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Rheumatology Advance Access originally published online on May 21, 2008
Rheumatology 2008 47(10):1452-1460; doi:10.1093/rheumatology/ken199
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© The Author 2008. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

REVIEWS

Osteoarthritis: a problem of growth not decay?

R. M. Aspden

Department of Orthopaedics, University of Aberdeen, Institute of Medical Sciences, Aberdeen, UK.

Correspondence to: R. M. Aspden, Department of Orthopaedics, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen AB25 2ZD, UK. E-mail: r.aspden{at}abdn.ac.uk


   Abstract
Top
 Abstract
Introduction
 Bone
 Ligament, capsule and synovium
 Muscle
 Obesity and adipose tissue
 Nervous system
 Vascular changes
 Articular cartilage
 Genetics and epigenetics
 Conclusions and clinical...
 Acknowledgements
 References
 
The traditional view of OA is that it is primarily a disease of articular cartilage that results, by altering the biomechanics of the joint, in secondary changes to the subchondral bone and, through secondary inflammation, other joint tissues. This focus on cartilage tends to ignore other musculoskeletal changes reported, especially those remote from affected joints. It has been proposed instead that generalized OA is a systemic musculoskeletal disorder with a metabolic component. Evidence for this position will be presented by summarizing changes identified in all the major musculoskeletal tissues. This will endeavour to show the links between these tissues, most of which have a common mesenchymal origin. Dysregulated tissue turnover, with the balance in favour of growth, will be seen to be a common thread underlying many of the changes described. It is proposed that the production of new tissue in the midst of existing tissue, in the wrong place and at the wrong time, could result in the changes observed and that reversion of cellular behaviour to an earlier, developmental-like, phenotype may provide a mechanism that could drive the disease process. New therapies may arise both from recognizing this whole musculoskeletal disease phenotype and by exploring what might be the factors underlying this cellular reversion.

KEY WORDS: Osteoarthritis, Systemic disease, Metabolic disease, Aetiology, Growth, Hypertrophy


   Introduction
Top
 Abstract
 Introduction
Bone
 Ligament, capsule and synovium
 Muscle
 Obesity and adipose tissue
 Nervous system
 Vascular changes
 Articular cartilage
 Genetics and epigenetics
 Conclusions and clinical...
 Acknowledgements
 References
 
Primary OA is a complex disorder whose aetiology is largely unknown. Descriptions of the pathogenesis of OA have undergone many revisions since it was first described but, despite the name, the focus in recent decades has predominantly been on the articular cartilage of the synovial joints as the affected tissue and biomechanics as the causative agent. Changes in other tissues are believed to be secondary; subchondral bone responding to abnormal biomechanics and other tissues to secondary inflammation and enforced inactivity (Fig. 1). Here I shall examine the effects of disease on other tissues and try to show that, although ‘cartilage first’ cannot be ruled out, it is not the only, or indeed necessarily the best, explanation for the hypertrophic changes commonly observed. Similarly, although biomechanics undoubtedly plays an important role in the progression of the disease its part in the incidence of primary generalized disease is less clear. It may be the factor that determines in any individual which joint displays the first symptoms but the underlying hypothesis here is that metabolic and systemic factors are already driving the disease process.


Figure 1
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  		FIG. 1. Risk factors for Primary OA and the target tissues. The traditional view recognizes systemic factors but tends to see these acting on the cartilage with secondary changes in bone and other tissues.

 
Disease definitions by professional societies and in text books try to include pathological changes in most other joint tissues and many articles start by mentioning whole joint involvement. Some, indeed, have advocated OA as a whole organ disease; the joint being the organ [1]. Despite this, most definitions and articles then move rapidly to focus almost exclusively on the articular cartilage and it has been pointed out that the enormous effort that goes into cartilage-related research shows that the attention paid to other tissues is merely lip-service [2]. The loss of cartilage is visible by radiography as ‘joint space narrowing’ and clearly the eventual loss of this smooth, compliant-bearing surface will have major implications for joint function. Until recently, however, the overwhelming attention given to this tissue had produced little in the way of therapeutic targets or any significant advance in our understanding of the aetiology of the disease. Following the identification of a plethora of degradative enzymes in cartilage and, in particular, the discovery that ADAMTS-5 (a disintegrin and metalloproteinase with thrombospondin-like motifs) is a major aggrecanase in articular cartilage and that its inactivation in a mouse model of OA markedly reduces cartilage degeneration [3, 4], this all seems to have changed. But has it? Successfully limiting cartilage degeneration may slow the progression of the disease but does it really treat the disease as a whole? It may, where cartilage damage or defective mechanical properties are the main drivers of incidence or progression, such as, for instance, following trauma or other secondary OA. But what about primary OA?

Clinically, a variety of signs and symptoms are used to define OA and it is interesting that more of these are related to bone (subchondral sclerosis, so-called ‘cysts’ and osteophyte formation) or functionally related to other tissues (pain, stiffness, limitation of movement and muscle weakness) than they are to cartilage which has no pain sensors and whose degeneration may have little biomechanical effect on joint function until it has almost gone. How can we explain the changes observed in so many other tissues? Traditionally all the other musculoskeletal changes have been attributed as secondary to cartilage degeneration; e.g. overloading of the bone, leading to sclerosis and pain, resulting in lower levels of activity, consequent muscle weakness and weight gain. But this still leaves a lot of questions unanswered. Why is the involvement of one joint such a high risk factor for disease in the contralateral joint [5, 6]? Why is hand OA so commonly found with large joint (hip or knee) OA [7–9]? Why is obesity linked to hand OA [10] and are the epidemiologists right to suggest a systemic involvement [6, 11]? Even when other tissues are recognized to play a vital role can all these unanswered questions and all changes in so many tissues described below all be attributed simply to biomechanical factors [2]?

In this article, I shall propose that OA, at least in its generalized form, is a systemic musculoskeletal disease (Fig. 2), further developing ideas presented previously [12]. Specifically, I suggest that it is characterized by excessive and poorly regulated growth of musculoskeletal tissues, possibly resulting from cells reverting to an earlier developmental phenotype. This results in new tissue being formed in the wrong place and at the wrong time resulting in a loss of proper function. I shall briefly discuss in turn the evidence underlying the changes in each tissue, leaving cartilage until last as it is here, perhaps, that counter-arguments may be the strongest. I will finish with a brief look at some factors that could underlie these changes; genetic, epigenetic and environmental. Painting on a broad canvas may challenge orthodoxy and stimulate research into new areas and, thereby, encourage a more holistic view of this disabling and costly disease.


Figure 2
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  		FIG. 2. Primary OA as a systemic disease. The hypothesis proposed here is that systemic factors result in altered metabolism and induce dysregulated turnover and growth of many tissues, although the underlying cause is still unknown. Local factors may modulate this and result in damage to specific joints.

 

   Bone
Top
 Abstract
 Introduction
 Bone
Ligament, capsule and synovium
 Muscle
 Obesity and adipose tissue
 Nervous system
 Vascular changes
 Articular cartilage
 Genetics and epigenetics
 Conclusions and clinical...
 Acknowledgements
 References
 
OA changes in juxta-articular bone are well known with sclerosis of the subchondral bone, the formation of cysts within it, and the development of osteophytes by endochondral ossification. Patients with OA pathology evident on hip radiographs were found to have a higher than average BMD not only in the hip but also in the distal radius, vertebrae and calcaneus [13]. Underlying this is evidence from scintigraphy, using technetium 99 m, showing higher levels of bone forming activity in joints with OA pathology [14–16]. Laboratory studies have found alterations in the bone matrix and in osteoblast behaviour. In the hip, there is a greater volume of cancellous bone; in our studies, it was increased by ~60% suggesting an increased formation of bone. Electron microscopy showed the cancellous bone to have an appearance similar to woven bone, found in fracture repair [17], with a reduced matrix mineralization [18–20]. Alongside this there was also evidence for enhanced osteoclastic activity [17] and for increased bone remodelling [21] (Fig. 3). Increased amounts of bone were found in the iliac crest of patients with OA of the hand [22, 23] and together with higher levels of growth factors [24] supported the suggestion that OA may be a part of a generalized bone disease.


Figure 3
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  		FIG. 3. Scanning electron micrograph of subchondral bone from a 75-yr-old patient with OA showing the porous and coarse texture of the bone matrix. (Scale bar 100 µm).

 
These matrix changes are reflected in cellular changes. It has been reported that osteoblasts from patients with hip OA express higher levels of mRNA for IL-6 and RANK [25]. Protein synthesis of various cytokines has been found to be increased in OA subchondral bone in general, including IL-8, IL-10 and TNF-{alpha} [26] and, more specifically, synthesis of IL-6, IL-8 and TGF-β was higher by osteoblasts from sites of sclerosis compared with non-sclerotic regions [27]. Both studies, therefore, suggest a pro-inflammatory environment and the active involvement of subchondral bone. An association between the ratio of RANKL/OPG [RANK Ligand and osteoprotegerin (OPG), which is a decoy receptor for RANKL] and bone turnover indices found in control tissue was lost in OA, suggesting that bone turnover is regulated differently in OA [21]. Similarly, studies using bone taken at knee arthroplasty found that osteoblasts expressed more IL-6 and Insulin-like Growth Factor-1 (IGF-1) [28] and were more responsive to IGF-1 stimulation, acting through p42/p44 mitogen-activated protein kinase (MAPK) [29]. Elevated production of prostaglandins and leukotrienes has been reported in osteoblasts and suggested as a marker of disease [30]. Inhibiting their production was then suggested as a possible therapeutic target [31]. The elevated levels of arachidonic acid found in bone marrow fat (see subsequently) may provide the starting material for these and be part of a positive feedback mechanism helping to drive the increased bone formation. Inhibiting the synthesis of prostaglandins, using NSAIDs, appears to reduce bone formation; they inhibit heterotopic bone formation following arthroplasty [32] and are reported to delay fracture healing in animal models [33].

Other factors may also be driving bone formation. Preliminary gene array studies of Wnt signalling pathways show that these are active in bone and that there is differential expression between osteoblasts from patients with OA and those with osteoporosis [34]. Wnts form a family of molecules primarily identified with developmental processes and organogenesis, hence we hypothesized that re-activation of these pathways could underlie some of the many growth process described subsequently. Bone growth in OA is characterized by osteophytosis and subchondral sclerosis. Osteophytes are outgrowths of bone capped by cartilage found in most patients at the margins of diarthrodial and zygoapophyseal joints and vertebral bodies or as outgrowths in the central portions of the articular space in ~15% of patients [35]. Osteophytes are features of OA and are formed by a process of endochondral ossification [36], with many similarities to bone formation during development (reviewed in [37]). This review also likened the signalling pathways activated during osteophyte formation to those found in callus formation during fracture repair [37]. Mechanical instability induced in animal models of OA, e.g. by severing a cruciate ligament, has been found to induce osteophytes and traditionally they have been viewed as being mechanically induced as an attempt to stabilize the joint. It is not obvious that mechanical loads are increased at the sites of osteophyte formation, especially at the joint margins and, indeed, mechanical factors have been found unnecessary [38]. It may be that these are places within the joint where new tissue can be formed without immediately being mechanically degraded. Bone growth in the absence of direct mechanical stimuli must look for other causes and one suggestion is that mechanical stimuli are transferred to biochemical signals, especially TGF-β [38, 39]. Similarly, sclerosis has traditionally been regarded as a reaction to cartilage loss and a resulting increase in loading of the joint. Several studies, however, have indicated that bone changes are evident concurrently with cartilage fibrillation [40] or even that sclerosis is evident radiographically before joint space narrowing [15, 41].

Against this background of increased bone formation, not only in the joint but also at distant sites, what is driving the formation of ‘cysts’? Cysts are cavities in the cancellous bone most common directly below the loaded articulating region [42]. They contain fluid and fibromyxoid material and are often surrounded by a rim of new bone and fibrous tissue. The mechanisms underlying cyst formation are still unclear and suggestions include either high pressure transmitted from the SF through subchondral microfractures [43] or traumatic bone necrosis following the loss of cartilage [44]. Whatever the initiating factors, removal of so much bone suggests activation of osteoclasts [42] and an imbalance between bone formation and removal. Early changes in the bone have been suggested by a recent study of OA patients in which sequential MR images indicated that cysts appeared to develop in regions of high MR signal, which have been described previously as ‘bone marrow oedema’ [45]. While they were careful not to extrapolate from oedema to cysts they did note that it is plausible that these areas of high signal are precursors to cyst formation. A pattern of bone marrow oedema has been shown to be associated with pain and subchondral microfractures even though the relationship with histopathological features of oedema was less clear [46]. Taken together these features raise the question of why, against a background of increased bone formation, and given that loading normally stimulates net bone formation, is there excessive bone formation in unloaded regions and bone resorption in loaded regions?

Finally, we have shown that the radiographic outline of the femoral head of patients with hip OA has a different shape to that of matched controls [47]. This shape can be quantified using Active Shape Modelling, which describes the shape in terms of independent ‘modes of variation’. Each image then receives a score for each mode, which describes how many S.D.s it lies from the overall mean. Figure 4 shows the modes found in this study to be most significantly associated with OA. This approach enabled discrimination of the OA group better than standard clinical assessment methods (Kellgren–Lawrence scores). In addition, those who progressed most rapidly to hip replacement could be identified as a sub-group [47]. It remains to be determined whether this was a pre-existing and, therefore, possibly predisposing shape or if this was due to early remodelling as the shape change could be seen to progress over the following 6 yrs.


Figure 4
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  		FIG. 4. Shape model overlaid on a radiograph and the three modes most significantly associated with OA. Illustrated are the ± 2 S.D. shapes for each mode; the solid line in each case shows the shape more commonly found in the OA group.

 

   Ligament, capsule and synovium
Top
 Abstract
 Introduction
 Bone
 Ligament, capsule and synovium
Muscle
 Obesity and adipose tissue
 Nervous system
 Vascular changes
 Articular cartilage
 Genetics and epigenetics
 Conclusions and clinical...
 Acknowledgements
 References
 
The joint capsule plays a vital, but commonly under-rated, role in the biomechanics of synovial joints, and capsular ligaments augment other ligaments and muscles to maintain joint stability [48]. In OA of the hip, progressive fibrosis of the capsule has been reported to result in thickening and shortening of the tissue and a loss of some of its customary flexibility [49]. Ruptures of the anterior cruciate ligament were found to be far more common in subjects with symptomatic knee OA [50]. Although it cannot be determined which came first, and such an injury is a known risk factor for secondary OA, it is possible that ligament damage arose after the onset of disease as a consequence of altered tissue biomechanical properties. Studies using the STR/ort mouse, which develops a spontaneous OA, have shown that cruciate ligament metabolism is up-regulated before radiological signs are present and that the tissue is weaker than in controls [51].

OA has not traditionally been seen as an inflammatory disorder and synovitis, common in early and late OA, is generally regarded as a secondary response to fragments of cartilage and soluble matrix molecules. It has been suggested that the synovial capsule and membrane, along with the subchondral bone, may account for many of the symptoms of the disease and that inflammation and stiffening within the joint capsule may accelerate joint destruction [52]. Elevated levels of cytokines, such as IL-1β and TNF-{alpha}, powerful regulators of inflammation, are found early in the disease process although it is not clear exactly where they are being produced [53]. This early appearance may, however, be indicative of a primary, chronic, if low-grade, inflammatory process [54, 55] rather than a response to tissue degradation.

The changes in quantity, appearance and viscosity of SF in OA are well documented in text books but, curiously, a recent study found high numbers of mesenchymal precursor cells in SF from OA patients [56]. Levels were higher than in RA; strongly suggesting that these are not simply arising as a consequence of an inflammatory process. These cells could form colonies and possessed the ability to differentiate down adipocytic, osteoblastic or chondrocytic pathways depending on the culture conditions. The origin of these cells is currently unknown but cells with stem cell-like properties are being identified in most joint tissues [57] and any of these tissues could, at least in principle, be the source. Multiplication of stem cells could underlie the proliferation of all the tissues being demonstrated here but their presence, and in what numbers, is only just beginning to be explored.


   Muscle
Top
 Abstract
 Introduction
 Bone
 Ligament, capsule and synovium
 Muscle
Obesity and adipose tissue
 Nervous system
 Vascular changes
 Articular cartilage
 Genetics and epigenetics
 Conclusions and clinical...
 Acknowledgements
 References
 
Most studies of muscle in OA have concentrated on the quadriceps, probably because of its controlling function in the knee joint. Quadriceps weakness associated with OA has been recognized in several studies [58, 59], along with a corresponding deficit in proprioception [60]. In the hip, a positive Trendelenburg sign is indicative of abductor muscle weakness and studies of the gluteus muscles have shown a greater loss of type-2 muscle fibres than in age-matched controls [61]. The traditional view is that this arises from disuse atrophy secondary to joint pain and that the instability resulting from muscle weakness leads to mechanical overload of the joint. This, however, is increasingly being questioned, to the extent that muscle motor and sensory dysfunction has been proposed as a causative factor in knee OA [62] and identified as a primary risk factor for knee pain and disability [63]. Some studies have reported that muscle changes were evident before symptomatic joint pain [63] and this could point to fundamental systemic pathology before the classic signs of joint degeneration are evident. A role in disease progression is less clear with some studies finding no association [64] while others claim to find a relationship [63].

In a prospective study, women who developed knee OA were found to have a highly significant, strong negative correlation between extensor strength and body weight [65], although in men a slight positive correlation was found, which did not quite reach significance. Roubenoff [66] has coined the phrase ‘sarcopenic obesity’ for muscle- and obesity-related changes in the elderly and pointed out that loss of muscle and gain of fat occur together and that this combination is particularly prevalent in OA. Atrophy of type-2 fibres and abnormal mosaic patterns of muscle fibre types were reported to be much more common in the vastus lateralis muscles of patients undergoing surgery for OA of the knee than in controls and it was suggested that these changes could arise from an associated motor neuron dysfunction. Similar abnormal mosaic patterns were not, however, found in the gluteus medius obtained from patients with OA of the hip or from control subjects [67]. Another study of changes in the vastus lateralis muscle of patients undergoing a total knee replacement reported evidence for neurogenic muscular atrophy in 32% in addition to atrophy of type-2 fibres attributed to reduced activity in all patients [68]. More surprisingly though, given the age and disease status of these individuals, this study also reported finding regenerative changes in 96% of those studied; further evidence for growth processes occurring at all levels in the musculoskeletal system. It is not clear why this should occur if OA is a degenerative cartilage disease of the elderly. Neuromuscular control and proprioception are also defective in OA [62, 69] and it may be that defective neuromuscular control provides a more satisfactory explanation than simple biomechanical joint instability for the feeling of ‘giving way’ reported by patients, especially for the hip joint which is intrinsically much more stable than the knee.


   Obesity and adipose tissue
Top
 Abstract
 Introduction
 Bone
 Ligament, capsule and synovium
 Muscle
 Obesity and adipose tissue
Nervous system
 Vascular changes
 Articular cartilage
 Genetics and epigenetics
 Conclusions and clinical...
 Acknowledgements
 References
 
Overall, the link between OA and obesity, generally seen as an increase in adipose tissue, is undisputed. Debate still exists, however, regarding the details of this relationship in different joints, between the sexes, between fat and lean mass, and between incidence and progression. Some recent reviews have explored this in more detail [70, 71]. Being overweight is known to predate the incidence of disease [72]. In both the Framingham and Chingford studies, [73, 74] BMI was linked to all patterns of knee OA. Links with hip OA were weaker but may exist with bilateral, but not unilateral, disease [72]. Biomechanical overloading is the favoured mechanism for subsequent cartilage degeneration but this is less obvious as an explanation for the relationship with hand OA [10, 75] in which increasing body mass would not be expected to increase loads in the finger joints. Increasingly, evidence is pointing away from a simple link between reduced activity due to joint pain leading to increased body mass. The discovery of adipokines secreted by adipose tissue, such as leptin, adiponectin and resistin, and the subsequent recognition of adipose tissue as an active endocrine organ has provided other possible mechanisms by which adipose tissue may have an effect on other tissues [71]. It has been established that leptin, for instance, can act both directly on osteoblasts [76] and chondrocytes [76, 77] as well as indirectly [78] on bone and has led to the suggestion of its direct involvement in OA [79]. Little is known yet of the actions of others of these factors, but recent reports have suggested a pro-inflammatory action for adiponectin and warned that the metabolic effects of the presence of adipose in and around joints cannot be ignored [80]. Finally, reducing fat mass was reported to give greater symptomatic relief than explained by the reduction in body weight [81], again suggesting a link other than mechanical.

However, There is not simply an increase in central adiposity in OA. We have shown that the bone marrow of cancellous bone from the femoral head contains twice the mass of fat per unit volume of tissue as osteoporotic (OP) bone [82]. This fat contains elevated levels of (n-6) fatty acids, especially arachidonic acid [82], which are substrates for the cyclo-oxygenase enzymes that result in the formation of prostaglandins, which are themselves pro-inflammatory mediators. MRI also indicates an altered distribution and proportion of fat in both the bone marrow and the muscles of patients with OA compared with age- and sex-matched healthy controls (Ahearn et al., submitted) (Fig. 5). Similarities between features of OA and atheromatous vascular disease have been noted [83] (see subsequently) and the role of lipids in calcification is an active area of study in the formation of atherosclerotic plaques [84] and the regulation of stem cell differentiation into osteoblasts and adipocytes [85]. Together these recent data strengthen support for our hypothesis that OA is a systemic disorder and that altered lipid metabolism may play a part in the progression, if not the incidence, of the disease [12].


Figure 5
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  		FIG. 5. Images showing the percentage of the MR signal that comes from fat. These were obtained from coronal images of the pelvis acquired on a Siemens Magnetom 0.95 T scanner (Siemens AG, Erlangen, Germany) and calculated using the Dixon 2-point technique [86]. Images were selected to show the mid-slice of the femur. Images from (a) control and (b) OA show different distributions of fat within the bone marrow. More fat was also found in and around the muscles, making identification of muscle boundaries difficult.

 

   Nervous system
Top
 Abstract
 Introduction
 Bone
 Ligament, capsule and synovium
 Muscle
 Obesity and adipose tissue
 Nervous system
Vascular changes
 Articular cartilage
 Genetics and epigenetics
 Conclusions and clinical...
 Acknowledgements
 References
 
Intractable pain is one of the key indicators for surgical treatment for OA. A review of pain mechanisms in OA has highlighted the importance of sensitization of both peripheral pain fibres, possibly by prostaglandins or other mediators, and the central nervous system, resulting in more diffuse symptoms and referred pain [87]. Although vascularization and innervation of OA cartilage has recently been reported [88], the deep-seated nature of the pain suggests that it is not simply a localized response to tissue damage or mechanical overload, although it may originate there. Once sensitization has occurred, however, trying to identify a unique source of pain may be too late as many sources may be contributing to the pain felt by the individual.

Pain fibres, however, are not the only neurological connection with the musculoskeletal system. Recent studies showing links between the endocrine, nervous and musculoskeletal systems, e.g the action of leptin on bone via a hypothalamic pathway [78], are emphasizing the importance of the interplay between these systems. Severe sensory neuropathy is known to cause rapid breakdown of joints; such as that found after minor trauma in patients with diabetic neuropathy, and was demonstrated in a dog model for OA in which interruption of sensory input from the ipsilateral limb promoted rapid progression of joint destruction after anterior cruciate ligament transection [60]. A growing number of neuropeptides and related enzymes have been detected in bone, including substance P, {alpha}-calcitonin gene-related peptide, vasointestinal peptide P, pituitary adenylate cyclase-activating peptide, neuropeptide Y, serotonin, glutamate, tyrosine hydroxylase and norepinephrine. Related receptors have been characterized to various bone cell lineages (reviewed in [89]). In addition, several additional genes have been identified, such as cocaine and amphetamine-regulated transcript (Cart), melanocortin 4 receptor (Mc4R) and the cannabinoid receptor CB1, which all show high levels of expression in the hypothalamus and the ability to regulate major physiological functions including bone remodelling, energy homeostasis and body weight [90]. The complexity of these mechanisms in musculoskeletal regulation is only just being appreciated but could the central nervous system play a pivotal role in the dysregulation of musculoskeletal homeostasis found in OA?


   Vascular changes
Top
 Abstract
 Introduction
 Bone
 Ligament, capsule and synovium
 Muscle
 Obesity and adipose tissue
 Nervous system
 Vascular changes
Articular cartilage
 Genetics and epigenetics
 Conclusions and clinical...
 Acknowledgements
 References
 
A vascular aetiology for OA has a long history [91] and a recent review has highlighted the possible roles that vascular pathology may play in the initiation and progression of OA [92]. Vascular invasion of the calcified cartilage from the subchondral bone has long been recognized as an early factor in the progression of the disease [93] and, more recently, it has been suggested that microvascular changes affecting the venous circulation in subchondral bone may accelerate the OA process, either by altering cartilage nutrition or through direct ischaemic effects on bone [71]. Epidemiological studies of comorbidity have indicated a high prevalence of vascular-related disorders in patients with end-stage hip OA and led to the suggestion that OA is linked to atheromatous vascular disease [84]. This has been framed into the recent hypothesis that OA, or at least structural progression of the disease, may be an atheromatous vascular disease of subchondral bone [94]. This hypothesis has the advantage of linking lipid and inflammatory processes, but may reflect a wider underlying process.


   Articular cartilage
Top
 Abstract
 Introduction
 Bone
 Ligament, capsule and synovium
 Muscle
 Obesity and adipose tissue
 Nervous system
 Vascular changes
 Articular cartilage
Genetics and epigenetics
 Conclusions and clinical...
 Acknowledgements
 References
 
Articular cartilage has been the focus of research into OA for decades and the literature is extensive. The role of the chondrocyte has been reviewed [95] and some key features are briefly summarized here. In OA, chondrocytes proliferate (clone) to form multiple cells within a chondron where typically in normal cartilage, even in the elderly, more than 2–3 cells is unusual. There is increased synthesis of the principal matrix molecules [53], including collagen type II [96] and aggrecan, but much of this seems to be exported to the SF rather than incorporated into tissue; elevated levels of aggrecan fragments in the synovial fluid have been taken to be a marker of increased turnover [97]. Curiously, a splice-variant form of type II collagen, Type IIA, normally expressed during development in chondroprogenitor cells, is re-expressed by adult articular chondrocytes in early and late-stage OA, indicating the potential reversion of the cells to an earlier developmental phenotype [98]. Elevated matrix synthesis is accompanied by increased synthesis of MMPs, prostaglandins and other inflammatory factors in OA tissue and this appears to be related to elevated levels of IL-1 and TNF-{alpha} [95, 99]. Interestingly, an association has been reported between histological severity of OA and lipid accumulation in the cartilage, especially arachidonic acid [100]. As in OA bone, these lipids, could provide a reservoir of pro-inflammatory precursors and are another indicator of abnormalities in lipid metabolism. Advancement and duplication of the tidemark [1, 101], which marks the junction between uncalcified and calcified cartilage, is another indicator of renewed growth and tissue formation, though the underlying mechanisms for this are still unknown.

Articular cartilage is a highly specialized tissue in which collagen fibrils reinforce a highly hydrated proteoglycan gel [102]; a biological fire-composite material. It is primarily the interactions between collagen and the other components that provide mechanical integrity [103–105], not simply a stiff collagen ‘network’ and a filler. Both the organization of the fibrils and interactions between the fibrils and the gel are tightly regulated during development to produce the appropriate mechanical properties. Proteoglycan, but not collagen, turnover then maintains the mechanical homeostasis of the adult tissue. A metabolically driven problem leading to excess synthesis of new matrix molecules together with a reversion of the chondrocytes to an earlier developmental phenotype could have the effect of weakening the tissue, either by trying to insert new tissue in the midst of old or by inappropriately trying to remodel the tissue. Such tissue weakening would then make it susceptible to mechanical damage. Chondrocytes, even in elderly tissue, respond to mechanical and chemokine stimuli [106] and to tissue damage [107], presumably to preserve the mechanical integrity. Once the tissue organization, including but not exclusively the spatial distribution of collagen, has been lost, however, it does not presently seem possible to restore it. The possible roles of the aggrecanases ADAMTS-4 and -5 in this process are currently the subject of intense investigation because of the promise they hold as targets for therapeutic interventions. Genetic variation in ADAMTS-5 appears to play no part in disease susceptibility [108] and a recent review has shown that in human tissue ADAMTS-5 is constitutively expressed whereas ADAMTS-4 is induced by pro-inflammatory cytokines [109]. Inhibiting whichever of these turns out to be the key player in cartilage destruction may provide a means of slowing cartilage loss but it is less clear whether this will be successful in curing the disease.


   Genetics and epigenetics
Top
 Abstract
 Introduction
 Bone
 Ligament, capsule and synovium
 Muscle
 Obesity and adipose tissue
 Nervous system
 Vascular changes
 Articular cartilage
 Genetics and epigenetics
Conclusions and clinical...
 Acknowledgements
 References
 
So what factors could underly the changes described above? OA is an age-related heritable disorder with a heritability reported to be between about 40% and 70% depending on the disease classification or the characteristic disease-related feature selected, which include obesity, muscle mass, and cartilage and bone turnover markers (reviewed in [110]). While some would try to split OA down in numerous subsets, depending largely on the joints affected, it may be that there is an underlying systemic predisposition and other factors, including biomechanics (which itself may have a genetic component e.g. hip or knee geometry), drive the particular joints most badly affected. Genetic linkage studies have so far identified a small number of genes that appear to confer susceptibility to OA. These include genes for IL-1, matrilin 3 (MATN3), IL-4 receptor {alpha}-chain (IL4R), secreted frizzle-related protein 3 (FRZB), the metalloproteinase ADAM12, asporin (ASPN) (reviewed in [111]), to which has been added growth differentiation factor 5 (GDF5), which appears stronger in Asian than European populations [112, 113] and, most recently, iodothyronine-deiodinase enzyme type 2 (D2) (DIO2) [114]. The mechanisms these represent are far from clear and much remains to be done to show a connection between genotype and phenotype. Gene association studies linked with the developing haplotype map (HapMap) [115] may help to identify haplotypes (i.e. combinations of several single nucleotide polymorphisms) related to disease incidence or progression. To achieve their maximum potential, however, both of these approaches are still dependent on rigorous definitions of disease phenotypes for OA, on which there is still no universal agreement.

More recently the discovery of other powerful mechanisms controlling gene transcription has opened up whole new areas of cellular regulation that have been little explored in relation to OA. Epigenetic modifications regulating chromatin structure, including histone methylation and acetylation, are transmissible at the cellular level and, starting from the early studies of the Dutch Famine Cohort, there is increasing evidence that these are heritable across generations [116] and may predispose to diseases such as hypertension [117] and to cardiovascular and diabetic mortality [118]. Alterations in DNA methylation, which can silence gene transcription, have been found in articular chondrocytes and proposed as having a role in the pathogenesis of OA [119, 120]. It will be interesting to see if similar modifications are found in mesenchymal stem cells from patients with OA and, if so, they may also be present in other musculoskeletal tissues. There is also increasing recognition that untranslated regions of DNA, rather than being ‘junk’, code for strands for RNA that control gene transcription and activation, and hence regulate almost all aspects of cellular behaviour. For instance, a class of short-stranded RNAs, called microRNAs (miRNA), can act as mediators of the RNA interference pathway and have been found to lead to silencing of their target genes. These have been found to regulate processes such as cell division and apoptosis [121], metabolism [122] and tumour proliferation, invasion and metastasis [123]. There is even evidence for activation related to diet; muscle defects emerged in Drosophila lacking the microRNA DmiR-1 only after they began the rapid phase of larval growth that begins with feeding on a protein-rich diet [124] and in mice miR-122 was shown to regulate cholesterol and fatty acid metabolism in the adult liver [125]. Finally, because most of the tissues affected by OA have a mesenchymal origin it may be that there are common mechanisms regulating them. Rather than investigating individual tissues or the signalling pathways one-at-a-time, large-scale gene expression studies in multiple tissues and studies of epigenetic modifications in mesenchymal tissues may enable common patterns of gene regulation to be identified.


   Conclusions and clinical implications
Top
 Abstract
 Introduction
 Bone
 Ligament, capsule and synovium
 Muscle
 Obesity and adipose tissue
 Nervous system
 Vascular changes
 Articular cartilage
 Genetics and epigenetics
 Conclusions and clinical...
Acknowledgements
 References
 
My hypothesis is that OA, at least in its primary, generalized form, is a problem that affects the whole musculoskeletal system. It results in dysregulated growth of tissue, possibly due to a reversion to an earlier developmental phenotype: faster turnover and proliferation of bone, increased adiposity leading to obesity, fibrosis of ligaments and joint capsule, altered muscle phenotype possibly including fat deposition and muscle weakness, proliferation of cartilage chondrocytes and increased matrix synthesis, but not incorporation, leading to weakened tissue and mechanical breakdown (Fig. 2). All the connective tissue cells derive from a mesenchymal origin and this, along with central neuronal regulation, may provide a source of common mechanisms driving the activity of these cell types. Identifying alterations in mesenchymal stem cells may provide new insights into the proliferation of these tissues. The particular joints affected most may be dependent on local biomechanical factors but the underlying disease is metabolic and systemic [12]. Elements of these pathological changes in the joints have been recognized before and Joseph Trueta commented, ‘The osteoarthritic process thus appears to be an attempt to transform a decaying joint into a youthful one’ [93]. Over 50 yrs on and our obsession with cartilage seems largely to have overshadowed many of these aspects of the primary disease process.

These observations have a number of clinical implications. The proliferation of tissues, including adipose, indicates that obesity may be a part of the disease process, not an independent self-inflicted factor. If epigenetic factors are involved, those up-regulating adiposity would compound the difficulty of losing weight for such patients. On the other hand, early dietary intervention to control weight may delay the incidence or slow the progression of disease [126], not simply by reducing the biomechanical demands on the joints but by modulating the adipokine profile. Such a holistic view also questions the ethical position of those who would refuse joint replacement surgery to obese OA patients who do not, or cannot, lose weight, even though such surgery may be more difficult and carry complications. Interventions such as the role of dietary fatty acids, known to be beneficial to cartilage [127] may be worth examining; as may be the role of exercise aimed at maintaining muscle fibre type, especially if these can be introduced early. Methods for identifying OA in its early stages, especially those who are going to progress most rapidly, then become paramount [47]. Such methods are also essential for the development and effective testing of disease modifying OA drugs (DMOADs) in relatively short periods of time. Identifying circulating or urinary factors, or combinations of factors, deriving from tissues other than cartilage, such as bone, muscle or fat, may also provide new biomarkers of disease. Tissue-engineering approaches to cartilage repair in OA are almost certain not to succeed. If the natural tissue has been destroyed and the underlying problem has not been addressed, what chance is there for implanted tissue to survive, especially as, at least initially, it is commonly biomechanically inferior to the original? There is a need to assess the whole patient, not just the sore joint. By doing this, and studying all the tissues involved, we may find the key underlying factors and be able to identify new therapeutic targets that can affect the onset of the disease or slow its progression from the early stages.

Formula


   Acknowledgements
Top
 Abstract
 Introduction
 Bone
 Ligament, capsule and synovium
 Muscle
 Obesity and adipose tissue
 Nervous system
 Vascular changes
 Articular cartilage
 Genetics and epigenetics
 Conclusions and clinical...
 Acknowledgements
References
 
I thank all the members, past and present, of the Orthopaedics Research Group whose work forms our contribution to the quest for a solution to this most disabling disease, and for their helpful criticism of the drafts of this article. I am grateful to all my surgical colleagues in the Grampian University Hospitals NHS Trust who have kindly allowed us to use tissue donated by their patients and provided many stimulating clinical insights.

Funding: The Medical Research Council, the Arthritis Research Campaign, the Engineering and Physical Sciences Research Council, the Sir Halley Stewart Trust and The Health Foundation funded research related to this work.

Disclosure statement: R.M.A. has received honoraria from Astra Zeneca and hold grant funding from TMRI Ltd.


   References
Top
 Abstract
 Introduction
 Bone
 Ligament, capsule and synovium
 Muscle
 Obesity and adipose tissue
 Nervous system
 Vascular changes
 Articular cartilage
 Genetics and epigenetics
 Conclusions and clinical...
 Acknowledgements
 References
 

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Submitted 20 February 2008; revised version accepted 15 April 2008.
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