Controversal question : Can normal age-related changes in cartilage be distinguished from early osteoarthritic changes?

1. L. A. Alekseeva, Russia
2. J. P. A. Arokoski, Finland
3. F. N. Birrell, United Kingdom
4. S. Bölükbaşi, Turkey
5. O. P. Bortkevych, Ukraine
6. P. Horák, Czech Republic
7. A. El Maghraoui, Morocco
8. A. Mahmoud Ali Elsayed, Egypt
9. A. Migliore, Italy
10. T. Pap, Germany
11. J. del Pino-Montes, Spain
12. C. A. F. Zerbini, Brazil

1. L. A. Alekseeva, Russia

Lyudmila A. ALEKSEEVA, MD, PhD
Department of Metabolic Disorders of
Musculoskeletal System
Osteoarthritis and Osteoporosis Laboratories
Research Institute of Rheumatology
(Russian Academy of Medical Sciences)
34 A, Kashirskoye shosse
115522 Moscow, RUSSIA

Currently, osteoarthritis (OA) is the most common of all the musculoskeletal diseases, and this relates to the general increase in life expectancy and the accumulation of risk factors. The main symptom of OA and immediate reason for seeking medical care is pain, and this remains a permanent symptom over time. Despite traditional use of analgesic and anti-inflammatory drugs, most patients with OA continue to experience pain.

There are many reasons for the occurrence of pain in OA and many factors determining its severity. The proportion of patients with so-called “painful” or overtly symptomatic knee OA increases with age and reaches almost 80% in the oldest age group.1 Moreover, the individual perception of pain by each patient cannot be ignored, and may depend not only on changes in the joint, but also on the emotional and social status of the patient.

The source of pain in OA can be almost any structure of the joint: the synovial membrane, bone, or soft tissues.2 Mechanisms of pain perception may include activation and local release of pro-inflammatory mediators, such as prostaglandins and cytokines. Clinically, however, there is often a disparity between the degree of pain perception and the extent of destructive changes in the joint. A study with functional magnetic resonance imaging revealed that numerous areas in the brain are involved in the occurrence of pain in OA. This study demonstrated that perception of pain in OA is a complex mechanism involving local factors and the activation of central pain pathways.3

On the other hand, articular cartilage has no innervation and cannot be a direct cause of pain, but the reduction in its thickness and volume with OA results in a higher load on the subchondral bone within the weight-bearing areas of the joint. Remodeling processes, which take place in these areas, lead to the development of osteosclerosis, osteophytes, and microfractures, and eventually to an increase in the stiffness of subchondral bone that can cause significant syndromic pain. Another cause of pain is the formation of foci of bone marrow edema and an increase in the intramedullary pressure.4

In recent years, evidence has accumulated about the role of subchondral bone in the development of OA. Subchondral bone has been found to be able to produce a large number of proinflammatory cytokines and growth factors. Changes in its microarchitecture can influence the intensity of pain, and the bone mineral density value in subchondral areas of the tibia can be considered as a predictor of OA progression. All of this demonstrates the importance of investigating pain in OA, especially given the available information that pain can affect disease prognosis. As was described in the National Health and Nutrition Examination Survey (NHANES)–1 and by Mazzuca and colleagues,5,6 the initial level of pain in the knee joint in OA is a risk factor for the development of functional impairment and radiological progression in the future. _
1. McAlindon TE, Cooper C, Kirwan JR, Dieppe PA. Knee pain and disability in the community. Br J Rheumatol. 1992;31:189-192.
2. Creamer P, Hunt M, Dieppe P. Pain mechanisms in osteoarthritis of the knee: effect of intraarticular anesthetic. J Rheumatol. 1996;23:1031-1036.
3. Sofat N, Ejindu V, Kiely P. What makes osteoarthritis painful? The evidence for local and central pain processing. Rheumatology. 2011;50:2157-2165.
4. Sowers MF, Hayes C, Jamadar D, et al. Magnetic resonance-detected subchondral bone marrow and cartilage defect characteristics associated with pain and X-ray-defined knee osteoarthritis. Osteoarthr Cartil. 2003;11:387-393.
5. Hassan BS, Doherty SA, Doherty M. Effect of pain reduction on postural sway, proprioception, and quadriceps strength in subjects with knee osteoarthritis. Ann Rheum Dis. 2002;61:422-428.
6. Mazzuca SA, Brandt KD, Schauwecker DS, et al. Severity of joint pain and Kellgren- Lawrence grade at baseline are better predictors of joint space narrowing than bone scintigraphy in obese woman with knee osteoarthritis. J Rheumatol. 2005;32:1540-1546.

2. J. P. A. Arokoski, Finland

Clinical Lecturer and Adjunct Professor
(docent) of Physical and Rehabilitation
Medicine, Department of Physical
and Rehabilitation Medicine
Kuopio University Hospital
P. O. B. 1777, FI-70211 Kuopio

The etiology of osteoarthritis (OA) is not fully understood, but there are known to be several predisposing risk factors for the condition.1 These include obesity, injuries to the joints, and—most importantly—old age. The prevalence and incidence of OA increases with age.2 However, although epidemiological studies seem to indicate that primary OA and aging are interrelated, aging does not directly cause OA.3 Age related changes in the musculoskeletal system may contribute to the development of OA by making the joints more susceptible to the effects of other OA risk factors.3 Several novel aging theories such as progressive apoptotic cell loss, mitochondrial degeneration, and cell senescence have been proposed to account for the cartilage degeneration in OA.4

The pathogenetic changes in primary, and especially early, OA are difficult to distinguish clinically from normal aging, but there are some differences discernible between these two fates of the joint. The current research in this area focuses on articular cartilage.

Age-related changes in cartilage
Articular cartilage undergoes significant structural and mechanical changes with age.2 Articular cartilage collagen and proteoglycan metabolism are relatively active during growth and adolescence, but in adult individuals, the metabolism within cartilage is more sluggish.5 There is evidence of an increasing prevalence of articular surface fibrillation with age,2 and cartilage also thins with age, suggesting a loss of the cartilage matrix.3

This might be due to the fact that chondrocytes become less responsive to the proliferative and anabolic effects of growth factors with increasing age.3 Aggrecan, the major cartilage proteoglycan, decreases in molecular size and content,5 and this would be expected to reduce cartilage stiffness and hydration.3 There is no major change in the content of total collagen and pyridinoline during aging, but there is a marked increase in the formation of advanced glycation end products, including pentosidine crosslinks, making the cartilage more brittle.3

Cartilage in osteoarthritis
OA is characterized by a deterioration and progressive loss of articular cartilage, and it manifests clinically with pain that does not occur in normal aged cartilage.1 In experimental models of OA, some of the first detectable abnormalities that can be observed even before there is any deterioration visible on the cartilage surface include a decrease in the superficial proteoglycan concentration, increased water content, and the separation and disorganization of the superficial collagen fibrils.1 In early OA, the synthesis of both type II collagen and proteoglycans is increased. Advanced OA with fibrillation is accompanied by a net loss and damage to type II collagen fibrils, as well as a loss of proteoglycans. The loss of proteoglycans and collagen results in diminished cartilage stiffness.

At the molecular level, OA is viewed as being a metabolically active process, including both cartilage destruction and repair.5 This equilibrium is regulated by the complex interplay between anabolic growth factors (especially TGFβ and IGF-1) and catabolic proinflammatory cytokines (especially IL-1 and TNFα). In a normal joint, these mediators are present at low levels to maintain the homeostasis of cartilage, but in OA, these processes become imbalanced, with the increased proteolytic degradation being mediated by matrix metalloproteinases, ie, collagenases and stromelysins.

Early diagnosis of osteoarthritis
The traditional diagnostic techniques, plain X-ray imaging or arthroscopic examination, can only detect late and major tissue changes in OA and are incapable of differentiating early cartilage OA changes from age-associated changes. However, early diagnosis would be highly advantageous as initial OA changes may still be reversible.6 Recent developments in quantitative imaging techniques, including magnetic resonance imaging and ultrasound methods, as well as more sensitive biomarkers, mean that diagnostic evaluation of cartilage in early OA may in the future become reality.6 _

1. Arokoski JPA, Jurvelin J, Väätäinen U, Helminen HJ. Normal and pathological adaptation of articular cartilage to joint loading. Scand J Med Sci Sports. 2000; 10:186-198.
2. Martin JA, Buckwalter JA. Roles of articular cartilage aging and chondrocyte senescence in the pathogenesis of osteoarthritis. Iowa Orthop J. 2001;21:1-7.
3. Loeser RF. Age-related changes in the musculoskeletal system and the development of osteoarthritis. Clin Geriatr Med. 2010;26:371-386.
4. Aigner T, Richter W. OA in 2011: age-related OA—a concept emerging from infancy? Nat Rev Rheumatol. 2012;10:70-72.
5. Goldring MB, Goldring SR. Osteoarthritis. J Cell Physiol. 2007;213:626-634.
6. Chu CR,Williams AA, Coyle CH, Bowers ME. Early diagnosis to enable early treatment of pre-osteoarthritis. Arthritis Res Ther. 2012;14:212.

3. F. N. Birrell, United Kingdom

Musculoskeletal Research Group
Institute of Cellular Medicine
4th Floor, Cookson
Framlington Place, Newcastle University
Newcastle NE2 4HH, UK

The short answer is yes. However, interest and a degree of controversy derive from the techniques that are available to discriminate between the two and consideration of whether osteoarthritis (OA) is a disease restricted to cartilage alone or should more correctly be considered a disease of the whole joint.

The main techniques used to investigate cartilage include imaging, histology, and gene expression profiling. Clinically, the most useful test would be one that is noninvasive and readily available. Unfortunately, plain radiographs usually provide no direct visualization of cartilage, unless chondrocalcinosis is present, and the indirect evidence is limited by difficulties in interpreting joint space, which is affected by positioning, and the variable interposition of other low-density tissues such as menisci. High-resolution musculoskeletal ultrasound and magnetic resonance imaging can directly visualize cartilage, but there is a lack of true population data on age-related changes, even with magnetic resonance imaging. Large studies, for example Osteoarthritis Initiative, sponsored by the National Institutes of Health in the United States,1 have focused on a single joint (the knee) and used convenience sampling.

Histological techniques include macroscopic examination of cartilage sections for thinning and fibrillation and microscopic examination with stains for proteoglycans (such as Safranin O). While grading systems for cartilage are discriminating for advanced disease, early OA changes may be difficult to discriminate from age-related change using grading systems for cartilage alone.2 Three other approaches to discriminate early OA changes are: microscopic examination of the whole joint, measurement of specific enzymes upregulated in OA, and gene expression profiling. Pathological changes around the joint in early OA include synovitis and ligament/enthesis and subchondral bone abnormalities: the importance of these changes relates to their association with pain, which in clinical studies has been of stronger importance than early joint space narrowing (although advanced disease has a very strong relationship with radiographic change,3 in contrast to earlier assertions). Specific enzymes, such as matriptase, are upregulated in OA cartilage,4 which suggests potential relevance as a target for treatment.

However, probably the most definitive current technique for distinguishing OA from age-related change alone in cartilage is gene expression profiling. A recent study by Loeser et al5 has shown that there are quite different profiles in young versus aged mice, with 493 genes showing differential expression and an age-related decrease in matrix gene expression and increase in immune and defense response gene expression. Thus, there is a characteristic aging gene profile signature in mice. Replication in humans will provide us with an invasive tool for discriminating age-related change: arguably a controversial answer to the controversial question.

A growing appreciation of OA as a disease of the whole joint suggests that a narrow focus on cartilage alone is, however, probably counterproductive. Ongoing longitudinal studies will allow us to define which changes in and around the joint are associated with progression and response to treatment. We should increasingly use these predictors and regard cartilage changes as just one of several key outcomes of OA. _

1. Osteoarthritis Initiative. Available at: Accessed November 21, 2012.
2. McNulty MA, Loeser RF, Davey C, Callahan MF, Ferguson CM, Carlson CS. Histopathology of naturally occurring and surgically induced osteoarthritis in mice. Osteoarthritis Cartilage. 2012;20:949-956.
3. Neogi T, Felson D, Niu J, et al. Association between radiographic features of knee osteoarthritis and pain: results from two cohort studies. BMJ. 2009;339: b2844.
4. Milner JM, Patel A, Davidson RK, et al. Matriptase is a novel initiator of cartilage matrix degradation in osteoarthritis. Arthritis Rheum. 2010;62:1955-1966.
5. Loeser RF, Olex AL, McNulty MA, et al. Microarray analysis reveals age-related differences in gene expression during the development of osteoarthritis in mice. Arthritis Rheum. 2012;64:705-717.

4. S. Bölükbaşi, Turkey

Department of Orthopedics
and Traumatology
Gazi University School of Medicine
06500 Besevler
Ankara, TURKEY

Currently, it is not possible to give an exact answer to this question. In order to begin to answer the question, one must first elucidate whether or not aging of the cartilage is the same process as cartilage degradation.

As the role of mitochondria is known in degenerative diseases, a study was conducted to investigate mitochondrial function in healthy chondrocytes and osteoarthritic chondrocytes, as well as age-related changes in mitochondria. The study showed that mitochondrial mass was increased in osteoarthritic chondrocytes, but no correlation was found between mitochondrial function and age in normal and osteoarthritic chondrocytes.1 This result suggests that cartilage aging and cartilage degradation are two separate processes.1

In another study, the matrix homeostasis of a healthy human ankle was evaluated.2 Type I collagen synthesis and denaturation were found to be associated with the pericellular matrix, and the type II collagen (CII) and proteoglycan content in the matrix were determined as remaining constant throughout life. Age had an important effect on the denaturation of CII, which decreased as age increased, relative to collagenase mediated cleavage.2 These observations suggest that cartilage aging and the osteoarthritic process are two separate processes, since the aging of the ankle cartilage bore no resemblance to the molecular degenerative changes of osteoarthritis.2 Thus, a clear difference emerges between aging and osteoarthritis.

On the basis of the two aforementioned studies, new investigative molecular studies could in the future be used routinely to help differentiate the early stage of osteoarthritis from cartilage aging. Currently, however, the results of studies such as these are not completely clear and remain to be clarified.

Additionally, contrary to the aforementioned results, aging is one of the most important risk factors in the development of osteoarthritis, and more than 50% of the population over the age of 60 years have osteoarthritic joints.3 Because osteoarthritis is a multifactorial disease and age is the major (but not only) risk factor, it is difficult to determine whether cartilage degradation and cartilage aging are different processes.

In an experimental study, the accumulation of advanced glycation end products (AGEs) was investigated in relation to osteoarthritis.3 AGEs adversely affect the formation of cartilage, lead to the formation of osteoarthritis, and increase with aging. In this study, the accumulation of AGEs was found to cause a tendency to develop osteoarthritis. The results showed that higher AGE levels in the cartilage increased the severity of osteoarthritis, and they provided the first in vivo molecular evidence to demonstrate the role of aging in the development of osteoarthritis.3

With the development of microarray technology, studies have emerged suggesting that gene expression analysis of subchondral bone can be conducted in early experimental osteoarthritis and can be used in its diagnosis and treatment.4 However, it is currently impossible to obtain suitable subchondral bone and cartilage samples from humans and animals in order to study the beginning and early stages of osteoarthritis.4 Another study indicated that by measuring certain biomarkers of bone, cartilage, and synovial metabolism (sC2C, uCTX-II, sCPII, uNTx, and sHA), changes in cartilage matrix and early structural changes in cartilage could be identified.5 This and many similar studies show that biomarkers may be important indicators of early-stage osteoarthritis. With such biomarkers, it could be possible to differentiate early osteoarthritis from cartilage aging.

To date, studies have not been able to clearly reveal the distinction between osteoarthritis and cartilage aging. It is therefore difficult to distinguish primary osteoarthritis in its early stages from cartilage aging, hence the need for further studies in this area. _

1. Manerio E, Martin MA, Andres MC, et al. Mitochondrial respiratory activity is altered in osteoarthritic human articular chondrocytes. Arthritis Rheum. 2003;48: 700-708.
2. Aurich M, Poole R, Reiner A, et al. Matrix homeostasis in aging normal human ankle cartilage. Arthritis Rheum. 2002;46:2903-2910.
3. De Groot J, Verzijl N, Wenting-van Wijk MJG, et al. Accumulation of advanced glycation end products as a molecular mechanism for aging as a risk factor in osteoarthritis. Arthritis Rheum. 2004;50:1207-1215.
4. Zhang Y, Fang H, Chen Y, et al. Gene expression analyses of subchondral bone in early experimental osteoarthritis by microarray. PloS One. 2012;7:1-19.
5. Ishijima M, Watari T, Naito K, et al. Relationships between biomarkers of cartilage, bone, synovial metabolism and knee pain provide insights into the origins of pain in early knee osteoarthritis. Arthritis Res Ther. 2011;13:R22.

5. O. P. Bortkevych, Ukraine

Department of Clinical Rheumatology
National Scientific Centre M. D. Strazhesko
Institute of Cardiology
5, Narodnogo Opolcheniya St, 03151

Osteoarthritis (OA) is a disease of the joint affecting all joint tissues. Similarly, joint aging is systemic. Age is the most prominent risk factor for OA, and although the relationship between aging and OA is well known, its mechanisms are not fully understood.

Joint changes that are both intrinsic and extrinsic (sarcopenia, altered bone remodeling, reduced proprioception) contribute to OA development. The concept that aging contributes to, but does not directly cause OA, is consistent with the multifactorial nature of the condition and the joints most commonly affected. OA normally develops after long periods of exposure to risk factors such as obesity, joint trauma, joint malalignment, or abnormal shape and leg length inequality. Age-related changes occur in the joint tissues of all individuals, most notably in articular cartilage. However, symptomatic, radiographic,macroscopic, ormicroscopic signs ofOA do not manifest in all individuals, even at an advanced age. This suggests that aging does not necessarily cause OA, rather agerelated changes provide a basis upon which OA can develop.

Individuals with OA risk factors may undergo an accelerated rate of change similar to that associated with aging, consistent with the concept that aging results from an imbalance between stressors causing damage and mechanisms that repair or protect against damage.

In both aging and OA, changes occur in the total amount and composition of articular cartilage extracellular matrix, which also undergoes proteolysis and other modifications. The superficial zone is where the earliest age-related changes occur in human articular cartilage. In OA, increased proteolytic activity in cartilage and synovial fluid causes cartilage matrix changes and increased degradation of collagen molecules. There is also a decrease in fixed charge density due to degradation and loss of aggrecan.

Normal aging involves a marked increase in the formation of advanced glycation end products, including pentosidine crosslinks. The resultant increased crosslinking of collagen molecules can alter the biomechanical properties of cartilage, resulting in increased stiffness and susceptibility to fatigue.

A highly prevalent change in aging cartilage is deposition of calcium-containing crystals due to increased pyrophosphate production by chondrocytes. Calcium crystals may stimulate chondrocyte production of inflammatory mediators and extracellular matrix–degrading enzymes, contributing to the onset and progression of OA, and may play a role in erosive OA, a more destructive form of OA most commonly seen in the distal interphalangeal joints in elderly women.

Age-associated cellular changes in articular cartilage include cell depletion and impaired responses to extracellular stimuli resulting in abnormal gene expression and cell differentiation. In full-thickness cartilage, cell density decreases with aging. In OA-affected cartilage, chondrocyte proliferation in the form of “cell clusters” or “cloning” has been observed in areas of fibrillation. Cells in these clusters express progenitor cell markers and a wide spectrum of proteins associated with abnormal chondrocyte activation and differentiation. This represents a tissue repair response of progenitor cells. The activation pattern of the cluster cells also underscores the notion that aging does not uniformly affect all cells in cartilage and that certain cell subsets in aging and OA-affected cartilage are capable of proliferation and activation.

With increasing age, chondrocytes become less responsive to the proliferative and anabolic effects of growth factors, which may contribute to an imbalance between anabolic and catabolic activity. Altered cell signaling in response to growth factors may also account for the reduced anabolic response with age.

Conceptually, age-related pathologies originate from limitations in the maintenance and repair mechanisms of DNA, anomalies in the antioxidant mechanisms that contribute to the detoxification of reactive oxygen species, or abnormalities in mechanisms for removal of abnormal proteins and organelles. A clear distinction between aging and OA has not always been provided, so that it can be difficult to differentiate primary age related changes from those that are part of the OA process. _

6. P. Horák, Czech Republic

Pavel HORÁK, MD, PhD
Department of Internal Medicine
Nephrology, Rheumatology, Endocrinology
Faculty of Medicine and Dentistry
Palacký University of Olomouc
I. P. Pavlova 6
772 00 Olomouc

Osteoarthritis (OA) is a slow-developing disease of the diarthrodial joints associated with progressive cartilage damage, soft tissue and subchondral bone changes, bony osteophytes, and joint inflammation. OA is most common in the hands, causing significant pain and functional loss, but involvement of the knees or hips is usually more disabling. Aging is the most important risk factor, followed by obesity, previous joint injury, female sex, and genetic disposition. Two fundamental mechanisms lead to OA: normal load on abnormal cartilage (primary OA) or abnormal load on normal cartilage (secondary OA). Although cartilage aging is universal, OA is not found in all elderly people; a proportion of them are free of symptomatic and radiographic OA, indicating the presence of additional risk and/or protective factors.

There are several theories explaining the pathogenesis of primary OA. The oldest theory, wear and tear of the cartilage matrix, emphasizes the effect of mechanical load over a lifetime. The extracellular matrix theory links OA to intrinsic changes in proteoglycans, the collagen network, and chondrocyte biology that are caused by advanced glycation end products and oxidative stress. The apoptotic theory views OA as the result of chondrocyte apoptosis or other types of cell death. The mitochondrial theory emphasizes the role of mitochondrial DNA damage, which may be advanced by inflammatory cytokines, contributing to chondrocyte energy failure and death. A recent theory on cell senescence describes OA as the increasing inability of the chondrocytes to keep up with mechanical or inflammatory attacks leading to failure in maintaining cartilage integrity.

The causes of cell aging remain unclear, but it is increasingly accepted that there are a limited number of cell replication cycles, culminating in replicative senescence. Replication is limited by telomere exhaustion. Telomeres are eroded by each division cycle, eventually down to the minimum length for DNA replication, resulting in cycle arrest.

In adults, subchondral bone isolates cartilage from the vascular system, resulting in no influx of progenitor cells into cartilage. Chondrocytes are post mitotic, with little or no cell turnover, and are among the oldest cells in the body. They accumulate age-related changes and are also unable to move from damaged regions due to the constraint of the extracellular matrix. Aside from aging, repeated injuries (joint instability) increase the requirements for replication and damage repair and thus contribute to the exhaustion of mitotic potential. As a result of the specific local environment, oxidatively damaged molecules can accumulate in chondrocytes, leading to a decreased ability to maintain matrix synthesis and homeostasis. Chondrocyte senescence reduces the ability to respond to growth factor stimulation, contributing to an imbalance in cartilage formation and degradation, as well as decreased chondrocyte anabolic activity. Furthermore, senescence- associated secretory phenotype (SASP) may negatively affect the local environment. Cells exhibiting SASP produce proinflammatory cytokines and matrix metalloproteinases very similar to those in OA. Another cell senescence factor, high-mobility group box protein 2, regulates gene transcription and decline in the superficial zone of aging chondrocytes and is associated with increased chondrocyte death in OA models.

Current findings support the view that cartilage aging usually occurs before overt primary OA. In many cases, it is impossible to distinguish the senescent chondrocyte from the osteoarthritic chondrocyte because cell senescence is the number one precondition for OA. There is some evidence of increased chondrocyte proliferation during the development of OA, and chondrocyte death has also been observed, with reduced numbers particularly in the superficial regions of cartilage. However, it is not clear if the cell damage and reactivity represent changes associated with the aging process, early OA, or a continuum from aging to OA.

A better understanding of the role of senescence biology in OA development may translate practically into the development of new strategies to delay the onset of chondrocyte senescence and prevent the development or progression of OA. _
1. Aigner T, Richter W. Age related OA—a concept emerging from infancy? Nat Rev Rheumatol. 2012;8:70-72.
2. Horton Jr WE, Bennion P, Yang L. Cellular, molecular, and matrix changes in cartilage during aging and osteoarthritis. J Musculoskelet Neuronal Interact. 2006;6:379-381.
3. Loeser RF. Aging and osteoarthritis. Curr Opin Rheumatol. 2011;23:492-496.
4. Anderson AS, Loeser RF. Why is osteoarthritis an age-related disease? Best Pract Res Clin Rheumatol. 2010;24:15-26.
5. Martin JA, Buckwalter JA. Aging, articular cartilage chondrocyte senescence and osteoarthritis. Biogerontology. 2002;3:257-264.
6. Loeser RF. Age-related changes in the musculoskeletal system and the development of osteoarthritis. Clin Geriatr Med. 2010;26:371-386.

7. A. El Maghraoui, Morocco

Professor of Rheumatology
Rheumatology Department
Military Hospital Mohammed V

Osteoarthritis (OA) is a common age-related disorder, often described as a chronic degenerative disease and thought by many to be an inevitable consequence of growing old. Epidemiological studies show that age remains the most prominent risk factor for the initiation and progression of primary OA in susceptible joints.1 The prevalence of OA increases with age: radiographic surveys of multiple joints (hands, spine, hips, and knees) reveal the presence of OA in at least one joint in over 80% of older adults.2 However, not all older adults with symptoms of joint pain have radiographic evidence of OA in the painful joint, and only about half of people with radiographic OA experience significant symptoms. Moreover, it is well-known that not all older adults develop OA and not all joints in the body are affected to the same degree. It is also well-known that radiographic OA changes, particularly osteophytes, are common in the aged population, but symptoms of joint pain are frequently independent of radiographic severity. Consequently, due to the discrepancies between osteoarthritic pain and radiographic evidence of OA, most current epidemiological studies define OA through a combination of clinical and radiographic criteria.

The current concept is that OA is a disease of the “whole joint,” which involves a complex series of molecular changes at the cell, matrix, and tissue levels and complex interactions between the tissues that make up the joint. Aging is the major risk factor, and it contributes to, but does not directly cause OA. This is consistent with the multifactorial nature of the condition and the differing joints most commonly affected. Besides age, the common risk factors for OA include obesity, previous joint injury, genetics, and anatomical factors including joint alignment. These risk factors appear to interact with age to determine which joints are affected by OA and how severe the condition will be. Thus, there are important differences between an aged joint and one with OA. Age-related mechanical stress on joint cartilage (arising from a number of factors, including altered gait, muscle weakness, degeneration of ligaments, changes in proprioception, and changes in body weight), and changes within the joint (including cell and matrix changes in joint tissues, thickening of the subchondral bone, variable degrees of synovial inflammation, loss of meniscal tissue, and hypertrophy of the joint capsule contributing to joint enlargement) contribute to the development of OA when other OA risk factors are also present.3 The pathological changes noted in the other joint tissues also contribute to the loss of normal joint function, and because, unlike cartilage, they contain pain fibers, these tissues are responsible for the pain experienced by people with OA.

Thus, it is very important to question how to distinguish normal age-related changes in cartilage that do not progress to OA from early changes that reliably do progress to OA. In this regard, magnetic resonance imaging (MRI) studies have shown promising results. New methodological approaches for quantitative assessment have been introduced, and an MRI-based definition of OA has been suggested.4 A recent study using MRI methods sensitive to cartilage matrix composition demonstrated that subjects at risk for OA have both higher and more heterogeneous cartilage T2 values than controls, and that T2 parameters are associated with morphologic degeneration.5 One could speculate that the development of these kinds of techniques could help to distinguish age-related changes in cartilage that predispose patients to OA from those that do not. More information is needed to better understand how aging changes in the bone, meniscus, and ligaments contribute to the development of OA. _
1. Aigner T, Richter W. OA in 2011: age-related OA—a concept emerging from infancy? Nat Rev Rheumatol. 2012;8:70-72.
2. Loeser RF. Age-related changes in the musculoskeletal system and the development of osteoarthritis. Clin Geriatr Med. 2010;26:371-386.
3. Heijink A, Gomoll AH, Madry H, et al. Biomechanical considerations in the pathogenesis of osteoarthritis of the knee. Knee Surg Sports Traumatol Arthrosc. 2012; 20:423-435.
4. Hunter DJ, Arden N, Conaghan PG, et al. Definition of osteoarthritis on MRI: results of a Delphi exercise. Osteoarthritis Cartilage. 2011;19:963-969.
5. Joseph GB, Baum T, Carballido-Gamio J, et al. Texture analysis of cartilage T2 maps: individuals with risk factors for OA have higher and more heterogeneous knee cartilage MR T2 compared to normal controls—data from the osteoarthritis initiative. Arthritis Res Ther. 2011;13:R153.

8. A. Mahmoud Ali Elsayed, Egypt

Adel Mahmoud ALI ELSAYED, MD
Professor of Internal Medicine
Head of Rheumatology Division
Ain Shams University
53 El Makrizy Street
Roxy, Cairo

Articular cartilage is a unique tissue from the perspective of aging, in that chondrocytes and the majority of the extracellular matrix proteins experience little turnover, thus resulting in a tissue that must withstand years of use and can also accumulate years of aging-associated changes. It has been known for a very long time that aging is the most prominent risk factor for the initiation and progression of osteoarthritis. This might be related to continuous mechanical wear and tear and/or time/age-related modifications of cartilage matrix components. In addition, a mere loss of viable cells over time due to apoptosis or any other mechanism might contribute. More recent evidence, however, supports the notion that stressful conditions for the cells might promote chondrocyte senescence and be particularly important in the progression of the osteoarthritic disease process.1

In animal models, aging predisposes articular cartilage to changes in viable cell density and to expression of specific proapoptotic genes. Also, fetal and young (but still skeletally mature) bovine chondrocytes behave similarly, while aged chondrocytes display diminished proliferation, slightly reduced proteoglycan accumulation, and significantly less collagen accumulation per cell compared with the younger cells. Histological observations and mechanical properties support these findings, and a particularly significant reduction in the tensile stiffness produced by aged chondrocytes compared with younger cells has been observed.2

In humans, chondrocytes from normal but aged subjects display biochemical properties closer to osteoarthritic-derived cartilage than to normal young cartilage, as indicated by cell morphology, cell proliferation rate, and patterns of protein secretion (in particular stromelysin-1 and interstitial collagenase).3 During aging, nonenzymatic glycation results in the accumulation of advanced glycation end products (AGEs) in cartilage collagen. The highest AGE levels are found in tissues with slow turnover, such as cartilage. AGEs exert their effects by adversely affecting the biomechanical, biochemical, and cellular characteristics of the tissue, as well as by modulating tissue turnover.

This ultimately increases cartilage stiffness and brittleness, increases chondrocyte-mediated proteoglycan degradation, reduces resistance to matrix metalloproteinase–mediated degradation, and decreases proteoglycan synthesis by chondrocytes. Articular cartilage becomes more prone to damage and development of osteoarthritis.4

In addition, an age-associated reduction in growth factor signaling and an increase in oxidative stress may also play an important role in the age-osteoarthritis connection.5

Although different studies have shown that age is inversely associated with cartilage volume, cartilage turnover, and aggrecan expression in healthy individuals, the exact differentiation between aged cartilage and early osteoarthritic cartilage seems difficult, and age-related changes leading to failure of human articular cartilage to resist damage are considered to be OA. _
1. Aigner T, Haag J, Martin J, Buckwalter J. Osteoarthritis: aging of matrix and cells—going for a remedy. Curr Drug Targets. 2007;8:325-331.
2. Tran-Khanh N, Hoemann CD, McKee MD, Henderson JE, Buschmann MD. Aged bovine chondrocytes display a diminished capacity to produce a collagen- rich, mechanically functional cartilage extracellular matrix. J Orthop Res. 2005;23:1354-1362.
3. Dozin B, Malpeli M, Camardella L, Cancedda R, Pietrangelo A. Response of young, aged and osteoarthritic human articular chondrocytes to inflammatory cytokines: molecular and cellular aspects. Matrix Biol. 2002;21:449-459.
4. DeGroot J. The age of the matrix: chemistry, consequence and cure. Curr Opin Pharmacol. 2004;4:301-305.
5. Loeser RF Jr. Aging cartilage and osteoarthritis—what’s the link? Sci Aging Knowledge Environ. 2004;pe31.

9. A. Migliore, Italy

Director UOS of Rheumatology
Hospital Villa S. Pietro

Aging is the main risk factor for primary osteoarthritis (OA) and OA is the disease most strongly correlated with aging. Both in humans and other animals, OA development seems to be not rigorously time-dependent, but to hold pace with the aging process. Despite older age being the greatest risk factor for OA, OA is not an unavoidable consequence of growing old. Moreover, radiographic changes indicative of OA—mainly osteophytes—are frequent in the aged population, but symptoms of joint pain may not correlate with the severity of radiographic findings in many older subjects.

OA is a degenerative disease characterized by structural changes to joint tissues that include synovial inflammation, catabolic destruction of articular cartilage, alterations in subchondral bone, and decreasing muscle strength.

This article will only address differences between cartilage changes caused by OA and those caused by aging. The effects of aging involve the whole articular cartilage. Major extracellular matrix changes comprise reduced cartilage thickness, proteolysis, advanced glycation, and calcification. Cellular changes consist of decreased cell density, cellular senescence with reduced chondrocyte survival, decreased mitotic and anabolic activity, anomalous cytokine excretion, and impaired cellular resistance.

One of the most pronounced age-related changes in chondrocytes is a senescent phenotype, which is caused mainly by the accumulation of reactive oxygen species (ROS) and advanced glycation end products. Senescent chondrocytes display an impaired ability to respond to many mechanical and inflammatory insults. Protein secretion is also altered in aging chondrocytes, as demonstrated by a decrease in anabolic activity and increased production of proinflammatory cytokines and matrix-degrading enzymes. The senescent secretory phenotype has some features in common with the OA chondrocyte phenotype, including increased production of cytokines and matrix metalloproteinases.

The age-related increase in ROS levels could play an important role in OA. The various inflammatory mediators that are increased in OA, including IL-1, IL-6, IL-8, TNF-α, and other cytokines, can all stimulate additional production of ROS. Excess ROS production can directly damage intracellular proteins and DNA, as well as the extracellular matrix, by stimulating matrix metalloproteinase production and activity, thus playing a significant role in stimulation of cartilage degradation in OA.

The extracellular and cellular changes in aging compound each other, leading to biomechanical dysfunction and tissue destruction. Some of these changes differ from those seen in OA, which is also characterized by cell activation with increased proliferation and gene expression. Disruption of the articular surface or superficial zone (SZ) seems to be a key triggering event for the chronic and progressive extracellular matrix degradation process leading to OA. The SZ contains the majority of mesenchymal stem cells in adult cartilage. The presence of stem cells endows the SZ with the capacity for self-renewal, which may be required to respond to mechanical stress. However, the SZ can be compromised by acute or chronic mechanical stress and by age-related cellular dysfunction. Once the SZ is disrupted, cartilage cells are activated, and through the production of matrix-degrading enzymes, lesions enlarge causing joint inflammation, pain, and dysfunction. Loss of cells (eg, via apoptosis) is among the major changes that occur in the SZ due to aging and exposure to mechanical stress.

Cartilage degradation results in the production of fragments of extracellular matrix molecules. Some of these molecules may be detected in blood, serum, synovial fluid, and urine, and can act as useful biomarkers. The ability to detect biomarkers of cartilage degradation may enable clinicians to differentiate the appearance of subclinical OA from natural joint aging. Biomarkers indicating early phases of degeneration would be useful in detecting preradiographic OA changes. Proteomic techniques have the potential to improve our understanding of OA pathophysiology. _

10. T. Pap, Germany

Thomas PAP, Experimental
Musculoskeletal Medicine
University Hospital Münster
Domagkstrasse 3
D-48149 Münster

Osteoarthritis (OA) is the most frequent joint disease and an important cause of disability in the Western world. It involves all parts of articular joints and is characterized primarily by the progressive, irreversible loss of articular cartilage. Given that the incidence of osteoarthritic changes increases with age, the question of whether OA is a mere aging phenomenon or as with cardiovascular disorders, cancer, or neurodegenerative diseases, becomes more frequent during aging because of the cumulative effects of pathogenic factors (which in principle can affect individuals at any age), is a controversial, yet important, one.

One main reason for the difficulty in answering this question is that the processes that lead to and characterize normal cartilage aging remain largely unknown. While it is well accepted that the composition of the extracellular matrix changes with aging, aside from the loss of proteoglycans, disease-specific alterations in osteoarthritic cartilage are poorly characterized and understood. Also, OA most likely does not constitute a uniform disease, but rather an initially complex yet ultimately narrow path of how cartilage responds to different types of stress. In this context, it has been suggested that inflammation is a distinguishing factor between normal aging and OA.1 However, the role of inflammation as a trigger and accelerating force of osteoarthritic changes remains controversial, and while some recent data suggest a key role for inflammatory signals, the most recent studies have failed to demonstrate a key role for IL-1–mediated inflammation in murine models of OA.2 Of interest, several lines of evidence indicate that osteoarthritic changes are linked to the reexpression in chondrocytes of molecules and pathways that are characteristic of different stages of endochondral ossification during embryonic development.3

Members of the syndecan family of transmembrane heparin sulfate proteoglycans, particularly syndecan-4, are prominent examples in this respect.4 We were able to show that syndecan- 4,which is expressed prominently in hypertrophic chondrocytes of developing joints in the embryo, is reexpressed both in human OA and in animal models of the disease, and its concentration correlates with disease severity.4 Interestingly, the loss of syndecan-4 in genetically modified mice, as well as its inhibition by specific antibodies, was capable of preventing the development of OA-like changes.4 These data are also of interest because according to recent data, increased expression of syndecan-2 can compensate for the loss of syndecan-4 during embryogenesis but not during OA, due to differential regulation of these two syndecans. While the exact mechanisms are not fully understood, these data suggest that while the program appears to be similar, the triggers and mechanisms of cartilage remodeling during endochondral ossification and OA may be distinct.

Given that during endochondral ossification, deposition of basic calcium phosphate crystals is an important part of bone formation, calcification of articular cartilage during OA is another indication of similarities between both conditions. Our group found that the calcification of hyaline cartilage is a regular event in human OA and is strongly associated with the hypertrophic differentiation of chondrocytes.5 The mechanisms involved in pathological cartilage calcification during OA, and particularly the pathways that link chondrocyte differentiation to the calcification of the surrounding matrix, are not completely understood. However, changes in the synthesis and transport of inorganic pyrophosphate, as well as in extracellular pyrophosphate metabolism, have been found to be associated with this process.6

Collectively, these data indicate that while mechanistically similar and part of a rather uniform program, the developmental processes that occur either during embryogenesis or during aging can be distinguished from the pathological changes seen in OA. Distinguishing factors appear to include the nature, strength, and duration of underlying stimuli. _
1. Furuzawa-Carballeda J, Macip-Rodriguez PM, Cabral AR. Osteoarthritis and rheumatoid arthritis pannus have similar qualitative metabolic characteristics and pro-inflammatory cytokine response. Clin Exp Rheumatol. 2008;26:554-560.
2. Bougault C, Gosset M, Houard X, et al. Stress-induced cartilage degradation does not depend on NLRP3 inflammasome in osteoarthritis. Arthritis Rheum. 2012;64: 3972-3981
3. Saito T, Fukai A, Mabuchi A, et al. Transcriptional regulation of endochondral ossification by HIF-2alpha during skeletal growth and osteoarthritis development. Nat Med. 2010;16:678-686.
4. Echtermeyer F, Bertrand J, Dreier R, et al. Syndecan-4 regulates ADAMTS-5 activation and cartilage breakdown in osteoarthritis. Nat Med. 2009;15:1072-1076.
5. Fuerst M, Bertrand J, Lammers L, et al. Calcification of articular cartilage in human osteoarthritis. Arthritis Rheum. 2009;60:2694-2703.
6. Bertrand J, Nitschke Y, Fuerst M, et al. Decreased levels of nucleotide pyrophosphatase phosphodiesterase 1 are associated with cartilage calcification in osteoarthritis and trigger osteoarthritic changes in mice. Ann Rheum Dis. 2012;71: 1249-1253.

11. J. del Pino-Montes, Spain

Professor of Medicine
University of Salamanca
Service of Rheumatology
University Hospital of Salamanca
Paseo San Vicente, 54
37007 Salamanca

Osteoarthritis (OA) is probably the most common chronic joint disorder. It is defined by focal lesions of the articular cartilage, a hypertrophic reaction in the subchondral bone, and new bone formation. OA is often considered a chronic degenerative disease, with degradation of articular cartilage attributed to wear and tear. Although aging is a known risk factor for OA, the condition is not a consequence of growing old, but involves a destructive chronic active inflammatory mechanism mediated by cells within the articular cartilage.1

In OA, there is a change in the normal adult chondrocyte state characterized by cell proliferation, cluster formation, and increased production of matrix proteins and matrix-degrading enzymes. Chondrocytes in OA cartilage express cytokine and chemokine receptors, matrix metalloproteinases (MMPs), and other proteins that enhance or modulate inflammatory and catabolic responses. MMPs such as aggrecanases and collagenases are found in the osteoarthritic joint. In early OA, MMP-3 and ADMTS-5 degrade aggrecan.2 Next, collagenases degrade type II collagen and the collagen network. As the articular cartilage matrix proteins are degraded, fragments of matrix proteins such as fibronectin and small leucine-rich proteoglycans are produced, which can feed back and stimulate further matrix destruction. This early stage may reflect an effort by the hypertrophic chondrocytes to repair cartilage damage. As OA progresses, the proteoglycan level eventually drops very low, causing cartilage to soften and lose elasticity, thereby further compromising joint surface integrity.

Aging produces a gradual loss of cartilage matrix as well as a decrease in cartilage hydration and cellularity. Aging cartilage is characterized by an age-related loss in the ability of cells and tissues to maintain homeostasis. Normal aging chondrocytes are reduced in number, rarely divide, and exhibit no cellular proliferation or hypertrophic cells. They show shortened telomeres characteristic of cellular senescence. However, aging chondrocytes can exhibit a senescence secretory phenotype, characterized by increased production of cytokines, MMPs, and several growth factors.3 As a result, in the elderly, there is increased age-related cartilage catabolism.

Besides these mechanisms, the chondrocyte anabolic response to growth factors decreases with age. Under such circumstances, the chondrocyte is unable to maintain cartilage homeostasis. Cell death has also been related to aging, and formation of advanced glycation end products (AGEs) increases with age.4 Modification of collagen by AGE formation results in increased crosslinking of collagen molecules affecting the biochemical properties of cartilage and making it more brittle. Moreover, there is an age-related increase in reactive oxygen species, and this may contribute to cell death and matrix degeneration.5

There is no clear frontier between the features of articular cartilage in aging and OA, and both share some common characteristics. Senescent and osteoarthritic chondrocytes share a secretory phenotype. Cell death has been observed during the development of OA as well as in aging cartilage. Age-related loss of autophagy, a protective mechanism for normal chondrocytes that protects cells during the stress response, is associated with cell death and OA development.6 Age-related changes in cartilage matrix could also be important in contributing to the development of OA. The increased accumulation and expression of AGEs that occurs in aging chondrocytes is associated with enhanced sensitivity to cytokines and chemokines, which trigger expression of MMPs. The increased production of reactive oxygen species could also play an important role in OA.

The relationship between aging and OA is well known, but the mechanisms by which aging predisposes the joint to OA development are not fully understood. Age-related changes observed in cell and cartilage matrix may increase the susceptibility to OA, but they do not directly cause it in older adults. More information is needed to better understand how aging changes in the bone, meniscus, and ligaments contribute to the development of OA. _
1. GoldringMB,Marcu KB. Cartilage homeostasis in health and rheumatic diseases. Arthritis Res Ther. 2009;11:224.
2. Wang M, Shen J, Jin H, Im HJ, Sandy J, Chen D. Recent progress in understanding molecular mechanisms of cartilage degeneration during osteoarthritis. Ann N Y Acad Sci. 2011;1240:61-69.
3. Leong DJ, Sun HB. Events in articular chondrocytes with aging. Curr Osteoporos Rep. 2011;9:196-201.
4. DeGroot J, Verzijl N, Wenting-van Wijk MJ, et al. Accumulation of advanced glycation end products as a molecular mechanism for aging as a risk factor in osteoarthritis. Arthritis Rheum. 2004;50:1207-1215.
5. Del Carlo M Jr, Loeser RF. Cell death in osteoarthritis. Curr Rheumatol Rep. 2008;10:37-42.
6. Goldring MB. Chondrogenesis, chondrocyte differentiation, and articular cartilage metabolism in health and osteoarthritis. Ther Adv Musculoskelet Dis. 2012; 4:269-285.

12. C. A. F. Zerbini, Brazil

Cristiano A. F. ZERBINI, MD
Rheumatology Department
Hospital Heliópolis
Rua Conego Xavier #276
04231-030, São Paulo, SP

Osteoarthritis (OA) is considered a characteristic age-related disease. Its prevalence increases with age, affecting 30% to 50% of adults aged over 65 years.1 Although it is the greatest risk factor for OA, older age alone is not responsible for its development. Age, obesity, female sex, previous trauma (knee injury), and hand OA were reported as consistent risk factors for knee OA in people aged 50 years and older.2 Risk factors for OA such as obesity, genetics, anatomical abnormalities, and joint injury are well known, but how they interact with age to initiate and develop OA is still unclear. Recent advances in molecular biology are starting to clarify the connection between cellular aging changes and the propensity to develop OA.

Chondrocytes are the only cell type in articular cartilage, and they particularly suffer during aging. They are responsible for the synthesis and breakdown of the cartilaginous matrix and are driven by signals from growth factors, cytokines, and the matrix itself. The chondrocytes of older cartilage are the same cells present in the cartilage during youth. Chondrocytes rarely divide or die in normal adult articular cartilage, with the same cells remaining active for many years. Chondrocytes have a very long lifespan, but in older individuals they may express changes characteristic of cell senescence. Cell senescence found in chondrocytes is called stress-induced or “extrinsic” senescence, as opposed to replicative or “intrinsic” senescence. Stress-induced senescence can develop from stimuli including activated oncogenes, ultraviolet radiation, and chronic inflammation. Stress-induced senescence is associated with oxidative DNA damage, which results in telomere shortening (as in replicative senescence). Many age-related changes in chondrocytes, particularly oxidative DNA damage, may induce development of the senescence-associated secretory phenotype (SASP).3 This phenotype when expressed in chondrocytesmay link the articular aging process with the development of OA. SASP is characterized by increased production of inflammatory mediators such as cytokines and matrix metalloproteinases, which may induce cartilaginous matrix degradation and joint impairment and may also be found in osteoarthritic cartilage. SASP expression in chondrocytes may be linked to the production of reactive oxygen species (ROS) by dysfunctional mitochondria, resulting in mitochondrial and nuclear DNA damage. Mitochondrial DNA damage can be observed in OA and is associated with increased matrix degradation and decreased matrix synthesis. ROS production may be induced by inflammatory cytokines such as IL-1β and TNF-α, and is also associated with mechanical injury to joints. An increase in ROS may contribute to chondrocyte death.4

Thus, ROS, mitochondrial dysfunction, and DNA damage may be features of chondrocyte senescence associated with development of SASP and may lead to cartilage matrix impairment and development of OA.

Aged and osteoarthritic chondrocytes have a reduced ability to respond to transforming growth factor-and insulin-like growth factor-1 (IGF-1) stimulation. This leads to a reduced capacity for matrix repair, and consequently, a degeneration of the articular cartilage. The decrease in chondrocyte responsiveness to IGF-1 is associated with increased ROS levels.5

Autophagy is a mechanism used by the cell to degrade and recycle dysfunctional proteins. It is an important mechanism by which cells are protected against stress. Autophagy declines with age, and its loss has been associated with increased chondrocyte death. Recent studies in autophagy have attempted to clarify the possible role of this process in senescence and OA.6

Thus, to answer the question, we must determine if and when the aging process results in the development of SASP. Senescent chondrocytes developing this phenotype are very similar to chondrocytes found in osteoarthritic joint tissues. In my opinion, development of this phenotype with its associated inflammatory cytokines, or lack of it, will determine how much we can distinguish between normal age-related changes in cartilage and early osteoarthritic changes. _
1. Lawrence RC, Felson DT, Helmick CG, et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States: Part II. Arthritis Rheum. 2008;58:26-35.
2. Blagojevic M, Jinks C, Jeffery A, et al. Risk factors for onset of osteoarthritis of the knee in older adults: a systematic review and meta-analysis. Osteoarthritis Cartilage. 2010;18:24-33.
3. Freund A, Orjalo AV, Desprez PY, et al. Inflammatory networks during cellular senescence: causes and consequences. Trends Mol Med. 2010;16:238-246.
4. Loeser RF. Aging and osteoarthritis. Curr Opin Rheumatol. 2011;23:492-496.
5. Yin W, Park JI, Loeser RF. Oxidative stress inhibits insulin-like growth factor-I induction of chondrocyte proteoglycan synthesis through differential regulation of phosphatidylinositol 3-Kinase-Akt and MEK-ERK MAPK signaling pathways. J Biol Chem. 2009;284:31972–31981.
6. Carames B, Taniguchi N, Otsuki S, et al. Autophagy is a protective mechanism in normal cartilage, and its aging-related loss is linked with cell death and osteoarthritis. Arthritis Rheum. 2010;62:791-801.