovial inflammation may be detected in the presence of mild or severe cartilage changes in OA [9]. Even when inflammation is secondary to other processes within the osteoarthritic joint, synovitis may yet make an important contribution to the symptoms and pathology of disease. Clinically detectable joint inflammation may predict a worse radiological outcome in OA [11]. Furthermore, in a lapine model of arthritis, joint damage was exacerbated after induction of inflammation in rabbit knees following meniscal tear [12]. Synovitis, therefore, although not a prerequisite for OA, may lead to a poor clinical outcome.

Mechanisms by which synovitis exacerbates structural damage in OA are likely to be complex. Hypotheses have included alterations in chondrocyte function, enhanced angiogenesis and changes in bone turnover [13, 14]. Novel therapeutic interventions aiming to inhibit synovitis in OA may not only improve short-term symptoms but also reduce pain and disability in the long term.

Angiogenesis is the growth of new capillary blood vessels from pre-existing vasculature. It occurs during essential physiological processes, such as embryogenesis, wound repair and the female menstrual cycle. Angiogenesis can also contribute to a variety of pathological conditions, including the unwanted vessel growth in chronic inflammatory diseases, and the growth and metastasis of tumours. The process is regulated by numerous activating and inhibitory factors (Table 1), which may vary from tissue to tissue, between disease and normal physiology, and during different phases of a continuous disease process.


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TABLE 1. Angiogenesis regulators localized to or released within osteoarthritic human synovium, synovial fluid and articular chondrocytes

 
Angiogenesis is a complex multistep process controlled by a wide range of positive and negative regulatory factors (Table 1). Detailed reviews have been published on the angiogenesis process [14, 64–66]. Activated endothelial cells detach from their neighbouring cells, through disruption of vascular endothelial cadherin junctions, resulting in increased vascular permeability. The endothelial basement membrane is degraded by proteolytic enzymes such as matrix metalloproteinases (MMPs), releasing matrix-bound angiogenic factors that, in turn, stimulate endothelial cell migration and proliferation. Capillary tube formation, deposition of a new basement membrane and anastomosis lead to blood flow. Factors produced by endothelial cells, such as platelet-derived growth factor, attract supporting cells such as pericytes, whilst vascular endothelial growth factor (VEGF) and the angiopoietins ensure the stability of the new vessel. The new vessels differentiate into arterioles, capillaries and venules whilst redundant vessels regress, a process that requires endothelial cell apoptosis. Finally, vasoregulatory systems are developed and a fully functional microvasculature is formed.


    Synovitis in osteoarthritis
 Top
 Abstract
 Introduction
 Synovitis in osteoarthritis
 Chronic synovitis
 Angiogenesis and inflammation
 Angiogenesis in the bone...
 Angiogenesis and the sensory...
 Therapeutic implications
 Conclusion
 References
 
Signs of acute synovitis may be apparent in patients with OA from time to time. However, the extent of subclinical inflammation in OA is now increasingly being recognized. Symptoms differ between acute and chronic inflammation and patients with OA may experience both: acute flares may occur either on the background of chronic synovitis or in an otherwise non-inflamed joint.

Acute inflammation usually has a sudden onset, becoming apparent over minutes or hours with the classic symptoms of heat, pain, redness and swelling. Chronic inflammation develops over a longer period of time and may persist for days, weeks or months. Neutrophils are the most abundant inflammatory cells in acute synovitis, whereas in chronic synovitis in OA, macrophages are most abundant, often with lymphocytic infiltrates [67].

Unlike chronic inflammation, in which inflammation and repair occur concurrently, the host response in acute inflammation leads to elimination of the irritant followed by resolution of the tissue to its original state. During chronic inflammation the joint remains abnormal even after inflammation subsides. Histological evidence of chronic synovitis may be present in the absence of overt clinical signs, and the contribution of chronic synovitis to symptoms of pain and stiffness may be overlooked [9, 68].

The causes of acute inflammatory flares of OA are multiple and incompletely understood. Patients will often attribute flares to particular activities, indicating that physical trauma may play a role. Acute inflammatory flares in OA may also be associated with the presence of calcium pyrophosphate dihydrate (CPPD) or hydroxyapatite crystals within the joint. CPPD crystal deposition is associated with OA of the knee, and manifests as radiological chondrocalcinosis or intermittent acute synovitis (pseudogout). Up to 25% of patients undergoing knee joint replacement surgery for OA have radiological evidence of chondrocalcinosis on preoperative radiographs (our unpublished observations). Nearly half of patients with chondrocalcinosis who present to a rheumatologist have associated generalized OA [69].

Pain is one of the classic symptoms of acute inflammation. This is mainly due to the sensitization of fine unmyelinated sensory nerves present in the osteoarthritic joint. However, this is not restricted to acute inflammation and chronic inflammation could also be a source of pain in OA.


    Chronic synovitis
 Top
 Abstract
 Introduction
 Synovitis in osteoarthritis
 Chronic synovitis
 Angiogenesis and inflammation
 Angiogenesis in the bone...
 Angiogenesis and the sensory...
 Therapeutic implications
 Conclusion
 References
 
Evidence and cause of inflammation in OA
There is now much evidence that subclinical inflammation is common in OA, even in the absence of acute inflammatory flares. Circulating markers of inflammation, such as C-reactive protein (CRP), may be elevated in OA compared with control populations without disease [1, 2, 70, 71]. Histological examination of synovium frequently indicates inflammatory cell infiltration, involving macrophages and T cells, increased cell turnover and angiogenesis [9, 72–75]. The recent use of magnetic resonance imaging to study patients with OA of the knee has demonstrated synovial thickening in 73% of patients with relatively early OA [76]. This synovial thickening was found to correspond to mild chronic synovitis [77]. Raised serum CRP may reflect subclinical inflammation in affected joints, mediated by cytokines entering the circulation. IL-6 is up-regulated during synovial inflammation, and can augment inflammatory angiogenesis [78–80]. IL-6 is thought to be the chief stimulator of CRP production [81]. IL-6 is produced by synovial cells, osteoblasts and chondrocytes, and is detectable by immunoassay in synovial fluid samples that have been harvested from joints affected by OA [82–84].

The causes of chronic synovitis in OA remain poorly understood. Fragments of cartilage (often referred to as ‘debris’) may be found within the synovium associated with giant cells typical of foreign body type reactions. Haemosiderin deposition suggests a possible role for recurrent minor haemarthrosis in some patients. Histological synovitis has also been described in patients with chondrocalcinosis, even in the absence of an acute flare [85], and it is likely that histological synovitis is more common in OA with chondrocalcinosis than in OA alone. CPPD crystals can be identified in synovial tissue and fluid from patients with chondrocalcinosis between attacks of acute synovitis, when they may be associated with histological evidence of chronic synovitis [85, 86]. In addition to their acute effects on neutrophils, CPPD crystals can induce the expression of inflammatory, angiogenic factors such as TNF-{alpha}, IL-6 and IL-8, by monocytes and macrophages, and they can also stimulate cell proliferation [87–90]. CPPD crystal types with a low propensity to induce acute inflammation may therefore contribute to chronic synovitis and angiogenesis in chondrocalcinosis.

Inflammation, pain and joint damage
The symptoms of chronic synovitis are less well understood than those of acute inflammation. Features of inflammation, such as minor elevations of CRP and infiltration of macrophages into the synovium and even lymphoid aggregates, are not necessarily associated in OA with the classic signs of inflammation; heat, redness, soft tissue swelling or effusion. Chronic synovitis is associated with marked changes in the central connections of sensory nerves, and changes in their synthesis and release of neurotransmitters and neuromodulators [7]. Furthermore, there is increased turnover of cells within the inflamed synovium: fibroblasts and blood vessels proliferate, macrophages are recruited, and there is increased cellular apoptosis [14]. Turnover within the synovial tissue is accompanied by retraction and growth of sensory nerve terminals [91, 92]. Peripheral nerve growth and injury are closely associated with enhanced pain sensation [93].

The ability of inflammation to cause pain depends upon the sensory innervation of the joint. Fine unmyelinated sensory nerves containing neuropeptides such as substance P (SP) and calcitonin gene-related peptide (CGRP) have been localized to the synovium, ligaments, tendons, menisci and the osteochondral junction in normal and osteoarthritic joints [92, 94, 95]. Such nerves may mediate slow, burning pain, as described by many patients with OA. Myelinated nerve fibres in the joint capsule and intra-articular structures may mediate the sudden pain on movement or pressure.

During inflammation, chemicals such as adenosine, prostaglandin (PG) E1 and PGF2{alpha}, leukotriene B4 and (8R-15S)-dihydroxyeicosa-(5E-9,11,132)-tetraenoic acid (8R-15S-diHETE) are released within the joint, where they sensitize nerves, resulting in increased firing to a given stimulus [96]. At the same time, inflammatory mediators such as bradykinin, histamine, 5-HT, PGE2, prostacyclin and acidosis stimulate nerves even in the absence of mechanical stimulation [95, 97]. Over a period of hours or days, recruitment of inflammatory cells and up-regulation of genes within the synovium generates cytokines such as IL-1, IL-6, IL-8 and TNF-{alpha}, in addition to nerve growth factor [97]. These factors further enhance peripheral sensitization, whilst neuronal plasticity contributes to central sensitization.

Inflammation may exacerbate cartilage degradation in osteoarthritis (Fig. 1). Patients with OA in whom radiological scores progress rapidly tend to have higher serum concentrations of CRP at baseline than do those whose disease progresses slowly [1, 2]. TNF-{alpha} and IL-1 stimulate chondrocytes to produce MMPs and plasminogen activator, which degrade matrix proteoglycans and collagen [98, 99]. Chondrocytes also produce further IL-1 that acts in an autocrine manner and further stimulates MMP and plasminogen activator production [42]. As discussed below, stimulation of angiogenesis by synovitis may also contribute to progressive joint damage in OA.



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FIG. 1. Interactions between inflammation and angiogenesis in the osteoarthritic joint. Blood vessel growth is regulated by a balance between angiogenic and anti-angiogenic factors within the joint. Inflammation may facilitate angiogenesis directly through the release of growth factors from cells such as macrophages, and also by stimulation or sensitization of other cells, such as chondrocytes, nerves and osteoblasts, that in turn release additional angiogenic factors. Angiogenesis at the osteochondral junction leads to endochondral ossification and the formation of osteophytes. Angiogenesis and joint damage further exacerbate inflammation. New vessels, which breach the tidemark may later become innervated and could be a source of pain. Through these mechanisms, angiogenesis and inflammation can contribute to pain and joint damage in OA. bFGF, basic fibroblast growth factor; CGRP, calcitonin gene-related peptide; IL-1, interleukin-1; MMP, matrix metalloproteinase; PGE2, prostaglandin E2; SP, substance P; TIMP, tissue inhibitor of metalloproteinases; TGF-ß, transforming growth factor-ß; TNF-{alpha}, tumour necrosis factor-{alpha}; VEGF, vascular endothelial growth factor.

 

    Angiogenesis and inflammation
 Top
 Abstract
 Introduction
 Synovitis in osteoarthritis
 Chronic synovitis
 Angiogenesis and inflammation
 Angiogenesis in the bone...
 Angiogenesis and the sensory...
 Therapeutic implications
 Conclusion
 References
 
Angiogenesis and chronic inflammation are closely integrated processes. Inflammation can stimulate angiogenesis, and angiogenesis can facilitate inflammation (Fig. 1). However, although chronic inflammation is almost always accompanied by angiogenesis, angiogenesis can occur in the absence of inflammation.

Inflammatory angiogenesis
Inflammatory mediators can either directly or indirectly stimulate angiogenesis. Inflammatory cells that produce these factors include the macrophages and mast cells that are present in abundance in chronically inflamed osteoarthritic synovium. There are some general mechanisms by which macrophages can induce angiogenesis. New vessel growth can be stimulated directly by factors secreted from macrophages [100]. Macrophages can be found in most sites where abnormal angiogenesis is occurring, for example in synovitis and in tumours. Many of the inflammatory mediators produced by these macrophages induce angiogenesis in vivo (Table 1). Macrophages can also secrete factors that stimulate other cells, such as endothelial cells and fibroblasts, to produce angiogenic factors such as VEGF [67, 78, 101].

Although not as well defined, neutrophils and lymphocytes have also been implicated in the induction of angiogenesis. Angiogenic factors such as basic fibroblast growth factor (bFGF) and VEGF may be produced by lymphocytes, and neutrophils may be involved in the early induction of angiogenesis [67, 102, 103].

As well as inflammatory cells, inflammatory conditions can also stimulate angiogenesis. Tissue hypoxia often occurs in inflamed tissue and is a potent stimulator of angiogenesis [104]. VEGF gene expression is up-regulated during hypoxia and it is thought that this stimulation of angiogenic factors is an attempt to relieve the low oxygen content of the tissue [104, 105]. Plasma extravasation and fibrin deposition also result in the generation of angiogenic factors such as kinins [106].

Angiogenesis is observed in the synovium of osteoarthritic joints, closely associated with chronic synovitis [63, 107]. The normal synovium is highly vascular in order to supply the normally avascular cartilage with nutrients and oxygen. In OA, increased endothelial cell proliferation is associated with new vessel formation [63]. Concurrent vascular regression results in little overall change in vascular density [73]. Instead, there is a redistribution of vessels within the synovium and a change towards a more immature phenotype [108]. Increased vascular turnover in the osteoarthritic synovium reflects a change in the balance between angiogenic and anti-angiogenic factors (Table 1). The extent of endothelial cell proliferation increases with increasing vascular density, increased macrophage infiltration and increased VEGF expression within the synovium, indicating that synovial neovascularization may be largely driven by synovitis [9]. Up-regulation of hypoxia inducible factor-1{alpha} in the osteoarthritic synovium is also associated with increased microvascular density and expression of angiogenic factors, indicating that hypoxia may play an additional mediating role [109].

The extent of angiogenesis and inflammation can vary widely between different patients with OA. Endothelial cell proliferation indices in synovia from groups of patients with OA are generally lower than those in RA, although vascular densities are similar [73]. However, angiogenesis in synovia from some patients with OA may reach levels comparable to some of the highest seen in RA [73]. Synovial fluid and serum levels of the angiogenic factor VEGF may be higher in groups of patients with RA compared with OA [110, 111]. However, VEGF levels in the synovial tissue of patients with OA have been found to be similar to those found in RA [112]. Also the formation of tubular networks that morphologically resemble capillaries have been induced to similar extents by synovial fluids from patients with OA or RA [113]. Some authors have, however, reported that synovial fluids from OA patients can display lower angiogenic potential than patients with RA [114]. The severity of histological inflammation in synovia from patients with OA can also reach similar levels to those observed in RA [9, 72]. Systemic markers of inflammation such as CRP are elevated in OA, but generally to a lesser extent than in RA [115].

Synovial inflammation and angiogenesis are enhanced in a substantial proportion of patients with OA. It remains unclear, however, whether this heterogeneity observed in cross-sectional studies reflects subgroups of patients with ‘inflammatory OA’, or inflammatory episodes that are common to all patients with OA. Synovial angiogenesis and inflammation are observed across the full range of disease severity, indicating that they are not unique to early- or late-stage disease [2, 9, 72].

Contribution of angiogenesis to inflammation
Angiogenesis may be most important in potentiating or perpetuating inflammation rather than in initiating it. Increased permeability of newly formed blood vessels to macromolecules facilitates oedema formation [116]. Adhesion molecules such as E-selectin are highly expressed by new vessels, facilitating inflammatory cell infiltration [117, 118]. The inflammatory response can also be maintained by new vessels transporting inflammatory cells, nutrients and oxygen to the site of inflammation [119]. It is also thought that deficient neural and peptide regulatory factors in the neovasculature may impair the vascular regulation of inflammation [120]. Angiogenesis may indirectly promote itself by increasing inflammatory cell infiltration, thereby increasing the availability of angiogenic factors produced by these cells. It has been speculated that, during early synovitis, angiogenesis may contribute to the transition from acute to chronic inflammation [14].


    Angiogenesis in the bone and cartilage of osteoarthritic joints
 Top
 Abstract
 Introduction
 Synovitis in osteoarthritis
 Chronic synovitis
 Angiogenesis and inflammation
 Angiogenesis in the bone...
 Angiogenesis and the sensory...
 Therapeutic implications
 Conclusion
 References
 
Angiogenesis occurs at the osteochondral junction as well as within the osteoarthritic synovium. Vascularization of the articular cartilage and osteophytes is characteristic of the pathology of OA [15]. The normal articular cartilage is avascular in the adult [60]. A deep layer of calcified cartilage lies between the tidemark and the osteochondral junction. Blood vessels may penetrate the calcified cartilage within fibrovascular channels originating from the subchondral bone [121]. With increasing severity of OA, these vascular channels breach the tidemark, and blood vessels may be found more superficially in the non-calcified articular cartilage. Blood vessels within the deep layers of the osteoarthritic articular cartilage are derived from the vasculature that is normally present in subchondral bone.

As in the synovium, vascularization of the articular cartilage may also be due to a change in the balance between angiogenic and anti-angiogenic factors (Table 1). Osteoarthritic articular cartilage displays reduced resistance to invasion by blood vessels in the chick embryo chorioallantoic membrane assay [122]. The sources of angiogenic signals to the subchondral bone remain poorly understood. Hypertrophic chondrocytes within the deeper layers of articular cartilage produce angiogenic factors [15] (Fig. 1). With disruption of the tidemark, angiogenic factors may also reach the osteochondral junction by mass transport and diffusion from the synovium through synovial fluid and the cartilage matrix [123]. Synovial fluids from patients with OA may stimulate endothelial tube formation in vitro [113], and synovial tissues and fluids from patients with OA contain a variety of angiogenic factors (Table 1 and Fig. 1). The subchondral bone may itself contribute or support angiogenic stimuli within the osteoarthritic joint, through expression of angiogenic factors by osteoblasts [124] (Fig. 1).

Endochondral ossification is the formation of calcified bone within a cartilage scaffold, and is the normal mechanism of growth at the epiphyses of long bones. Differentiated chondrocytes proceed through a series of late differentiation steps, resulting in mature hypertrophic chondrocytes that express alkaline phosphatase and secrete matrix proteins such as collagen X [125]. Hypertrophic chondrocytes then undergo apoptosis, leaving a cartilaginous matrix that is mineralized prior to the formation of new bone [126]. Where endochondral ossification is undesirable, for example in normal articular cartilage, this late chondrocyte differentiation is subject to negative regulation.

Angiogenesis is required for endochondral ossification [127]. In growing long bones, hypertrophic chondrocytes produce angiogenic factors, including VEGF [125]. New blood vessels grow from the underlying bone into channels created by the chondrocytes. In turn, arrest of late chondrocyte differentiation may be overcome by factors produced by vascular endothelial cells, including proteases and bone morphogenic proteins [125, 128, 129]. Vascular invasion of articular cartilage may, therefore, further stimulate chondrocyte differentiation with a switch to collagen I and X production [122]. Chondrocytes induce vascular invasion, and vascular invasion is a prerequisite for new bone formation. Inhibition of endogenous angiogenic factors, VEGF for example, impairs endochondral ossification, resulting in hypertrophy of the cartilaginous growth plate [130].

Fibrovascular channels within the articular cartilage are typically cuffed with bone, although their tips may be in direct contact with the cartilage. It is likely that this new bone formation at the osteochondral junction recapitulates, in some respects, endochondral ossification in the growth plate and that the new blood vessels contribute to bone formation [127]. The articular cartilage in OA becomes thinner, therefore, not only by loss of articular surface but also through an advancing wave of ossification at the osteochondral junction.

The growth of osteophytes at the joint margin also occurs through the process of endochondral ossification [131] (Fig. 1). Cartilaginous extensions of the articular surface become invaded by blood vessels, and bone extends from the subchondral structures. The bony core of the fully developed osteophyte contains trabeculae and marrow cavities that are continuous with the adjacent subarticular bone, with no clear boundary between the two [131].


    Angiogenesis and the sensory nervous system
 Top
 Abstract
 Introduction
 Synovitis in osteoarthritis
 Chronic synovitis
 Angiogenesis and inflammation
 Angiogenesis in the bone...
 Angiogenesis and the sensory...
 Therapeutic implications
 Conclusion
 References
 
Angiogenesis and pain
Whereas a contribution of angiogenesis to inflammation is by now generally accepted, the role of angiogenesis in pain remains less well established. As discussed above, any facilitation of inflammation may itself contribute to the symptoms of pain. New vessel formation may, in addition, facilitate pain through structural reorganization of the joint.

Capillary growth can occur over a period of days and differentiation of blood vessels into arteries and veins occurs over days or weeks. Innervation is a more protracted process. Peripheral nerves do not proliferate, but rather grow by neurite extension or arborization. Growth of fine unmyelinated sensory nerves follows angiogenesis in a wide variety of tissues [94, 120]. Sensory nerves can be localized within polyether sponges approximately 2 weeks after subcutaneous implantation in rats [120]. Full-thickness skin grafts in man, however, may remain only partially innervated many years after grafting [132]. Growing and damaged peripheral nerves display sensitization, and are associated with increased pain sensation [93]. It is likely, therefore, that the neo-innervation that follows from angiogenesis may itself contribute to the pain experience during chronic synovitis.

Some articular structures are not normally innervated, for example articular cartilage and intervertebral discs [60]. In OA, the articular cartilage becomes vascularized, and these new vessels may be associated with new sensory nerves [133] (Fig. 1). Osteophytes are new bony structures that develop by endochondral ossification at the borders of the osteoarthritic joint [131]. Angiogenesis is an essential stage in endochondral ossification and sensory innervation of the osteophyte may in part explain the association between radiological osteophytosis and pain reporting. In so-called degenerative disc disease, intervertebral discs are invaded by blood vessels which themselves may be accompanied by sensory nerves [134, 135]. High compressive forces, hypoxia and acidosis within the articular cartilage and intervertebral disc may stimulate these new nerves, thereby contributing to persistent pain even after inflammation has subsided.

Sensory nerves as mediators of angiogenesis and inflammation
Fine unmyelinated sensory nerves not only respond to inflammation; they may also initiate or facilitate inflammation through the release of vasoactive substances into the joint (Fig. 1). Neuropeptides such as SP and CGRP are released into peripheral tissues, where they act on specific cell surface receptors localized to blood vessels. SP enhances plasma extravasation through interaction with the neurokinin NK1 class of G protein-coupled receptor, and CGRP is a potent vasodilator [136–138]. Activation of sensory nerves causes the classic wheal and flare responses of acute neurogenic inflammation [96]. More recently, evidence has accumulated that persistent activity in fine unmyelinated nerves is accompanied by cellular infiltration (‘neurogenic chronic infiltration’) [139]. Furthermore, SP and CGRP can enhance endothelial cell proliferation, migration and capillary tube formation in vitro, and angiogenesis in vivo [140–142]. Recent work with specific NK1 receptor antagonists has revealed that endogenously released SP contributes to the early stages of angiogenesis in capsaicin- and carrageenan/kaolin-induced synovitis [143, 144]. Neuropeptides interact with other acute inflammogens such as bradykinin during the initiation of angiogenesis in acute inflammation [144].


    Therapeutic implications
 Top
 Abstract
 Introduction
 Synovitis in osteoarthritis
 Chronic synovitis
 Angiogenesis and inflammation
 Angiogenesis in the bone...
 Angiogenesis and the sensory...
 Therapeutic implications
 Conclusion
 References
 
Pharmaceutical agents designed to modify the progress of inflammation in rheumatological conditions have largely been developed for RA. The intensive search for anti-angiogenic agents has been driven by therapeutic potential in oncology. The mechanisms of inflammation and angiogenesis may differ between OA, RA and cancer but this need not exclude the application of existing therapies to diseases that were previously thought of as ‘degenerative’. Perhaps the greatest therapeutic potential, however, will come from finding mechanisms of inflammation and angiogenesis that are disease-specific. Drugs that broadly inhibit inflammation or angiogenesis may have limited applicability to OA because of the potential toxicity that follows the inhibition of such biologically important processes. Patients' desire to take medications is often determined by short-term gains, and targeting inflammation may be attractive in OA if, in addition to retarding disease progression, it relieves symptoms of pain and stiffness. Treatments that only improve long-term prognosis may yet be desirable to patients even in the absence of short-term symptomatic benefits. This is particularly the case when rapid determination of efficacy is possible, as with antihypertensive therapies and cholesterol lowering agents. Angiogenesis inhibitors could fall into this group for OA if biomarkers can be identified that predict long-term success in clinical trials.

The testing of potentially disease-modifying agents in OA requires large numbers of patients studied for years due to the normally slow progression of the disease and the relative insensitivity to change of existing radiological outcomes. It is understandable, therefore, if pharmaceutical companies are only willing to undertake such studies when there is good preclinical evidence of likely efficacy. Much has been learnt over the past few years on the characteristics of inflammation and angiogenesis in human OA. Animal models of OA, however, have often been developed with cartilage pathology in mind, and the roles of angiogenesis and inflammation in these models remains uncertain. Further studies over the next few years are likely to overcome many of these technological difficulties, raising the hope of therapeutic advance in the foreseeable future.


    Conclusion
 Top
 Abstract
 Introduction
 Synovitis in osteoarthritis
 Chronic synovitis
 Angiogenesis and inflammation
 Angiogenesis in the bone...
 Angiogenesis and the sensory...
 Therapeutic implications
 Conclusion
 References
 
Osteoarthritis is a group of chronic, disabling conditions of complex aetiology that affect the synovial joints. It is a major public health issue with a substantial economic impact, and is expected to increase as the population ages. At present, treatment is centred on relief of pain through analgesic and anti-inflammatory agents, with total joint replacement surgery rescuing those in whom conservative management has failed. Angiogenesis and inflammation are important processes in the pathophysiology of osteoarthritis (Fig. 2). They can contribute to joint damage by stimulating MMP production and endochondral ossification. Pain, the major symptom of OA, can be caused or enhanced by inflammation and angiogenesis. Angiogenesis may introduce sensory nerves into the aneural cartilage, and inflammation can sensitize nerves present in the joint. Angiogenesis, inflammation and innervation are highly interconnected, and each may up-regulate the others. Inhibition of inflammation and angiogenesis may provide effective therapeutics for the treatment of OA by improving symptoms and retarding joint damage.



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FIG. 2. Summary of the relationship between inflammation, neurovascular plasticity and the symptoms of osteoarthritis. Inflammation can stimulate angiogenesis, and angiogenesis can facilitate inflammation. These two processes can contribute to damage of the osteoarthritic joint through cartilage degradation and osteophyte formation. Angiogenesis can also lead to innervation of the articular cartilage that could be a source of pain in OA. The sensitization of sensory nerves by inflammatory mediators is also a source of pain, and sensitized nerves can cause neurogenic inflammation and initiate new vessel growth.

 
The authors have declared no conflicts of interest.


    References
 Top
 Abstract
 Introduction
 Synovitis in osteoarthritis
 Chronic synovitis
 Angiogenesis and inflammation
 Angiogenesis in the bone...
 Angiogenesis and the sensory...
 Therapeutic implications
 Conclusion
 References
 

  1. Conrozier T, Chappuis-Cellier C, Richard M, Mathieu P, Richard S, Vignon E. Increased serum C-reactive protein levels by immunonephelometry in patients with rapidly destructive hip osteoarthritis. Rev Rhum Engl Ed 1998;65:759–65.[Medline]
  2. Spector TD, Hart DJ, Nandra D et al. Low-level increases in serum C-reactive protein are present in early osteoarthritis of the knee and predict progressive disease. Arthritis Rheum 1997;40:723–7.[ISI][Medline]
  3. Case JP, Baliunas AJ, Block JA. Lack of efficacy of acetaminophen in treating symptomatic knee osteoarthritis: a randomized, double-blind, placebo-controlled comparison trial with diclofenac sodium. Arch Intern Med 2003;163:169–78.[Abstract/Free Full Text]
  4. Cicuttini FM, Baker J, Hart DJ, Spector TD. Association of pain with radiological changes in different compartments and views of the knee joint. Osteoarthritis Cartilage 1996;4:143–7.[ISI][Medline]
  5. Freemont AJ, Peacock TE, Goupille P, Hoyland JA, O'Brien J, Jayson MI. Nerve ingrowth into diseased intervertebral disc in chronic back pain. Lancet 1997;350:178–81.[CrossRef][ISI][Medline]
  6. Gill SE, Bonnet CS, Suri S, Wilson D, Walsh DA. Neurovascular invasion at the osteochondral junction in osteoarthritis. Rheumatology 2004;43:ii5.
  7. Niissalo S, Hukkanen M, Imai S, Tornwall J, Konttinen YT. Neuropeptides in experimental and degenerative arthritis. Ann N Y Acad Sci 2002;966:384–99.[Abstract/Free Full Text]
  8. Bradley LA, Alberts KR. Psychological and behavioral approaches to pain management for patients with rheumatic disease. Rheum Dis Clin North Am 1999;25:215–32.[ISI][Medline]
  9. Haywood L, McWilliams DF, Pearson CI et al. Inflammation and angiogenesis in osteoarthritis. Arthritis Rheum 2003;48:2173–7.[CrossRef][ISI][Medline]
  10. Sowers M, Jannausch M, Stein E, Jamadar D, Hochberg M, Lachance L. C-reactive protein as a biomarker of emergent osteoarthritis. Osteoarthritis Cartilage 2002;10:595–601.[CrossRef][ISI][Medline]
  11. Ledingham J, Regan M, Jones A, Doherty M. Factors affecting radiographic progression of knee osteoarthritis. Ann Rheum Dis 1995;54:53–8.[Abstract]
  12. Fam AG, Morava-Protzner I, Purcell C, Young BD, Bunting PS, Lewis AJ. Acceleration of experimental lapine osteoarthritis by calcium pyrophosphate microcrystalline synovitis. Arthritis Rheum 1995;38:201–10.[Medline]
  13. Pelletier JP, Martel-Pelletier J, Abramson SB. Osteoarthritis, an inflammatory disease: potential implication for the selection of new therapeutic targets. Arthritis Rheum 2001;44:1237–47.[CrossRef][ISI][Medline]
  14. Walsh DA. Angiogenesis and arthritis. Rheumatology 1999;38:103–12.[Free Full Text]
  15. Pufe T, Petersen W, Tillmann B, Mentlein R. The splice variants VEGF121 and VEGF189 of the angiogenic peptide vascular endothelial growth factor are expressed in osteoarthritic cartilage. Arthritis Rheum 2001;44:1082–8.[CrossRef][ISI][Medline]
  16. Shahrara S, Volin MV, Connors MA, Haines GK, Koch AE. Differential expression of the angiogenic Tie receptor family in arthritic and normal synovial tissue. Arthritis Res 2002;4:201–8.[CrossRef][ISI][Medline]
  17. Nouri AM, Panayi GS, Goodman SM. Cytokines and the chronic inflammation of rheumatic disease. I. The presence of interleukin-1 in synovial fluids. Clin Exp Immunol 1984;55:295–302.[ISI][Medline]
  18. Koch AE, Kunkel SL, Burrows JC et al. Synovial tissue macrophage as a source of the chemotactic cytokine IL-8. J Immunol 1991;147:2187–95.[Abstract/Free Full Text]
  19. Lafyatis R, Thompson NL, Remmers EF et al. Transforming growth factor-beta production by synovial tissues from rheumatoid patients and streptococcal cell wall arthritic rats. Studies on secretion by synovial fibroblast-like cells and immunohistologic localization. J Immunol 1989;143:1142–8.[Abstract/Free Full Text]
  20. Di Giovine FS, Nuki G, Duff GW. Tumour necrosis factor in synovial exudates. Ann Rheum Dis 1988;47:768–72.[Abstract]
  21. Saha N, Moldovan F, Tardif G, Pelletier JP, Cloutier JM, Martel-Pelletier J. Interleukin-1beta-converting enzyme/caspase-1 in human osteoarthritic tissues: localization and role in the maturation of interleukin-1beta and interleukin-18. Arthritis Rheum 1999;42:1577–87.[CrossRef][ISI][Medline]
  22. Park CC, Morel JC, Amin MA, Connors MA, Harlow LA, Koch AE. Evidence of IL-18 as a novel angiogenic mediator. J Immunol 2001;167:1644–53.[Abstract/Free Full Text]
  23. Mirshahi F, Pourtau J, Li H et al. SDF-1 activity on microvascular endothelial cells: consequences on angiogenesis in in vitro and in vivo models. Thromb Res 2000;99:587–94.[CrossRef][ISI][Medline]
  24. Kanbe K, Takagishi K, Chen Q. Stimulation of matrix metalloprotease 3 release from human chondrocytes by the interaction of stromal cell-derived factor 1 and CXC chemokine receptor 4. Arthritis Rheum 2002;46:130–7.[CrossRef][ISI][Medline]
  25. Ruth JH, Volin MV, Haines GK III et al. Fractalkine, a novel chemokine in rheumatoid arthritis and in rat adjuvant-induced arthritis. Arthritis Rheum 2001;44:1568–81.[CrossRef][ISI][Medline]
  26. Volin MV, Woods JM, Amin MA, Connors MA, Harlow LA, Koch AE. Fractalkine: a novel angiogenic chemokine in rheumatoid arthritis. Am J Pathol 2001;159:1521–30.[Abstract/Free Full Text]
  27. Risau W, Drexler H, Mironov V et al. Platelet-derived growth factor is angiogenic in vivo. Growth Factors 1992;7:261–6.[Medline]
  28. Hamerman D, Taylor S, Kirschenbaum I et al. Growth factors with heparin binding affinity in human synovial fluid. Proc Soc Exp Biol Med 1987;186:384–9.[Abstract]
  29. Pufe T, Bartscher M, Petersen W, Tillmann B, Mentlein R. Expression of pleiotrophin, an embryonic growth and differentiation factor, in rheumatoid arthritis. Arthritis Rheum 2003;48:660–7.[CrossRef][ISI][Medline]
  30. Souttou B, Raulais D, Vigny M. Pleiotrophin induces angiogenesis: involvement of the phosphoinositide-3 kinase but not the nitric oxide synthase pathways. J Cell Physiol 2001;187:59–64.[CrossRef][ISI][Medline]
  31. Koch AE, Halloran MM, Haskell CJ, Shah MR, Polverini PJ. Angiogenesis mediated by soluble forms of E-selectin and vascular cell adhesion molecule-1. Nature 1995;376:517–9.[CrossRef][ISI][Medline]
  32. Koch AE, Turkiewicz W, Harlow LA, Pope RM. Soluble E-selectin in arthritis. Clin Immunol Immunopathol 1993;69:29–35.[CrossRef][ISI][Medline]
  33. Klimiuk PA, Sierakowski S, Latosiewicz R et al. Soluble adhesion molecules (ICAM-1, VCAM-1, and E-selectin) and vascular endothelial growth factor (VEGF) in patients with distinct variants of rheumatoid synovitis. Ann Rheum Dis 2002;61:804–9.[Abstract/Free Full Text]
  34. Fukushi J, Morisaki T, Shono T et al. Novel biological functions of interleukin-4: formation of tube-like structures by vascular endothelial cells in vitro and angiogenesis in vivo. Biochem Biophys Res Commun 1998;250:444–8.[CrossRef][ISI][Medline]
  35. Cicuttini FM, Byron KA, Maher D, Wootton AM, Muirden KD, Hamilton JA. Serum IL-4, IL-10 and IL-6 levels in inflammatory arthritis. Rheumatol Int 1995;14:201–6.[ISI][Medline]
  36. Millward-Sadler SJ, Mackenzie A, Wright MO et al. Tachykinin expression in cartilage and function in human articular chondrocyte mechanotransduction. Arthritis Rheum 2003;48:146–56.[CrossRef][ISI][Medline]
  37. Meats JE, McGuire MK, Ebsworth NM, Englis DJ, Russell RG. Enhanced production of prostaglandins and plasminogen activator during activation of human articular chondrocytes by products of mononuclear cells. Rheumatol Int 1984;4:143–9.[CrossRef][ISI][Medline]
  38. Palmer RM, Hickery MS, Charles IG, Moncada S, Bayliss MT. Induction of nitric oxide synthase in human chondrocytes. Biochem Biophys Res Commun 1993;193:398–405.[CrossRef][ISI][Medline]
  39. Tetlow LC, Woolley DE. Histamine stimulates the proliferation of human articular chondrocytes in vitro and is expressed by chondrocytes in osteoarthritic cartilage. Ann Rheum Dis 2003;62:991–4.[Abstract/Free Full Text]
  40. Parker WL, Goldring MB, Philip A. Endoglin is expressed on human chondrocytes and forms a heteromeric complex with betaglycan in a ligand and type II TGFbeta receptor independent manner. J Bone Miner Res 2003;18:289–302.[ISI][Medline]
  41. Pfander D, Cramer T, Weseloh G et al. Hepatocyte growth factor in human osteoarthritic cartilage. Osteoarthritis Cartilage 1999;7:548–59.[CrossRef][ISI][Medline]
  42. Ollivierre F, Gubler U, Towle CA, Laurencin C, Treadwell BV. Expression of IL-1 genes in human and bovine chondrocytes: a mechanism for autocrine control of cartilage matrix degradation. Biochem Biophys Res Commun 1986;141:904–11.[ISI][Medline]
  43. Van Damme J, Bunning RA, Conings R, Graham R, Russell G, Opdenakker G. Characterization of granulocyte chemotactic activity from human cytokine-stimulated chondrocytes as interleukin 8. Cytokine 1990;2:106–11.[Medline]
  44. Villiger PM, Lotz M. Differential expression of TGF beta isoforms by human articular chondrocytes in response to growth factors. J Cell Physiol 1992;151:318–25.[ISI][Medline]
  45. Shinmei M, Masuda K, Kikuchi T, Shimomura Y. The role of cytokines in chondrocyte mediated cartilage degradation. J Rheumatol Suppl 1989;18:32–4.[Medline]
  46. Olee T, Hashimoto S, Quach J, Lotz M. IL-18 is produced by articular chondrocytes and induces proinflammatory and catabolic responses. J Immunol 1999;162:1096–100.[Abstract/Free Full Text]
  47. Nakanishi T, Kimura Y, Tamura T et al. Cloning of a mRNA preferentially expressed in chondrocytes by differential display-PCR from a human chondrocytic cell line that is identical with connective tissue growth factor (CTGF) mRNA. Biochem Biophys Res Commun 1997;234:206–10.[CrossRef][ISI][Medline]
  48. Shimo T, Nakanishi T, Nishida T et al. Connective tissue growth factor induces the proliferation, migration, and tube formation of vascular endothelial cells in vitro, and angiogenesis in vivo. J Biochem (Tokyo) 1999;126:137–45.[Abstract]
  49. Martel-Pelletier J, McCollum R, Fujimoto N, Obata K, Cloutier JM, Pelletier JP. Excess of metalloproteases over tissue inhibitor of metalloprotease may contribute to cartilage degradation in osteoarthritis and rheumatoid arthritis. Lab Invest 1994;70:807–15.[ISI][Medline]
  50. Maione TE, Gray GS, Petro J et al. Inhibition of angiogenesis by recombinant human platelet factor-4 and related peptides. Science 1990;247:77–9.[ISI][Medline]
  51. Endresen GK. Evidence for activation of platelets in the synovial fluid from patients with rheumatoid arthritis. Rheumatol Int 1989;9:19–24.[CrossRef][ISI][Medline]
  52. Marabini S, Matucci-Cerinic M, Geppetti P et al. Substance P and somatostatin levels in rheumatoid arthritis, osteoarthritis, and psoriatic arthritis synovial fluid. Ann N Y Acad Sci 1991;632:435–6.[ISI][Medline]
  53. Woltering EA, Barrie R, O'Dorisio TM et al. Somatostatin analogues inhibit angiogenesis in the chick chorioallantoic membrane. J Surg Res 1991;50:245–51.[ISI][Medline]
  54. van der Schaft DW, Toebes EA, Haseman JR, Mayo KH, Griffioen AW. Bactericidal/permeability-increasing protein (BPI) inhibits angiogenesis via induction of apoptosis in vascular endothelial cells. Blood 2000;96:176–81.[Abstract/Free Full Text]
  55. Punzi L, Peuravuori H, Jokilammi-Siltanen A, Bertazzolo N, Nevalainen TJ. Bactericidal/permeability increasing protein and proinflammatory cytokines in synovial fluid of psoriatic arthritis. Clin Exp Rheumatol 2000;18:613–5.[ISI][Medline]
  56. Volpert OV, Fong T, Koch AE et al. Inhibition of angiogenesis by interleukin 4. J Exp Med 1998;188:1039–46.[Abstract/Free Full Text]
  57. Pfander D, Cramer T, Deuerling D, Weseloh G, Swoboda B. Expression of thrombospondin-1 and its receptor CD36 in human osteoarthritic cartilage. Ann Rheum Dis 2000;59:448–54.[Abstract/Free Full Text]
  58. Lotz M, Moats T, Villiger PM. Leukemia inhibitory factor is expressed in cartilage and synovium and can contribute to the pathogenesis of arthritis. J Clin Invest 1992;90:888–96.[ISI][Medline]
  59. Martel-Pelletier J, Zafarullah M, Kodama S, Pelletier JP. In vitro effects of interleukin 1 on the synthesis of metalloproteases, TIMP, plasminogen activators and inhibitors in human articular cartilage. J Rheumatol Suppl 1991;27:80–4.[Medline]
  60. Moses MA, Sudhalter J, Langer R. Identification of an inhibitor of neovascularization from cartilage. Science 1990;248:1408–10.[ISI][Medline]
  61. Hiraki Y, Inoue H, Iyama K et al. Identification of chondromodulin I as a novel endothelial cell growth inhibitor. Purification and its localization in the avascular zone of epiphyseal cartilage. J Biol Chem 1997;272:32419–26.[Abstract/Free Full Text]
  62. Hiraki Y, Mitsui K, Endo N et al. Molecular cloning of human chondromodulin-I, a cartilage-derived growth modulating factor, and its expression in Chinese hamster ovary cells. Eur J Biochem 1999;260:869–78.[Abstract/Free Full Text]
  63. Walsh DA, Haywood L. Angiogenesis: a therapeutic target in arthritis. Curr Opin Investig Drugs 2001;2:1054–63.[Medline]
  64. Liekens S, De Clercq E, Neyts J. Angiogenesis: regulators and clinical applications. Biochem Pharmacol 2001;61:253–70.[CrossRef][ISI][Medline]
  65. Koch AE. Review: angiogenesis: implications for rheumatoid arthritis. Arthritis Rheum 1998;41:951–62.[CrossRef][ISI][Medline]
  66. Arenberg DA, Strieter RM. Angiogenesis. In: Gallin JI, Synderman R, eds. Inflammation: Basic Principles and Clinical Correlates. Philadelphia: Lippincott Williams & Wilkins, 1999;851–63.
  67. Lingen MW. Role of leukocytes and endothelial cells in the development of angiogenesis in inflammation and wound healing. Arch Pathol Lab Med 2001;125:67–71.[ISI][Medline]
  68. Sturmer T, Brenner H, Koenig W, Gunther KP. Severity and extent of osteoarthritis and low grade systemic inflammation as assessed by high sensitivity C reactive protein. Ann Rheum Dis 2004;63:200–5.[Abstract/Free Full Text]
  69. Dieppe PA, Alexander GJ, Jones HE et al. Pyrophosphate arthropathy: a clinical and radiological study of 105 cases. Ann Rheum Dis 1982;41:371–6.[Abstract]
  70. Sharif M, Elson CJ, Dieppe PA, Kirwan JR. Elevated serum C-reactive protein levels in osteoarthritis. Br J Rheumatol 1997;36:140–1.[Free Full Text]
  71. Wolfe F. The C-reactive protein but not erythrocyte sedimentation rate is associated with clinical severity in patients with osteoarthritis of the knee or hip. J Rheumatol 1997;24:1486–8.[ISI][Medline]
  72. Smith MD, Triantafillou S, Parker A, Youssef PP, Coleman M. Synovial membrane inflammation and cytokine production in patients with early osteoarthritis. J Rheumatol 1997;24:365–71.[ISI][Medline]
  73. Walsh DA, Wade M, Mapp PI, Blake DR. Focally regulated endothelial proliferation and cell death in human synovium. Am J Pathol 1998;152:691–702.[Abstract]
  74. Haynes MK, Hume EL, Smith JB. Phenotypic characterization of inflammatory cells from osteoarthritic synovium and synovial fluids. Clin Immunol 2002;105:315–25.[CrossRef][ISI][Medline]
  75. Oehler S, Neureiter D, Meyer-Scholten C, Aigner T. Subtyping of osteoarthritic synoviopathy. Clin Exp Rheumatol 2002;20:633–40.[ISI][Medline]
  76. Fernandez-Madrid F, Karvonen RL, Teitge RA, Miller PR, Negendank WG. MR features of osteoarthritis of the knee. Magn Reson Imaging 1994;12:703–9.[CrossRef][ISI][Medline]
  77. Fernandez-Madrid F, Karvonen RL, Teitge RA, Miller PR, An T, Negendank WG. Synovial thickening detected by MR imaging in osteoarthritis of the knee confirmed by biopsy as synovitis. Magn Reson Imaging 1995;13:177–83.[CrossRef][ISI][Medline]
  78. Cohen T, Nahari D, Cerem LW, Neufeld G, Levi BZ. Interleukin 6 induces the expression of vascular endothelial growth factor. J Biol Chem 1996;271:736–41.[Abstract/Free Full Text]
  79. Houssiau FA, Devogelaer JP, Van Damme J, de Deuxchaisnes CN, Van Snick J. Interleukin-6 in synovial fluid and serum of patients with rheumatoid arthritis and other inflammatory arthritides. Arthritis Rheum 1988;31:784–8.[ISI][Medline]
  80. Uson J, Balsa A, Pascual-Salcedo D et al. Soluble interleukin 6(IL-6) receptor and IL-6 levels in serum and synovial fluid of patients with different arthropathies. J Rheumatol 1997;24:2069–75.[ISI][Medline]
  81. Gabay C, Kushner I. Acute-phase proteins and other systemic responses to inflammation. N Engl J Med 1999;340:448–54.[Free Full Text]
  82. Hoyland JA, Freemont AJ, Sharpe PT. Interleukin-6, IL-6 receptor, and IL-6 nuclear factor gene expression in Paget's disease. J Bone Miner Res 1994;9:75–80.[ISI][Medline]
  83. Middleton J, Manthey A, Tyler J. Insulin-like growth factor (IGF) receptor, IGF-I, interleukin-1 beta (IL-1 beta), and IL-6 mRNA expression in osteoarthritic and normal human cartilage. J Histochem Cytochem 1996;44:133–41.[Abstract/Free Full Text]
  84. Vignon E, Balblanc JC, Mathieu P, Louisot P, Richard M. Metalloprotease activity, phospholipase A2 activity and cytokine concentration in osteoarthritis synovial fluids. Osteoarthritis Cartilage 1993;1:115–20.[Medline]
  85. Couderc P, Phelip X, Mouries D, Gras JP, Pasquier D, Cabanel G. The synovial membrane in articular chondrocalcinosis. Clinico-pathological data. Rev Rhum Mal Osteoartic 1978;45:703–6.[Medline]
  86. Swan A, Heywood B, Chapman B, Seward H, Dieppe P. Evidence for a causal relationship between the structure, size, and load of calcium pyrophosphate dihydrate crystals, and attacks of pseudogout. Ann Rheum Dis 1995;54:825–30.[Abstract]
  87. Cheung HS, Story MT, McCarty DJ. Mitogenic effects of hydroxyapatite and calcium pyrophosphate dihydrate crystals on cultured mammalian cells. Arthritis Rheum 1984;27:668–74.[ISI][Medline]
  88. Guerne PA, Terkeltaub R, Zuraw B, Lotz M. Inflammatory microcrystals stimulate interleukin-6 production and secretion by human monocytes and synoviocytes. Arthritis Rheum 1989;32:1443–52.[ISI][Medline]
  89. Liu R, O'Connell M, Johnson K, Pritzker K, Mackman N, Terkeltaub R. Extracellular signal-regulated kinase 1/extracellular signal-regulated kinase 2 mitogen-activated protein kinase signaling and activation of activator protein 1 and nuclear factor kappaB transcription factors play central roles in interleukin-8 expression stimulated by monosodium urate monohydrate and calcium pyrophosphate crystals in monocytic cells. Arthritis Rheum 2000;43:1145–55.[CrossRef][ISI][Medline]
  90. Meng ZH, Hudson AP, Schumacher HR Jr, Baker JF, Baker DG. Monosodium urate, hydroxyapatite, and calcium pyrophosphate crystals induce tumor necrosis factor-alpha expression in a mononuclear cell line. J Rheumatol 1997;24:2385–8.[ISI][Medline]
  91. Buma P, Verschuren C, Versleyen D, Van der Kraan P, Oestreicher AB. Calcitonin gene-related peptide, substance P and GAP-43/B-50 immunoreactivity in the normal and arthrotic knee joint of the mouse. Histochemistry 1992;98:327–39.[CrossRef][ISI][Medline]
  92. Mapp PI, Kidd BL, Gibson SJ et al. Substance P-, calcitonin gene-related peptide- and C-flanking peptide of neuropeptide Y-immunoreactive fibres are present in normal synovium but depleted in patients with rheumatoid arthritis. Neuroscience 1990;37:143–53.[CrossRef][ISI][Medline]
  93. Mayer DJ, Mao J, Holt J, Price DD. Cellular mechanisms of neuropathic pain, morphine tolerance, and their interactions. Proc Natl Acad Sci USA 1999;96:7731–6.[Abstract/Free Full Text]
  94. Fortier LA, Nixon AJ. Distributional changes in substance P nociceptive fiber patterns in naturally osteoarthritic articulations. J Rheumatol 1997;24:524–30.[ISI][Medline]
  95. Perrot S, Guilbaud G. Pathophysiology of joint pain. Rev Rhum Engl Ed 1996;63:485–92.[Medline]
  96. Konttinen YT, Kemppinen P, Segerberg M et al. Peripheral and spinal neural mechanisms in arthritis, with particular reference to treatment of inflammation and pain. Arthritis Rheum 1994;37:965–82.[ISI][Medline]
  97. Kidd BL, Urban LA. Mechanisms of inflammatory pain. Br J Anaesth 2001;87:3–11.[Abstract/Free Full Text]
  98. Smith RJ, Justen JM, Ulrich RG, Lund JE, Sam LM. Induction of neutral proteinase and prostanoid production in bovine nasal chondrocytes by interleukin-1 and tumor necrosis factor alpha: modulation of these cellular responses by interleukin-6 and platelet-derived growth factor. Clin Immunol Immunopathol 1992;64:135–44.[CrossRef][ISI][Medline]
  99. Sandy JD. Proteolytic degradation of normal and osteoarthritic cartilage matrix. In: Brandt KD, Doherty M, Lohmander LS, eds. Osteoarthritis. New York: Oxford University Press, 2003;82–91.
  100. Sunderkotter C, Goebeler M, Schulze-Osthoff K, Bhardwaj R, Sorg C. Macrophage-derived angiogenesis factors. Pharmacol Ther 1991;51:195–216.[CrossRef][ISI][Medline]
  101. Ben-Av P, Crofford LJ, Wilder RL, Hla T. Induction of vascular endothelial growth factor expression in synovial fibroblasts by prostaglandin E and interleukin-1: a potential mechanism for inflammatory angiogenesis. FEBS Lett 1995;372:83–7.[CrossRef][ISI][Medline]
  102. Blotnick S, Peoples GE, Freeman MR, Eberlein TJ, Klagsbrun M. T lymphocytes synthesize and export heparin-binding epidermal growth factor-like growth factor and basic fibroblast growth factor, mitogens for vascular cells and fibroblasts: differential production and release by CD4+ and CD8+ T cells. Proc Natl Acad Sci USA 1994;91:2890–4.[Abstract/Free Full Text]
  103. Kibbey MC, Corcoran ML, Wahl LM, Kleinman HK. Laminin SIKVAV peptide-induced angiogenesis in vivo is potentiated by neutrophils. J Cell Physiol 1994;160:185–93.[ISI][Medline]
  104. Jackson JR, Minton JA, Ho ML, Wei N, Winkler JD. Expression of vascular endothelial growth factor in synovial fibroblasts is induced by hypoxia and interleukin 1beta. J Rheumatol 1997;24:1253–9.[ISI][Medline]
  105. Bunn HF, Poyton RO. Oxygen sensing and molecular adaptation to hypoxia. Physiol Rev 1996;76:839–85.[Abstract/Free Full Text]
  106. van Hinsbergh VWM, Koolwijk P, Hanemaaijer R. Role of fibrin and plasminogen activators in repair-associated angiogenesis: In vitro studies with human endothelial cells. In: Goldberg ID, Rosen EM, eds. Regulation of angiogenesis. Basel: Birkhauser, 1997:391–411.
  107. Giatromanolaki A, Sivridis E, Athanassou N et al. The angiogenic pathway ‘vascular endothelial growth factor/flk-1(KDR)-receptor’ in rheumatoid arthritis and osteoarthritis. J Pathol 2001;194:101–8.[CrossRef][ISI][Medline]
  108. Stevens CR, Blake DR, Merry P, Revell PA, Levick JR. A comparative study by morphometry of the microvasculature in normal and rheumatoid synovium. Arthritis Rheum 1991;34:1508–13.[ISI][Medline]
  109. Giatromanolaki A, Sivridis E, Maltezos E et al. Upregulated hypoxia inducible factor-1alpha and -2alpha pathway in rheumatoid arthritis and osteoarthritis. Arthritis Res Ther 2003;5:R193–201.[CrossRef][ISI][Medline]
  110. Lee SS, Joo YS, Kim WU et al. Vascular endothelial growth factor levels in the serum and synovial fluid of patients with rheumatoid arthritis. Clin Exp Rheumatol 2001;19:321–4.[ISI][Medline]
  111. Harada M, Mitsuyama K, Yoshida H et al. Vascular endothelial growth factor in patients with rheumatoid arthritis. Scand J Rheumatol 1998;27:377–80.[CrossRef][ISI][Medline]
  112. Koch AE, Harlow LA, Haines GK et al. Vascular endothelial growth factor. A cytokine modulating endothelial function in rheumatoid arthritis. J Immunol 1994;152:4149–56.[Abstract/Free Full Text]
  113. Semble EL, Turner RA, McCrickard EL. Rheumatoid arthritis and osteoarthritis synovial fluid effects on primary human endothelial cell cultures. J Rheumatol 1985;12:237–41.[ISI][Medline]
  114. Lupia E, Montrucchio G, Battaglia E, Modena V, Camussi G. Role of tumor necrosis factor-alpha and platelet-activating factor in neoangiogenesis induced by synovial fluids of patients with rheumatoid arthritis. Eur J Immunol 1996;26:1690–4.[ISI][Medline]
  115. Sipe JD. Acute-phase proteins in osteoarthritis. Semin Arthritis Rheum 1995;25:75–86.[ISI][Medline]
  116. Dvorak HF, Brown LF, Detmar M, Dvorak AM. Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis. Am J Pathol 1995;146:1029–39.[Abstract]
  117. Koch AE, Burrows JC, Haines GK, Carlos TM, Harlan JM, Leibovich SJ. Immunolocalization of endothelial and leukocyte adhesion molecules in human rheumatoid and osteoarthritic synovial tissues. Lab Invest 1991;64:313–20.[ISI][Medline]
  118. Fox SB, Turner GD, Gatter KC, Harris AL. The increased expression of adhesion molecules ICAM-3, E- and P-selectins on breast cancer endothelium. J Pathol 1995;177:369–76.[ISI][Medline]
  119. Jackson JR, Seed MP, Kircher CH, Willoughby DA, Winkler JD. The codependence of angiogenesis and chronic inflammation. Faseb J 1997;11:457–65.[Abstract/Free Full Text]
  120. Walsh DA, Hu DE, Mapp PI, Polak JM, Blake DR, Fan TP. Innervation and neurokinin receptors during angiogenesis in the rat sponge granuloma. Histochem J 1996;28:759–69.[ISI][Medline]
  121. Bromley M, Bertfield H, Evanson JM, Woolley DE. Bidirectional erosion of cartilage in the rheumatoid knee joint. Ann Rheum Dis 1985;44:676–81.[Abstract]
  122. Fenwick SA, Gregg PJ, Rooney P. Osteoarthritic cartilage loses its ability to remain avascular. Osteoarthritis Cartilage 1999;7: 441–52.[CrossRef][ISI][Medline]
  123. Sledge CB, Reddi AH, Walsh DA, Blake DR. Biology of the normal joint. In: Ruddy S, Harris EDJ, Sledge CB, eds. Kelley's Textbook of Rheumatology, Vol. 1. Philadelphia: W. B. Saunders, 2001;1–26.
  124. Deckers MM, van Bezooijen RL, van der Horst G et al. Bone morphogenetic proteins stimulate angiogenesis through osteoblast-derived vascular endothelial growth factor A. Endocrinology 2002; 143:1545–53.[Abstract/Free Full Text]
  125. Babarina AV, Mollers U, Bittner K, Vischer P, Bruckner P. Role of the subchondral vascular system in endochondral ossification: endothelial cell-derived proteinases derepress late cartilage differentiation in vitro. Matrix Biol 2001;20:205–13.[CrossRef][ISI][Medline]
  126. Stevens DA, Williams GR. Hormone regulation of chondrocyte differentiation and endochondral bone formation. Mol Cell Endocrinol 1999;151:195–204.[CrossRef][ISI][Medline]
  127. Bittner K, Vischer P, Bartholmes P, Bruckner P. Role of the subchondral vascular system in endochondral ossification: endothelial cells specifically derepress late differentiation in resting chondrocytes in vitro. Exp Cell Res 1998;238:491–7.[CrossRef][ISI][Medline]
  128. Chen P, Vukicevic S, Sampath TK, Luyten FP. Osteogenic protein-1 promotes growth and maturation of chick sternal chondrocytes in serum-free cultures. J Cell Sci 1995;108:105–14.[Abstract/Free Full Text]
  129. Bouletreau PJ, Warren SM, Spector JA et al. Hypoxia and VEGF up-regulate BMP-2 mRNA and protein expression in microvascular endothelial cells: implications for fracture healing. Plast Reconstr Surg 2002;109:2384–97.[ISI][Medline]
  130. Maes C, Carmeliet P, Moermans K et al. Impaired angiogenesis and endochondral bone formation in mice lacking the vascular endothelial growth factor isoforms VEGF164 and VEGF188. Mech Dev 2002;111:61–73.[CrossRef][ISI][Medline]
  131. Moskowitz RW, Goldberg VM. Studies of osteophyte pathogenesis in experimentally induced osteoarthritis. J Rheumatol 1987;14:311–20.[ISI][Medline]
  132. Hermanson A, Dalsgaard CJ, Bjorklund H, Lindblom U. Sensory reinnervation and sensibility after superficial skin wounds in human patients. Neurosci Lett 1987;74:377–82.[CrossRef][ISI][Medline]
  133. Stephens RW, Ghosh P, Taylor TK. The pathogenesis of osteoarthrosis. Med Hypotheses 1979;5:809–16.[CrossRef][ISI][Medline]
  134. Kauppila LI. Ingrowth of blood vessels in disc degeneration. Angiographic and histological studies of cadaveric spines. J Bone Joint Surg Am 1995;77:26–31.[Abstract]
  135. Ashton IK, Roberts S, Jaffray DC, Polak JM, Eisenstein SM. Neuropeptides in the human intervertebral disc. J Orthop Res 1994;12:186–92.[ISI][Medline]
  136. Brain SD, Williams TJ, Tippins JR, Morris HR, MacIntyre I. Calcitonin gene-related peptide is a potent vasodilator. Nature 1985;313:54–6.[ISI][Medline]
  137. Eglezos A, Giuliani S, Viti G, Maggi CA. Direct evidence that capsaicin-induced plasma protein extravasation is mediated through tachykinin NK1 receptors. Eur J Pharmacol 1991;209:277–9.[CrossRef][ISI][Medline]
  138. Xu XJ, Dalsgaard CJ, Maggi CA, Wiesenfeld-Hallin Z. NK-1, but not NK-2, tachykinin receptors mediate plasma extravasation induced by antidromic C-fiber stimulation in rat hindpaw: demonstrated with the NK-1 antagonist CP-96,345 and the NK-2 antagonist Men 10207. Neurosci Lett 1992;139:249–52.[CrossRef][ISI][Medline]
  139. DeLeo JA, Yezierski RP. The role of neuroinflammation and neuroimmune activation in persistent pain. Pain 2001;90:1–6.[CrossRef][ISI][Medline]
  140. Haegerstrand A, Dalsgaard CJ, Jonzon B, Larsson O, Nilsson J. Calcitonin gene-related peptide stimulates proliferation of human endothelial cells. Proc Natl Acad Sci USA 1990;87:3299–303.[Abstract/Free Full Text]
  141. Ziche M, Morbidelli L, Pacini M, Geppetti P, Alessandri G, Maggi CA. Substance P stimulates neovascularization in vivo and proliferation of cultured endothelial cells. Microvasc Res 1990;40: 264–78.[ISI][Medline]
  142. Ziche M, Morbidelli L, Geppetti P, Maggi CA, Dolara P. Substance P induces migration of capillary endothelial cells: a novel NK-1 selective receptor mediated activity. Life Sci 1991;48:PL7–11.[CrossRef][ISI][Medline]
  143. Seegers HC, Hood VC, Kidd BL, Cruwys SC, Walsh DA. Enhancement of angiogenesis by endogenous substance P release and neurokinin-1 receptors during neurogenic inflammation. J Pharmacol Exp Ther 2003;306:8–12.[Abstract/Free Full Text]
  144. Seegers HC, Avery PS, McWilliams DF, Haywood L, Walsh DA. Combined effect of bradykinin B2 and neurokinin-1 receptor activation on endothelial cell proliferation in acute synovitis. FASEB J 2004;18:762–4.[Abstract/Free Full Text]
Submitted 27 February 2004; Accepted 28 June 2004





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