PREFACE

Assalamualaikum Wr Wb I would like to thank to the one supreme God, Allah S.W.T for all blessing so through my works I could finish this paper in time. This paper would not have been possible without encourage from my family, my friends and so many lecturer whom I most grateful. Thank to my family that has supported me during writing this paper, our lecturer dr. Arsanto Triwidodo Sp. OT, FICS, K Spine, MHKes for him guidance and help on this paper. This paper, titled Metabolic Factors in Osteoarthritis I arranged in order to complete my assignment for the department of surgery of Koja Hospital. And also I want to thank my friends for their helps. Without their helps and supports, I would not able to finish this paper. To many other individuals who contributed while I was writing this paper. This paper is still far from perfect. There are a lot of mistakes in the writing, whether the grammar or the theory. I hope, after reading this paper, readers could give me some advices and critics that would develop my ability to write another better paper in the future. I apologize for all mistakes that I made in this paper; I hope this paper could be useful to the readers. Wassalamualaikum Wr Wb

Jakarta, November 2012

Sodiqa Aksiani

CHAPTER 1 OSTEOARTHRITIS

Osteoarthritis is the most common type of joint disease, affecting more than 20 million individuals in the United States alone. It represents a heterogeneous group of conditions resulting in common histopathologic and radiologic changes. It can be thought of as a degenerative disorder arising from biochemical breakdown of articular (hyaline) cartilage in the synovial joints. However, the current view holds that osteoarthritis involves not only the articular cartilage but also the entire joint organ, including the subchondral bone and synovium. Osteoarthritis predominantly involves the weight-bearing joints, including the knees, hips, cervical and lumbosacral spine, and feet. Other commonly affected joints include the distal interphalangeal (DIP), proximal interphalangeal (PIP), and carpometacarpal (CMC) joints. Although osteoarthritis was previously thought to be caused largely by excessive wear and tear, increasing evidence points to the contributions of abnormal mechanics and inflammation. Therefore, the term degenerative joint disease is no longer appropriate in referring to osteoarthritis. Historically, osteoarthritis has been divided into primary and secondary forms, though this division is somewhat artificial. Secondary osteoarthritis is conceptually easier to understand: It refers to disease of the synovial joints that results from some predisposing condition that has adversely altered the joint tissues (eg, trauma to articular cartilage or subchondral bone). Secondary osteoarthritis can occur in relatively young individuals.1 The definition of primary osteoarthritis is more nebulous. Although this form of osteoarthritis is related to the aging process and typically occurs in older individuals, it is, in the broadest sense of the term, an idiopathic phenomenon, occurring in previously intact joints and having no apparent initiating factor. Some clinicians limit the term primary osteoarthritis to the joints of the hands (specifically, the DIP and PIP joints and the joints at the base of the thumb). Others include the knees, hips, and spine (apophyseal articulations) as well.

As underlying causes of osteoarthritis are discovered, the term primary, or idiopathic, osteoarthritis may become obsolete. For instance, many investigators believe that most cases of primary osteoarthritis of the hip may, in fact, be due to subtle or even unrecognizable congenital or developmental defects. No specific laboratory abnormalities are associated with osteoarthritis. Rather, it is typically diagnosed on the basis of clinical findings, with or without radiographic studies (see Workup). The goals of osteoarthritis treatment include pain alleviation and improvement of functional status. Nonpharmacologic interventions are the cornerstones of osteoarthritis therapy and include the following:

Patient education Application of heat and cold Weight loss Exercise Physical therapy Occupational therapy Joint unloading, in certain joints (eg, knee and hip) pharmacologic therapy includes corticosteroid injection and

Intra-articular

viscosupplementation, which may provide pain relief and have an anti-inflammatory effect on the affected joint. Oral pharmacologic therapy begins with acetaminophen for mild or moderate pain without apparent inflammation. If the clinical response to acetaminophen is not satisfactory or the clinical presentation is inflammatory, consider nonsteroidal anti-inflammatory drugs (NSAIDs). (See Medication.) If all other modalities are ineffective and osteotomy is not viable, or if a patient cannot perform his or her daily activities despite maximal therapy, arthroplasty is indicated. The high prevalence of osteoarthritis entails significant costs to society. Direct costs include clinician visits, medications, and surgical intervention. Indirect costs include such items as time lost from work.
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Costs associated with osteoarthritis can be particularly significant for elderly persons, who face potential loss of independence and who may need help with daily living activities. As the populations of developed nations age over the coming decades, the need for better understanding of os Anatomy Joints can be classified in either functional or structural terms. A functional classification, based on movement, would categorize joints as follows:

Synarthroses (immovable) Amphiarthroses (slightly moveable) Diarthroses (freely moveable)

A structural classification would categorize joints as follows:

Synovial Fibrous Cartilaginous

Normal synovial joints allow a significant amount of motion along their extremely smooth articular surface. These joints are

composed of the following:

Articular cartilage Subchondral bone Synovial membrane Synovial fluid Joint capsule

The normal articular surface of synovial joints consists of articular cartilage (composed of chondrocytes) surrounded by an extracellular matrix that includes various macromolecules, most importantly
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proteoglycans and collagen. The cartilage facilitates joint function and protects the underlying subchondral bone by distributing large loads, maintaining low contact stresses, and reducing friction at the joint. Synovial fluid is formed through a serum ultrafiltration process by cells that form the synovial membrane (synoviocytes). Synovial cells also manufacture hyaluronic acid (HA, also known as hyaluronate), a glycosaminoglycan that is the major noncellular component of synovial fluid. Synovial fluid supplies nutrients to the avascular articular cartilage; it also provides the viscosity needed to absorb shock from slow movements, as well as the elasticity required to absorb shock from rapid movements. Pathophysiology Primary and secondary osteoarthritis are not separable on a pathologic basis, though bilateral symmetry is often seen in cases of primary osteoarthritis, particularly when the hands are affected.1. Traditionally, osteoarthritis was thought to affect primarily the articular cartilage of synovial joints; however, pathophysiologic changes are also known to occur in the synovial fluid, as well as in the underlying (subchondral) bone, the overlying joint capsule, and other joint tissues.1 Although osteoarthritis has been classified as a noninflammatory arthritis, increasing evidence has shown that inflammation occurs as cytokines and metalloproteinases are released into the joint. These agents are involved in the excessive matrix degradation that characterizes cartilage degeneration in osteoarthritis. In early osteoarthritis, swelling of the cartilage usually occurs, because of the increased synthesis of proteoglycans; this reflects an effort by the chondrocytes to repair cartilage damage. This stage may last for years or decades and is characterized by hypertrophic repair of the articular cartilage. As osteoarthritis progresses, however, the level of proteoglycans eventually drops very low, causing the cartilage to soften and lose elasticity and thereby further compromising joint surface integrity. Microscopically, flaking and fibrillations (vertical clefts) develop along the normally smooth articular cartilage on the surface of an osteoarthritic joint. Over time, the loss of cartilage results in loss of joint space.

In major weight-bearing joints of persons with osteoarthritis, a greater loss of joint space occurs at those areas experiencing the highest loads. This effect contrasts with that of inflammatory arthritides, in which uniform joint-space narrowing is the rule. In the osteoarthritic knee, for example, the greatest loss of joint space is commonly seen in the medial femorotibial compartment, though the lateral femorotibial compartment and patellofemoral compartment may also be affected. Collapse of the medial or lateral compartments may result in varus or valgus deformities, respectively. Erosion of the damaged cartilage in an osteoarthritic joint progresses until the underlying bone is exposed. Bone denuded of its protective cartilage continues to articulate with the opposing surface. Eventually, the increasing stresses exceed the biomechanical yield strength of the bone. The subchondral bone responds with vascular invasion and increased cellularity, becoming thickened and dense (a process known as eburnation) at areas of pressure. The traumatized subchondral bone may also undergo cystic degeneration, which is attributable either to osseous necrosis secondary to chronic impaction or to the intrusion of synovial fluid. Osteoarthritic cysts are also referred to as subchondral cysts, pseudocysts, or geodes (the preferred European term) and may range from 2 to 20 mm in diameter. Osteoarthritic cysts in the acetabulum (see the image below) are termed Egger cysts.

This radiograph demonstrates osteoarthritis of the right hip, including the finding of sclerosis at the superior aspect of the acetabulum. Frequently, osteoarthritis at the hip is a bilateral finding, but it may occur unilaterally in an individual who has a previous history of hip trauma that was confined to that one side. At areas along the articular margin, vascularization of subchondral marrow, osseous metaplasia of synovial connective tissue, and ossifying cartilaginous protrusions lead to irregular outgrowth of new bone (osteophytes). Fragmentation of these osteophytes or of the articular cartilage itself results in the presence of intra-articular loose bodies (joint mice).
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Along with joint damage, osteoarthritis may also lead to pathophysiologic changes in associated ligaments and the neuromuscular apparatus. For example, lateral collateral ligament complex abnormalities are common in knee osteoarthritis. Pain mechanisms in osteoarthritis Pain, the main presenting symptom of osteoarthritis, is presumed to arise from a combination of mechanisms, including the following:

Osteophytic periosteal elevation Vascular congestion of subchondral bone, leading to increased intraosseous pressure Synovitis with activation of synovial membrane nociceptors Fatigue in muscles that cross the joint Overall joint contracture Joint effusion and stretching of the joint capsule Torn menisci Inflammation of periarticular bursae Periarticular muscle spasm Psychological factors Crepitus (a rough or crunchy sensation) Central pain sensitization

When the spine is involved in osteoarthritis, especially the lumbar spine, the associated changes are very commonly seen from L3 through L5. Symptoms include pain, stiffness, and occasional radicular pain from spinal stenosis. Foraminal narrowing is caused by facet arthritic changes that result in compression of the nerve roots. Acquired spondylolisthesis is a common complication of arthritis of the lumbar spine.

Etiology
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The daily stresses applied to the joints, especially the weight-bearing joints (eg, ankle, knee, and hip), play an important role in the development of osteoarthritis. Most investigators believe that degenerative alterations in osteoarthritis primarily begin in the articular cartilage, as a result of either excessive loading of a healthy joint or relatively normal loading of a previously disturbed joint. External forces accelerate the catabolic effects of the chondrocytes and further disrupt the cartilaginous matrix. Risk factors for osteoarthritis include the following1 :

Age Obesity Trauma Genetics (significant family history) Reduced levels of sex hormones Muscle weakness Repetitive use (ie, jobs requiring heavy labor and bending) Infection Crystal deposition Acromegaly Previous inflammatory arthritis (eg, burnt-out rheumatoid arthritis) Heritable metabolic causes (eg, alkaptonuria, hemochromatosis, and Wilson disease) Hemoglobinopathies (eg, sickle cell disease and thalassemia) Neuropathic disorders leading to a Charcot joint (eg, syringomyelia, tabes dorsalis, and diabetes)

Underlying morphologic risk factors (eg, congenital hip dislocation and slipped femoral capital epiphysis)

Disorders of bone (eg, Paget disease and avascular necrosis)

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Previous surgical procedures (eg, meniscectomy)

Advancing age With advancing age come reductions in cartilage volume, proteoglycan content, cartilage vascularization, and cartilage perfusion. These changes may result in certain characteristic radiologic features, including a narrowed joint space and marginal osteophytes. However, biochemical and pathophysiologic findings support the notion that age alone is an insufficient cause of osteoarthritis. Obesity Obesity increases the mechanical stress in a weight-bearing joint. It has been strongly linked to osteoarthritis of the knees and, to a lesser extent, of the hips. A study that evaluated the associations between body mass index (BMI) over 14 years and knee pain at year 15 in 594 women found that a higher BMI at year 1 and a significant increase in BMI over 15 years were predictors of bilateral knee pain at year 15.1 The association between BMI increase and knee pain was independent of radiographic changes. In addition to its mechanical effects, obesity may be an inflammatory risk factor for osteoarthritis. Obesity is associated with increased levels (both systemic and intra-articular) of adipokines (cytokines derived from adipose tissue), which may promote chronic, lowgrade inflammation in joints.1 Other causes Trauma or surgery (including surgical repair of traumatic injury) involving the articular cartilage, ligaments, or menisci can lead to abnormal biomechanics in the joints and accelerate osteoarthritis. Although repairs of ligament and meniscal injuries usually restore joint function, osteoarthritis has been observed 5-15 years afterward in 50-60% of patients.1 Insults to the joints may occur even in the absence of obvious trauma. Microtrauma may also cause damage, especially in individuals whose occupation or lifestyle involves frequent squatting, stair-climbing, or kneeling. Muscle dysfunction compromises the bodys neuromuscular protective mechanisms, leading to increased joint motion and ultimately resulting in osteoarthritis. This effect underscores the need for continued muscle toning exercises as a means of preventing muscle dysfunction.
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Genetics A hereditary component, particularly in osteoarthritis presentations involving multiple joints, has long been recognized.1 Several genes have been directly associated with osteoarthritis, and many more have been determined to be associated with contributing factors, such as excessive inflammation and obesity. Genes in the BMP (bone morphogenetic protein) and WNT (wingless-type) signaling cascades have been implicated in osteoarthritis. Two genes in particular,GDF5 (growth and differentiation factor 5) and FRZB (frizzled related protein) have been identified in the articular cartilage in animal studies and share a strong correlation with osteoarthritis.1 Genome-wide association studies (GWAS) have identified an association between osteoarthritis of large joints and the MCF2L gene. This gene is key in neurotrophin-mediated regulation of peripheral nervous system cell motility.2 Genetic factors are also important in certain heritable developmental defects and skeletal anomalies that can cause congenital misalignment of joints. These may result in damage to cartilage and the structure of the joint. Currently, clinical genetic testing is not offered to patients who have osteoarthritis unless they also have other anomalies that could be associated with a genetic condition. In the future, testing may allow individualization of therapeutics.

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Epidemiology Age-related demographics Primary osteoarthritis is a common disorder of the elderly, and patients are often asymptomatic. Approximately 80-90% of individuals older than 65 years have evidence of radiographic primary osteoarthritis.2 Symptoms typically do not become noticeable until after the age of 50 years. The prevalence of the disease increases dramatically among persons older than 50 years, likely because of age-related alterations in collagen and proteoglycans that decrease the tensile strength of the joint cartilage and because of a diminished nutrient supply to the cartilage.3 Sex-related demographics In individuals older than 55 years, the prevalence of osteoarthritis is higher among women than among men.Women are especially susceptible to osteoarthritis in the DIP joints of the fingers. Women also have osteoarthritis of the knee joints more frequently than men do, with a female-to-male incidence ratio of 1.7:1. Women are also more prone to erosive osteoarthritis, with a female-to-male ratio of about 12:1. Race-related demographics Interethnic differences in the prevalence of osteoarthritis have been noted. The disorder is more prevalent in Native Americans than in the general population. Disease of the hip is seen less frequently in Chinese patients from Hong Kong than in age-matched white populations. Symptomatic knee osteoarthritis is extremely common in China.1 In persons older than 65 years, osteoarthritis is more common in whites than in blacks. Knee osteoarthritis appears to be more common in black women than in other groups. Jordan et al found that in comparison with whites, African American men and women had a slightly higher prevalence of radiographic and symptomatic knee osteoarthritis but a significantly higher prevalence of severe radiographic knee osteoarthritis. Prognosis The prognosis in patients with osteoarthritis depends on the joints involved and on the severity of the condition. No proven disease- or structure-modifying drugs for osteoarthritis are currently known; consequently, pharmacologic treatment is directed at symptom relief.
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A systematic review found the following clinical features to be associated with more rapid progression of knee osteoarthritis1:

Older age Higher BMI Varus deformity Multiple involved joints

Patients with osteoarthritis who have undergone joint replacement have a good prognosis, with success rates for hip and knee arthroplasty generally exceeding 90%. However, a joint prosthesis may have to be revised 10-15 years after its placement, depending on the patients activity level. Younger and more active patients are more likely to require revisions, whereas the majority of older patients will not.

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CHAPTER 2 METABOLIC FACTORS IN OSTEOARTHRITIS Obesity is an important risk factor for the development and progression of osteoarthritis (OA). Recently, the paradigm that obesity predisposes people to OA because of extramechanical loading only has shifted to the paradigm that metabolic factors (adipokines) are also involved in the pathophysiology of OA. Introduction In the previous issue of Arthritis Research & Therapy, Massengale and

colleagues [1] investigate the association between leptin and symptomatic hand osteoarthritis (OA). Leptin is one of the adipokines, an umbrella name for various metabolic factors produced by fat tissue. Excess of fat has long been recognized as an important risk factor for the development and progression of OA. The quite new interest in the metabolic role of fat excess in OA is boosted by the observation that fat excess is also a risk factor for developing OA in non-weight-bearing joints, such as those in the hand. The present view is that obesity leads to OA because of not only mechanical but also metabolic effects. In the investigation of the metabolic effect of fat in OA, hand joints are preferable to hips or knees because the former are not weight-bearing and therefore the metabolic effect does not need to be separated from a biomechanical effect. However, the number of studies on adipokines in hand OA is very small. In the above-mentioned cross-sectional study of more than 1,000 patients, Massengale and colleagues did not find an association between leptin and hand OA. In that study, hand OA is defined by an algorithm that incorporates symptoms and physical examination. What the authors show is interesting because it challenges the basic science evidence that leans toward the deleterious effect of leptin on cartilage, 2 a major tissue involved in OA. Their study is complementary to one of ours: in possibly the only other study of leptin in hand OA, we showed that baseline leptin had no association with the worsening of hand OA on radiographs during 6 years of follow-up. 3 Adiponectin is another adipokine that has received considerable attention in basic research in OA. The three published clinical studies on adiponectin and hand OA separately provide evidence for each of the possible associations: a protective effect, no effect, or a positive damaging effect. Whereas we found that adiponectin was protective against long-term radiographic worsening of hand OA, 3 Filkov and colleagues showed, in a cross-sectional
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study, that the serum level of adiponectin was higher in women with erosive hand OA (often considered a particularly severe type of hand OA) than in women with 'usual' hand OA. A cross-sectional study by Choe and colleagues 5 did not find any difference in adiponectin levels of women with hand OA and those of women without it. These results from clinical studies are in line with the results from basic research. At present, there is no agreement that adiponectin is 'good' or 'bad' for joint cartilage. For example, Kang and colleagues 6 demonstrated a catabolic effect of adiponectin on cartilage, whereas Chen and colleagues 7 showed a protective effect.

Efforts to expand our knowledge of adipokines in OA are clearly needed. Additional clinical studies are needed and perhaps should focus on hand OA. Currently, the body of evidence on the role of adipokines in knee OA is stronger than in hand OA. However, although studies on weight-bearing joints allow a better understanding of pathophysiology of fat in OA, separating the metabolic from the biomechanical effect of fat excess in weight-bearing joints will always be difficult. Large follow-up studies with radiographic hand OA will teach us much about the role of adipokines in OA. A remark on the measurement of excess of fat should be made. Body mass index, which is commonly used, is actually only a proxy of human body fat. This might explain the conflicting results of studies of obesity and OA. Other ways to assess obesity, such as waist circumference, waist-to-hip ratio, and fat mass, 8 should also be used in examining obesity as

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a risk factor for OA. Since pain is the main reason that patients with OA visit their doctor, the role of adipokines in pain could also be investigated. We can speculate that adipokines might exert their effect on nociceptors in the joints. Basic science studies in OA investigate mostly the effect of adipokines on cartilage, but tissues such as synovium and bone marrow are also involved in OA, so it is also pertinent to explore the effect of adipokines on these tissues. Interest in the role of adipokines is growing not only in OA but also in atherosclerotic cardiovascular disease. 9 OA and cardiovascular disease share obesity and increasing age as important risk factors. This has fuelled speculation that OA and cardiovascular disease are related. Adipokines might stimulate the formation of atherosclerotic plaques that subsequently limit the blood flow to the joint and therefore impair cartilage nutrition. This mechanism is intriguing because, if this hypothesis can be proven, adipokines will be the grand unification theory that relates OA to atherosclerotic cardiovascular diseases. 10 In summary, the story of the role of adipokines in OA continues and there remains optimism that one day we will elucidate the metabolic role of fat in OA since we know that obese people do not walk on their hands. Mechanobiology in obesityinduced osteoarthritis The overload effect on joint cartilage may explain part of the increased risk of osteoarthritis, at least for osteoarthritis of the knee, in overweight people. A recent discovery in the discipline of cartilage biology is the presence of mechanoreceptors at the surface of chondrocytes, which are sensitive to pressure and link extracellular environment to intracellular signalling cascades. Three types of mechanoreceptors have been described on chondrocytes: the stretchactivated channels, the 51 integrin and CD44. Compression and stretch stimulate integrins and stretchactivated channels leading to the activation of signalling pathways (mitogenactivated protein kinase, NFB), as well as the release of second messengers (calcium, Inositol triphosphate and Adenosine monophosphate cyclic). 1 After mechanoreceptor activation, cytokines, growth factors and metalloproteinases may be expressed, and mediators such as prostaglandins or nitric oxide may be produced.2 As experimental studies have shown that under specific conditions overload may trigger both inhibition of matrix synthesis and cartilage degradation, we can speculate that obesity may induce cartilage damage through activation of these mechanoreceptors. In the same manner, the mechanoreceptors expressed on osteoblasts3,4 may also be involved in the impaired response of chondrocytes to the obesityinduced overload.
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Adipokines: the metabolic link between obesity and osteoarthritis? Even if it is usually accepted that mechanical loading contributes to joint cartilage destruction in overweight patients, recent advances in the physiology of adipose tissue add further insights in understanding the relationship between obesity and osteoarthritis. Indeed, the positive association between overweight or obesity and osteoarthritis is observed not only for knee joints but also for nonweight bearing joints, such as hands.5 Furthermore, if weight loss may prevent the onset of osteoarthritis, the loss of body fat is more closely related to symptomatic benefit than is the loss of body weight.6 These patterns of joint involvement suggest that joint damage may be caused by systemic factors such as adipose factors, so called adipokines, which may provide a metabolic link between obesity and osteoarthritis. Today, adipose tissue, traditionally viewed as a passive store of energy, is considered to be a real endocrine organ that releases a large number of factors, including cytokines, such as interleukin 1 and tumour necrosis factor , as well as adipokines, such as leptin, adiponectin, resistin, visfatin, and so on, and new ones that are yet to be discovered. These adipokines exhibit pleiotropic functions mediated through both central and peripheral systems, including haemostasis, lipid and glucose metabolism, reproductive functions, blood pressure regulation, insulin sensitivity, bone formation and angiogenesis. So, recent data strengthen the hypothesis that osteoarthritis is a systemic disorder in which dysregulation of lipid homeostasis can be one of the pathophysiological mechanisms leading to osteoarthritis. Recent studies provide evidence for a key role of leptin in cartilage homoeostasis. Leptin and its functional receptor have been identified in human chondrocytes and trigger intracellular signal transduction through the activation of STATs 1 and 5, but not STAT 3. Leptin may have important biological effects in chondrocytes, on both growth factor synthesis and anabolism, and also on catabolism. Leptin expression is strongly upregulated in various articular tissues that undergo strong structural and biochemical changes during osteoarthritisfor example, cartilage, osteophytes and subchondral bonewhen compared with normal tissues. Interestingly, the pattern and level of leptin expression are related to the grade of cartilage destruction, and parallel those of growth factors (insulinlike growth factor I and transforming growth factor 1). The intraarticular injection of leptin into the rat knee joint has a stimulatory effect on proteoglycan synthesis and is associated with increased expression of insulinlike growth factor I and TGF1. In addition to mature cartilage, leptin is also produced in resting and prehypertrophic chondrocytes in the growth plate of mice. In cultured human chondrocytes, leptin increases both the proliferation and the extracellular
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matrix synthesis, but in a biphasic manner, with a reduced stimulating effect at the highest concentrations. Leptin may thus have a beneficial effect on cartilage synthesis either directly or through the upregulation of growth factors. However, an excess of leptin may account for decreased extracellular matrix synthesis and may lead to lesions similar to those found in osteoarthritis with a high intraarticular level of growth factors. The increased expression of leptin in markedly damaged cartilage suggests that leptin may trigger cartilage destruction, especially when associated with some local factors. The adipokine synergises with proinflammatory cytokines, such as interleukin 1, to increase nitric oxide production, which is known to interfere with chondrocytes function resulting, in the loss of cartilage matrix through induction of apoptosis, activation of metalloproteinases, and inhibition of proteoglycan and type II collagen synthesis. Little is known about the contribution of adiponectin and resistin in osteoarthritisaffected joints. Available data related to the potential effects of these adipokines in joint disorders indicated that they may have an active role in the pathogenesis of chronic inflammatory joint diseases such as rheumatoid arthritis. The inducing effect of adiponectin on metalloproteinase 1 expression in synovial fibroblasts from patients with osteoarthritis suggests that this adipokine may also be associated with key pathways of cartilage matrix degradation. In patients with osteoarthritis, leptin, adiponectin and resistin are detected in both the synovial fluid and in the plasma. The adipokines exhibit different patterns of distribution between the joint and the circulating compartment: plasma levels of resistin and adiponectin exceed those in the paired synovial fluid, whereas leptin concentrations in synovial fluid are higher than their plasma counterparts. As was found in plasma from obese people when compared with normal subjects, the leptin to adiponectin ratio was shown to be higher in the synovial fluid of patients with osteoarthritis than in plasma. The resulting imbalance between two adipokines known to have opposite biological effects in various diseases such as diabetes or inflammation may contribute to the initiation and/or progression of osteoarthritis. Interestingly, this high level of leptin is associated with a decline in the soluble leptin receptor level, leading to a large rise in free leptin in synovial fluid, the presumed biologically active form of this adipokine. Moreover, a larger amount of free leptin is found in the synovial fluid from female patients with osteoarthritis than in that from male patients, and may explain why obesity and female sex are both risk factors for the development of osteoarthritis.

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To date, no clear mechanism could explain the changes in the adipokine levels in the synovial fluid compared with plasma. Various tissues obtained from human osteoarthritisaffected joints release leptin and adiponectin. Among these tissues, the synovium and infrapatellar fat pad produce the highest amounts of adipokines. Until recently, the fat pad, which is an extrasynovial but an intraarticular tissue, had been neglected. However, this adipose tissue is able to release growth factors, cytokines and adipokines. Cross talk between the adipocytes and other cells located in the fat pad (macrophages), or in its vicinity (synoviocytes), may also regulate the production of various factors in the joint. Interestingly, osteophytes, which are osteocartilaginous metaplastic tissues, represent the major source of leptin but not of adiponectin. Altogether, these findings indicate that further investigations on the effect of the infrapatellar fat pad and its derived adipokines on chondrocyte metabolism would be helpful to better understand the pathogenesis of (knee) osteoarthritis.

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Is there a role for obesityinduced atherosclerosis? In addition to osteoarthritis, obesity is commonly associated with vascular disease. An interesting hypothesis about the role of atherosclerosis in the progression of osteoarthritis has recently been proposed. Microvascular changes predominantly affecting the venous circulation are early events occurring in subchondral bone during osteoarthritis. This vascular disease in subchondral bone may accelerate the osteoarthritis process either by altering cartilage nutrition or through direct ischaemic effects on bone. The vascular obstruction and the resulting intraosseous hypertension may also alter the mechanical properties of the bone, which exhibits thereafter a reduced ability to absorb shocks, leading to increased susceptibility of the cartilage to breakdown. Whether the use of statins as a specific treatment for the atheromatous vascular disease would be beneficial for osteoarthritis remains to be established. Is there any role for obesityinduced diabetes mellitus? Obesityassociated diabetes mellitus may represent an additional factor in the pathophysiology of osteoarthritis through the formation of advanced glycation end products (AGEs). The accumulation of AGEs found in articular cartilage during osteoarthritis progression leads to increased stiffness of collagen due to AGE crosslinking. This damage to the collagen network may alter the mechanical properties of the extracellular matrix, and may lead to cartilage changes associated with osteoarthritis. In addition, articular chondrocytes
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express the functional receptor for AGEs, which induces mitogenactivated protein kinase, NFB activity and metalloproteinase 13 production when stimulated with ligands. Modifications of normal cartilage by AGEs also increase matrix degradation and decrease proteoglycan synthesis by chondrocytes. Further studies are required to determine whether diabetesinduced accumulation of AGEs occurs in cartilage from obese patients, providing thereby a molecular mechanism by which obesity is a risk factor for the development of osteoarthritis.
Figure 1a

In conclusion, many recent studies allow us to better understand the relationships between osteoarthritis and obesity. Although it is evident that mechanical components

contribute to joint destruction in overweight people, osteoarthritis is considered not only a disease of articular cartilage but also a systemic disorder in which circulating factors linked to altered lipid and glucose

metabolism may explain the diversity of pathophysiological generalised changes found in the

osteoarthritis.

However,

potential contribution of adiposederived cytokines in osteoarthritis would not preclude the involvement of other mechanisms,

including activation of mechanoreceptors, vascular dysfunction in subchondral bone and accumulation of AGEs in cartilage. Further investigations are thus needed to find new pharmacological tools and new orientations in the treatment and prevention of this joint disease. Adiponectin receptors expression in OA cartilage3 Immunohistochemical study demonstrated that all OA cartilage samples expressed both AdipoR1 and AdipoR2; AdipoR2 was expressed through all layers, whereas AdipoR1 was expressed mainly in the superficial layer of OA cartilage (Figure 1a). Both AdipoR1 (49.0 9.9% versus 11.7 4.6%; P < 0.05 by Wilcoxon matched-pairs signed-rank test) and AdipoR2 (87.2 2.7% versus 41.7 6.9%; P < 0.05) were significantly more expressed in
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the lesional cartilage area than in the nonlesional area. When the expression levels of AdipoR1 and AdipoR2 were compared, the AdipoR2 was more strongly stained than AdipoR1 in both nonlesional (staining intensity score ranges from 1~2 versus 0~1) and lesional area (staining intensity score ranges, 3 versus 1~3). Additionally, the percentage of AdipoR2-positive chondrocytes was significantly higher than that of AdipoR1-positive chondrocytes in both nonlesional and lesional areas (each P < 0.05). However, the counts of AdipoR1-stained chondrocytes were increased at a higher rate than those of AdipoR2-stained chondrocytes (4.2 versus 2.1 times; Figure 1b). The percentages of AdipoR1- or AdipoR2positive chondrocytes were not shown to be correlated with either age or BMI.

(figure 1b)

Osteoarthritis and Type 2 Diabetes

Because osteoarthritis (OA) and type 2 diabetes are both common conditions, they are likely to occur together by coincidence. But the two share at least two major risk factors: age and weight.

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Age: Osteoarthritis is largely a disease of wear and tear on joints. The older you are, the more you have used your joints, making OA more likely. The risk for type 2 diabetes also increases with age, largely because people become less active, gain weight and lose muscle mass as they age. Half of all people diagnosed with diabetes are over 55.

Weight: Obesity affects the joints by increasing the stress on them. For every pound you gain, you add four pounds of pressure on your knees. Over time, the added stress contributes to joint wear and tear. Obesity also affects the internal organs. Fatty tissues of the body produce chemical compounds that increase insulin resistance, which increases blood glucose levels. The heart and blood vessels become stressed as they strain to pump blood through a larger body mass and contend with the inflammatory chemicals being produced by fat cells.

No, arthritis does not cause diabetes and diabetes does not cause arthritis. However, diabetes does sometimes have accompanying joint symptoms, and a sedentary lifestyle and obesity can contribute to or worsen both.

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