metabolic factors in oa

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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


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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.


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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)

Intra-articular pharmacologic therapy includes corticosteroid injection and

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 astime 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.


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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 slippedfemoral 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, low-

grade 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) andFRZB (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 theMCF2L 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 theyalso 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 osteoarthritisare 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 patientsactivity 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 extra-

mechanical loading only has shifted to the paradigm that metabolic factors (adipokines) are

also involved in the pathophysiology of OA.

Introduction

In the previous issue ofArthritis 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 orknees 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-termradiographic 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).1After mechanoreceptor activation, cytokines, growth factors and metalloproteinases

may be expressed, and mediators such as prostaglandins or nitric oxide may be

produced.2As 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 osteoblasts3,4may also be involved in the

impaired response of chondrocytes to the obesityinduced overload.
http://www.ncbi.nlm.nih.gov/pubmed/15095818http://www.ncbi.nlm.nih.gov/pubmed/15095818http://www.ncbi.nlm.nih.gov/pubmed/15095818http://www.ncbi.nlm.nih.gov/pubmed/15232421http://www.ncbi.nlm.nih.gov/pubmed/15232421http://www.ncbi.nlm.nih.gov/pubmed/15232421http://www.ncbi.nlm.nih.gov/pubmed/7684161http://www.ncbi.nlm.nih.gov/pubmed/7684161http://www.ncbi.nlm.nih.gov/pubmed/8769095http://www.ncbi.nlm.nih.gov/pubmed/8769095http://www.ncbi.nlm.nih.gov/pubmed/8769095http://www.ncbi.nlm.nih.gov/pubmed/8769095http://www.ncbi.nlm.nih.gov/pubmed/7684161http://www.ncbi.nlm.nih.gov/pubmed/15232421http://www.ncbi.nlm.nih.gov/pubmed/15095818


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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 lipidhomeostasis 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.

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 changes found ingeneralised osteoarthritis. However, the

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

Figure 1a
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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 (eachP< 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 AdipoR2-

positive 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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REFERENCES

1. Osteoarthritis overview. Available athttp://emedicine.medscape.com/article/330487-overview. Accessed:

November, 9th 2012.

2. Obesity and Osteoarthritis. Available athttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC1798356/ . Accessed:

November, 9th 2012.

3. Adiponectin is a potential catabolic mediator in osteoarthritis cartilage.Available at:http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3046544/.

Accessed: November, 20th 2012.

4. MillwardSadler S J, Salter D M. Integrindependent signal cascades inchondrocyte mechanotransduction. Ann Biomed Eng 2004. 32435446.446.

[PubMed]

5. Guilak F, Fermor B, Keefe F J, Kraus V B, Olson S A, Pisetsky D S. et al Therole of biomechanics and inflammation in cartilage injury and repair. Clin

Orthop Relat Res 2004. 4231726.26. [PubMed]

6. Wang N, Butler J P, Ingber D E. Mechanotransduction across the cell surfaceand through the cytoskeleton. Science 1993. 26011241127.1127. [PubMed]

7. Cicuttini F, Baker J, Spector T. The association of obesity with osteoarthritisof the hand and knee in women: a twin study. J Rheumatol 1996. 231221

1226.1226. [PubMed]

8. Toda Y, Toda T, Takemura S, Wada T, Morimoto T, Ogawa R. Change inbody fat, but not body weight or metabolic correlates of obesity, is related to

symptomatic relief of obese patients with knee osteoarthritis after a weight

control program. J Rheumatol 1998. 2521812186.2186. [PubMed]

9. Figenschau Y, Knutsen G, Shahazeydi S, Johansen O, Sveinbjornsson B.Human articular chondrocytes express functional leptin receptors. Biochem

Biophys Res Commun 2001. 287190197.197. [PubMed]

10.Dumond H, Presle N, Terlain B, Mainard D, Loeuille D, Netter P. et alEvidence for a key role of leptin in osteoarthritis. Arthritis Rheum 2003.

4831183129.3129. [PubMed]

11.Osteoarthritis and Diabetes. Available athttp://www.arthritis.org/arthritis-and-diabetes.php. Accessed: November, 9th 2012.
http://emedicine.medscape.com/article/330487-overviewhttp://emedicine.medscape.com/article/330487-overviewhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3046544/http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3046544/http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3046544/http://www.arthritis.org/arthritis-and-diabetes.phphttp://www.arthritis.org/arthritis-and-diabetes.phphttp://www.arthritis.org/arthritis-and-diabetes.phphttp://www.arthritis.org/arthritis-and-diabetes.phphttp://www.arthritis.org/arthritis-and-diabetes.phphttp://www.arthritis.org/arthritis-and-diabetes.phphttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3046544/http://emedicine.medscape.com/article/330487-overview


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