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jurnal muskuloskeletal

Clin Geriatr Med. Author manuscript; available in PMC Aug 1, 2011.

Published in final edited form as:

Clin Geriatr Med. Aug 2010; 26(3): 371–386.

doi:  10.1016/j.cger.2010.03.002

PMCID: PMC2920876

NIHMSID: NIHMS193463

Age-Related Changes in the Musculoskeletal System and the Development of Osteoarthritis

Richard F. Loeser, MD

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Abstract

Synopsis

Osteoarthritis (OA) is the most common cause of chronic disability in older adults. Although classically considered a “wear and tear” degenerative condition of articular joints, recent studies have demonstrated an inflammatory component to OA that includes increased activity of a number of cytokines and chemokines in joint tissues which drive production of matrix degrading enzymes. Rather than directly causing OA, aging changes in the musculoskeletal system contribute to the development of OA by making the joint more susceptible to the effects of other OA risk factors that include abnormal biomechanics, joint injury, genetics, and obesity. Age-related sarcopenia and increased bone turnover may also contribute to the development of OA. Understanding the basic mechanisms by which aging affects joint tissues should provide new targets for slowing or preventing the development of OA.

Keywords: aging, osteoarthritis, articular cartilage, elderly, cell senescence, oxidative stress

Introduction

The prevalence of osteoarthritis (OA) increases with age such that 30 to 50% of adults over the age of 65 years suffer from this condition^{1, 2}. Radiographic changes of OA, in particular the presence of osteophytes, are even more common such that radiographic surveys of multiple joints (hands, spine, hips and knees) reveal OA in at least one joint in over 80% of older adults³. However, only about half of people with radiographic OA experience significant symptoms. Likewise, not all older adults with symptoms of joint pain have radiographic evidence OA in the painful joint. In a study of 480 adults over the age of 65 years who reported chronic knee pain, only about 50% had radiographic evidence of knee OA⁴.

Although OA is most common in the hands, involvement of the knees and hips is usually much more disabling. Radiographic involvement of the distal interphalangeal joints in the hand was present in more than half of men over the age of 65 and more than half of women over the age of 55years⁵ but only thirteen percent of men and 26% of women over the age of 70 were found to have symptomatic hand OA⁶. The prevalence of radiographic knee osteoarthritis in subjects aged 60 and higher increased with each decade of life from 33% among those aged 60-70 to 43.7% among those over 80 years of age while the prevalence of symptomatic knee OA in these subjects was 9.5% and increased with age in women but not men⁷. In the Johnson Country Osteoarthritis cohort, the prevalence of radiographic knee OA rose from 26.2% in the 55-64 year range to nearly half of participants in the 75+ group and the prevalence of symptomatic knee OA likewise increased from 16.3% to 32.8% between these age groups⁸. Symptomatic hip OA in this cohort was reported as 5.9% in the 45-54 age group increasing to 17% in the 75+ age group⁹.

The relationship between aging and OA is well known but the mechanisms for how aging predisposes the joint to developing OA are still not fully understood. Changes both intrinsic to the joint as well as those extrinsic (such as sarcopenia, altered bone remodeling and reduced proprioception) contribute to the development of OA. The concept that aging contributes to, but does not directly cause OA, is consistent with the multifactorial nature of this condition and the disparity in which joints are most commonly affected. In this chapter, current concepts of the biology of OA will be reviewed and the relationship between aging and the development of OA will be considered.

The Pathobiology of Osteoarthritis

OA is a multifactorial condition but the pathological changes seen in osteoarthritic joints have common features no matter what the cause(s) of the condition in a given individual. These features include degradation of the articular cartilage starting at the joint surface and progressing to full thickness loss, thickening of the subchondral bone with accumulation of poorly mineralized matrix, osteophyte formation at the margins of joint surfaces, variable degrees of synovial inflammation with limited pannus formation, degeneration of ligaments and, in the knee the menisci, with eventual ligamentous rupture and meniscal extrusion, and hypertrophy of the joint capsule contributing to joint enlargement (Figure 1). In some individuals, increased subchondral bone remodeling results in bone marrow lesions detected on MRI and, in many older adults, calcification in the articular cartilage and/or the menisci is seen on plain radiographs. In the articular cartilage, the earliest changes at the joint surface occur in the areas that receive the greatest mechanical forces. As OA progresses, the loss of the articular cartilage affects joint movement due to the loss of a smooth lubricated surface responsible for the normal gliding motion of the joint. The pathological changes noted in the other joint tissues also contribute to the loss of normal joint function and, because unlike the cartilage they contain pain fibers, these tissues are responsible for the pain experienced by people with OA.

Pathology of osteoarthritis

There are reasons to believe that although OA has common pathological features seen once the disease becomes advanced, it may start with selected features that are dependent on the initiating factors in a given individual. For example, in an individual with post-traumatic OA resulting from rupture of the anterior cruciate ligament the condition likely started with a period of acute joint inflammation with synovitis and cartilage matrix destruction followed later by development of bony changes while in an individual with OA related to obesity it may have started with increased bone formation followed by articular cartilage matrix destruction and secondary synovial inflammation stimulated by release of cartilage matrix fragments. The early stages of OA have been difficult to study. Most people do not develop symptoms until significant joint damage has occurred, commonly after age 50-60 years, but there is radiographic evidence for OA in a significant percent of women beginning in the early 40's¹⁰. Researchers are attempting to develop biomarkers and advanced imaging techniques that could detect early stage disease but given the slowly progressive nature of OA it will be some time before sufficient information is available to determine the predictive power of these techniques.

At the cell and tissue level, cartilage in OA is characterized by an imbalance in matrix synthesis and matrix degradation. The chondrocyte is the only cell type present in articular cartilage and therefore is responsible for both the synthesis and the breakdown of the cartilaginous extracellular matrix¹¹. Signals generated by cytokines, growth factors, and the matrix regulate chondrocyte metabolic activity. In the early stages of OA, there is evidence of increased matrix synthesis, although not all the matrix proteins produced are the same as those made by normal adult articular chondrocytes. There is increased expression of the fetal form of type II collagen (type IIA)¹² and of type III collagen and fibronectin^{13, 14} as well as proteoglycans with altered sulfation patterns¹⁵. Progressively, excessive matrix degradation overwhelms matrix synthesis and this appears to be due to inflammatory and catabolic signals that are present in excess of the anti-inflammatory and anabolic signals (Figure 2). Pro-inflammatory cytokines found in OA cartilage include IL-1, IL-6, IL-7, IL-8, and TNF-α to name just a few. The presence of a large number of inflammatory mediators within the articular cartilage indicates that OA is much more inflammatory than previously thought. The excess of inflammatory signals inhibits matrix synthesis and promotes increased production of matrix degrading enzymes, including matrix metalloproteinases (MMPs), aggrecanases, and other proteases that degrade the cartilage matrix. As OA develops, chondrocytes can assume a hypertrophic phenotype characterized by production of type X collagen, alkaline phosphatase, and matrix metalloproteinase (MMP)-13 (collagenase-3)¹³.

Figure 2

Catabolic and anabolic factors that regulate chondrocyte function

Chondrocyte death has been observed during the development of OA but whether this is an early or late event is not clear^{16, 17}. Because cartilage lacks an abundant supply of stem or progenitor cells, the loss of chondrocytes to cell death results in a decline in cell numbers. This is most apparent in the superficial region of the articular cartilage. Although normally adult articular chondrocytes rarely divide, there is evidence for cell proliferation during the development of OA resulting in clusters of chondrocytes being present. However, these cells are unable to maintain the matrix which may be due at least in part to a reduced ability to respond to growth factor stimulation further contributing to an imbalance in matrix synthesis and degradation.

In contrast to matrix loss in the articular cartilage, the subchondral bone undergoes increased matrix production resulting in a thickening of this region. Older theories of OA suggested that the increased subchondral bone resulted in increased stiffness that contributed to the degradation of the overlying cartilage by increasing local stresses^{18, 19}. However, later studies found that the subchondral bone in OA was poorly mineralized and perhaps less stiff than normal bone^18-20. More recently, studies have focused on inflammatory mediators produced by subchondral bone cells that could diffuse through the calcified cartilage zone or enter through cracks in the calcified cartilage and negatively affect the overlying articular cartilage²¹. The presence of localized areas of increased bone remodeling detected by bone scans or by MRI has been noted in areas of cartilage loss and is associated with pain in OA²². The correlation of these lesions in the knee with the location of excessive loading, i.e., medial bone lesions in association with varus alignment and lateral lesions with valgus alignment, suggest they are mechanically mediated²³.

The degree of synovitis present in OA is variable. In people with OA severe enough to require knee replacement, about a third of patients had marked synovitis, one third moderate synovitis, and one third little to no synovitis²⁴. This suggests that synovitis may be important in a subset of people with OA but it is not required to progress to end-stage disease. However, an arthroscopic study of people with early OA did find an association between the presence of synovitis and progression of cartilage lesions measured a year later²⁵. Studies of OA synovial fluid have revealed the presence of inflammatory cytokines that could be involved in stimulating cartilage destruction as well as destruction of other joint tissues such as the meniscus and ligaments. The growth factor TGF-β, although an important contributor to cartilage matrix production, may be responsible for the stimulation of synovial hypertrophy as well as osteophyte formation²⁶.

Although the synovium is involved in OA, the extent of inflammation is usually less than that found in rheumatoid arthritis (RA) where pannus formation is much more extensive and appears to be directly responsible for joint tissue destruction. The extent of synovial inflammation as well as higher systemic levels of inflammatory mediators has been used to classify RA as inflammatory arthritis and OA as “non-inflammatory”. However, as noted above, inflammatory mediators are responsible for joint tissue destruction in OA and elevated serum levels of CRP²⁷ and cytokines including IL-6²⁸ in people with OA indicate that inflammation plays a role in OA as well as RA.

Risk Factors for Development of OA in the Elderly

Besides age, the common risk factors for OA include obesity, previous joint injury, genetics, and anatomical factors including joint shape and alignment²⁹. Additional factors include gender, race, and nutritional factors, such as vitamin D deficiency^{30, 31}. These risk factors appear to interact with age to determine which joints are affected by OA and how severe the condition will be (Figure 3). A joint injury earlier in life predisposes that particular joint to OA later in life³². There is also evidence to suggest that an older adult will develop OA faster than a younger adult after an acute joint injury such as an anterior cruciate ligament tear³³. Other age-related factors that contribute to the development of OA include a decline in muscle strength, loss of proprioception, degenerative changes in the meniscus and joint ligaments, increased bone turnover, as well as calcification of joint tissues^{29, 34, 35}.

Relationship between osteoarthritis risk factors and aging changes that interact to promote the development of osteoarthritis

In terms of knee OA, recent MRI studies have revealed the important role of the meniscus. Incidental meniscal damage on MRI is quite common in the elderly, ranging from a prevalence of 19% in women aged 50-59 to 56% in men in the 70-90 year-old age group³⁶. The prevalence increased to 63% in symptomatic subjects with at least moderate radiographic OA measured by plain films. In a longitudinal study, symptomatic subjects with significant meniscal damage had an odds ratio of 7.4 for the development of radiographic knee OA³⁷. These studies suggest that age-related changes in the meniscus may contribute to meniscal degeneration that in turn may contribute to the development and progression of knee OA.

Recent MRI studies have also shown that anterior cruciate ligament (ACL) disruption is common in older adults with knee OA, even without a known history of trauma³⁸. A well known risk factor for the development of post-traumatic knee OA, age-related changes in the ACL may predispose the ligament to spontaneous rupture or rupture after minimal trauma. Changes which occur in aging ligaments such as increased stiffness from collagen crosslinking combined with decreasing fibril diameter may increase the risk for ACL tears³⁹. Studies are needed to better characterize aging changes in joint ligaments and determine if the mechanisms are similar to those occurring in other soft-tissues in the joint such as the cartilage and meniscus.

As detailed above, the subchondral bone is clearly involved in the development of OA and knowledge is being gained on the mechanisms which seem related to increased bone remodeling and the laying down of an abnormal matrix, processes that are potentially affected by aging^{19, 40}. Bone marrow lesions detected by MRI in people with OA are associated with pain and with disease progression^{22, 23, 41}. First thought to represent edema because of their bright appearance on T2-weighted MRI, these areas most likely represent areas of localized remodeling⁴². The association of bone marrow lesions with malalignment suggests excessive loading may play a role in their development. Increasing age has been shown to be a risk factor for the development of bone marrow lesions in asymptomatic individuals⁴³. This is another area where future research may help elucidate how aging changes in a tissue outside of cartilage contributes to the risk of OA progression in older adults.

Finally, calcification and crystal formation within joint tissues are common findings in older adults that may play a role in OA progression. The association between calcium pyrophosphate deposition disease (CPPD) and the presence of radiographic osteoarthritis has been well established^{35, 44}; however, the role of calcium crystals in the progression of OA has been debated. Some believe that OA and CPPD are common but separate age-related conditions and others believe that the two are closely connected^{35, 45, 46}. Since OA and calcium pyrophosphate are equally associated with osteophyte formation, it has been suggested that mechanical stress may induce release of chemokines which encourage both proliferative bone changes and calcium pyrophosphate formation^{47, 48}. Crystals within the articular cartilage or in the synovium could stimulate toll-like receptors on chondrocytes and synovial cells resulting in production of inflammatory mediators⁴⁹. Crystals may play a role in erosive OA, a more destructive form of OA seen most commonly in the distal digits of the hands in elderly women in which inflammation is a prominent component^{50, 51}.

The Contribution of Aging in Cells and Tissues to the Development of OA

Cell Senescence

Most of the work to date on the relationship between aging changes at the cellular level and the development of OA has focused on the articular cartilage. Given the similarities between chondrocytes and meniscal cells these studies probably also relate to aging in the meniscus but more studies need to be done in that specific tissue. Normally there is little to no cell turnover in adult articular cartilage⁵² and so chondrocytes are thought to be long-lived cells and as such can accumulate age-related changes over many years. In many tissues, senescent cells can be replaced by differentiation of cells from a local pool of progenitor cells but in adult articular cartilage it is not clear if such a pool exists. Recent studies have challenged the notion that cartilage does not contain progenitor cells but these studies were performed with either bovine tissue from very young animals⁵³ or OA tissue⁵⁴, the latter of which might have included cells from other tissues such as the synovium or bone marrow which can make their way to the cartilage when it is severely damaged. Even if there is a local pool of progenitor cells, they do not appear to be capable of replacing senescent, damaged, or dead cells in the articular cartilage.

There does appear to be an age-related reduction in the number of chondrocytes in cartilage and a further loss of cells in OA cartilage but the extent of cell death is debated^{16, 17, 55}. A 30% fall in cell density between the ages of 30 and 70 years has been described in human hip specimens⁵⁶. However, a study of human knees found less than 5% cell loss with aging⁵². Although many studies have reported apoptotic chondrocytes in OA cartilage¹⁷, few have examined apoptosis in cartilage with normal aging with the exception of a study in rat cartilage that found evidence of increased apoptosis with aging⁵⁷. An age-related decline in levels of the high-mobility group box (HMGB) protein 2, which is expressed in the superficial zone of cartilage, might contribute to an increase in chondrocyte death⁵⁸. HMGB2 is a nonhistone chromatin protein that can serve as a transcriptional regulator. Deletion of HMGB2 in transgenic mice was found to cause an early onset of OA-like changes in the superficial zone of cartilage that were associated with an increase in susceptibility of chondrocytes to cell death.

Chondrocytes have been shown to exhibit telomere shortening⁵⁹, a classic feature of cell senescence, but since chondrocytes rarely divide it is unlikely that the shortened telomeres represent replicative senescence. Classic replicative senescence requires over 30-40 population doublings⁶⁰ which would be unlikely to occur in adult cartilage. Telomere shortening can also occur from extrinsic or “stress-induced” senescence that results from the chronic effects of oxidative damage, activated oncogenes, and inflammation^{61, 62}. This form of cell senescence is much more likely in cartilage, where oxidative stress and chronic inflammation could be factors⁶³.

The concept of cell senescence has developed beyond classic replicative senescence which refers to the inability of senescent cells to undergo further cell division. There is mounting evidence that cell senescence can also result in a phenotypic alteration of cells called the senescent secretory phenotype^{62, 64}. This phenotype is characterized by the increased production of cytokines including IL-1, IL-6, and IL-8, matrix metalloproteinases, and growth factors such as EGF. The accumulation of cells expressing the senescent secretory phenotype can contribute to tissue aging and given the increased production of cytokines and MMPs in OA cartilage may directly link aging to the development of OA (Table 1). There is evidence for increased MMP-3 and MMP-13 in cartilage with aging⁶⁵ as well as an age-related accumulation of collagen neoepitopes representing denatured or cleaved collagen^{66, 67}. Cleavage of type II collagen by MMPs has been noted in cartilage from hip joints of older individuals⁶⁶ as well as in “normal appearing” knee cartilage taken at autopsy⁶⁵. However, since these joints are commonly affected by OA, it is not clear if the collagen damage represents aging changes, early OA, or a continuum from aging to OA.

Aging Changes in Joint Tissues and the Contribution of Aging to the Development of OA.

Cell senescence in cartilage has been associated with a decline in the ability of chondrocytes to respond to growth factors and this could be an important contributing factor to the change in the balance of anabolic and catabolic activity seen in OA. Key matrix stimulating growth factors in cartilage include IGF-I, OP-1 (BMP-7), and TGF-β. There is substantial evidence for a decline in the chondrocyte response to IGF-I with aging^68-70 and in chondrocytes isolated from OA cartilage^{69, 71}. There is evidence that the decline in IGF-I response (or IGF-I resistance) is due to altered cell signaling. A reduced ability of IGF-I to activate cell signaling was noted in aging rat cartilage⁷⁰ and in aged equine chondrocytes^{72, 73}. Because IGF-I is an important autocrine survival factor in cartilage⁷⁴ the age-related decline in IGF-I signaling may play a role in age-related cell death. The expression and amount of OP-1 present in cartilage declines with age⁷⁵ which may be related to increased DNA methylation at the OP-1 promoter⁷⁶. Likewise, levels of TGF-β2 and TGF-β3 (but not TGF-β1) decline with age as does the level of the TGF-β receptor I and II⁷⁷. Similar to IGF-I, age-related alterations in the TGF-β signaling pathway have been described and these may also contribute to the development of OA⁷⁸.

Aging in the Cartilage Matrix

Age-related changes that occur in the cartilage matrix can also contribute to the development of OA. There is evidence from knee MRI studies that cartilage thins with aging, particularly at the femoral side of the joint⁷⁹ and at the patella⁸⁰, suggesting a gradual loss of cartilage matrix with aging. This could be due to a loss of cells and the reduced growth factor activity discussed above but could also be due to something as simple as reduced water content. Articular cartilage is about 70-80% water. The water content in cartilage is controlled to a large extent by the presence of aggrecan, a large “aggregating” proteoglycan found in the cartilage matrix. Aggrecan contains highly sulfated glycosaminoglycan chains that are negatively charged and therefore very hydrophilic and are responsible for the resiliency in cartilage. Age-related changes in the size, structure, and sulfation of aggrecan have been reported^81-84 which reduce cartilage resiliency and hydration⁸⁵.

Perhaps the best studied aging-related matrix protein modification in cartilage is the accumulation of advanced glycation end-products (AGEs). AGEs are produced by the spontaneous nonenzymatic glycation of proteins that occurs when reducing sugars including glucose, fructose or ribose, react with lysine or arginine residues⁸⁶. Because the articular cartilage has a relatively low turnover rate, it is particularly susceptible to AGE formation which in other tissues occurs most commonly in diabetics with chronically elevated glucose levels. Type II collagen, the most abundant matrix protein in cartilage, has a half-life that has been calculated to be over 100 years⁸⁷.

The accumulation of AGEs in knee cartilage has been suggested to play a role in the development of osteoarthritis^{86, 88}. Modification of collagen by AGE formation results in increased cross-linking of collagen molecules. The most common AGE-related cross link is pentosidine which has been found to be present in cartilage in increasing amounts with age^{87, 89, 90}. Formation of excessive collagen cross-links affects the biomechanical properties of cartilage resulting in increased stiffness making the cartilage more brittle⁹¹ and increasing the susceptibility of the tissue to fatigue failure⁸⁹. Increased levels of AGEs in cartilage have also been associated with a decline in anabolic activity⁹². Although reported in a small study that used tissue removed at the time of joint replacement, amyloid has been detected in meniscal tissue from older adults⁹³ suggesting additional age-related matrix changes may play a role in the development of OA.

The Role of Age-related Oxidative Stress and Oxidative Damage in OA

The theory that aging changes in tissues are the result of oxidative damage from the chronic production of endogenous reactive oxygen species (ROS) or “free radicals” was proposed in the 1950's⁹⁴ and is still relevant to aging in joint tissues such as the articular cartilage. Human articular chondrocytes actively produce several different forms of ROS including superoxide, hydroxyl radical, hydrogen peroxide, as well as reactive nitrogen species, most notably nitric oxide^95-97. Increased levels of intracellular ROS were recently detected in cartilage from old when compared to young adult rats⁹⁸. Normally the levels of ROS are controlled by the balance of ROS production and the presence of various anti-oxidants. Glutathione is an important intracellular anti-oxidant and when levels of ROS are in excess the ratio of oxidized to reduced glutathione is changed. Previous studies have detected an increase in oxidized glutathione with age in chondrocytes isolated from normal ankle tissue⁹⁹. There is also evidence that levels of anti-oxidant enzymes, including catalase and superoxide dismutase, are present at lower levels with aging^{98, 100} and in OA cartilage¹⁰¹.

Because of the slow turnover of cells and matrix in cartilage, it is likely that damage from excessive ROS would accumulate over time. Evidence for oxidative damage in articular cartilage was provided by a study showing increased nitrotyrosine (a measure of oxidative damage to proteins) with aging, as well as with OA¹⁰². Increased levels of ROS can result in DNA damage which has been noted in OA cartilage¹⁰³ including in mitochondrial DNA¹⁰⁴. This can affect cell viability and matrix production. Oxidative stress can also contribute to the senescent phenotype of chondrocytes¹⁰⁵. The resistance to IGF-I noted in aging and OA chondrocytes may also be related to excessive levels of ROS that have been shown to interfere with normal IGF-I signaling resulting in reduced matrix production¹⁰⁶. This could also occur indirectly by the production of oxidized low-density lipoproteins in cartilage which can in turn contribute to chondrocyte senescence and reduced chondrocyte signaling¹⁰⁷.

An aging-related increase in ROS levels could play an important role in the development of OA¹⁰⁸. The various inflammatory mediators found to be increased in OA, including IL-1, IL-6, IL-8, TNF-α, and other cytokines can all stimulate the further production of ROS and ROS in turn can be involved in the increased production of MMPs¹⁰⁹. In support of a role for ROS in the development of OA, the use of several anti-oxidant vitamins along with selenium (a glutathione peroxidase co-factor) was shown to reduce the development of OA in a mouse model¹¹⁰, N-acetylcysteine (NAC) reduced cartilage destruction and chondrocyte apoptosis in a rat OA model¹¹¹ and in impact-loaded osteochondral explants¹¹² and low intake of anti-oxidant vitamins has been associated with OA progression in humans¹¹³. But we still have much to learn about ROS and oxidative stress in aging and OA in order to define more specific targets. In human clinical trials of chronic age-related diseases, the use of general anti-oxidants or anti-oxidant vitamins has had modest or no benefit. Defining the specific mechanisms by which ROS act, including their role in the regulation of cell signaling, should provide novel and more specific targets for therapies that would represent an advance over non-directed treatment with general anti-oxidants.

Conclusion

In summary, age is a primary risk factor for the development of OA, likely due to aging changes in cells and tissues that make the joint more susceptible to damage and less able to maintain homeostasis. OA is characterized by an imbalance between catabolic and anabolic activity driven by local production of inflammatory mediators in the cartilage and surrounding joint tissues. The senescent secretory phenotype likely contributes to this imbalance through the increased production of cytokines and MMPs and a reduced response to growth factors. More information is needed to better understand how aging changes in the bone, meniscus, and ligaments contribute to the development of OA. Oxidative stress appears to play an important role in the link between aging and OA. Understanding the basic mechanisms by which excessive ROS affect cell function at the molecular level may provide the knowledge needed to develop novel preventative treatments for OA.

Acknowledgments

This work was supported by the National Institute on Aging (RO1 AG16697 and the Wake Forest University Claude D. Pepper Older Americans Independence Center P30 AG021332), the National Institute on Arthritis, Musculoskeletal and Skin Diseases (RO1 AR49003), the American Federation for Aging Research, and the Dorothy Rhyne Kimbrell and Willard Duke Kimbrell Professorship.

Footnotes

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References

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(1):26–35. [PMC free article] [PubMed]

2. Murphy L, Schwartz TA, Helmick CG, et al. Lifetime risk of symptomatic knee osteoarthritis. Arthritis Rheum. 2008;59(9):1207–1213. [PubMed]

3. Lawrence JS, Bremner JM, Bier F. Osteo-arthrosis. Prevalence in the population and relationship between symptoms and x-ray changes. Ann Rheum Dis. 1966;25(1):1–24. [PMC free article] [PubMed]

4. Miller ME, Rejeski WJ, Messier SP, et al. Modifiers of change in physical functioning in older adults with knee pain: the Observational Arthritis Study in Seniors (OASIS). Arthritis Rheum. 2001;45(4):331–339. [PubMed]

5. van Saase JL, van Romunde LK, Cats A, et al. Epidemiology of osteoarthritis: Zoetermeer survey. Comparison of radiological osteoarthritis in a Dutch population with that in 10 other populations. Ann Rheum Dis. 1989;48(4):271–280. [PMC free article] [PubMed]

6. Zhang Y, Niu J, Kelly-Hayes M, et al. Prevalence of symptomatic hand osteoarthritis and its impact on functional status among the elderly: The Framingham Study. American journal of epidemiology. 2002;156(11):1021–1027. [PubMed]

7. Felson DT, Naimark A, Anderson J, et al. The prevalence of knee osteoarthritis in the elderly. The Framingham Osteoarthritis Study. Arthritis Rheum. 1987;30(8):914–918. [PubMed]

8. Jordan JM, Helmick CG, Renner JB, et al. Prevalence of knee symptoms and radiographic and symptomatic knee osteoarthritis in African Americans and Caucasians: the Johnston County Osteoarthritis Project. J Rheumatol. 2007;34(1):172–180. [PubMed]

9. Jordan JM, Helmick CG, Renner JB, et al. Prevalence of hip symptoms and radiographic and symptomatic hip osteoarthritis in African Americans and Caucasians: the Johnston County Osteoarthritis Project. J Rheumatol. 2009;36(4):809–815. [PMC free article] [PubMed]

10. Sowers M, Lachance L, Hochberg M, et al. Radiographically defined osteoarthritis of the hand and knee in young and middle-aged African American and Caucasian women. Osteoarthritis Cartilage. 2000;8(2):69–77. [PubMed]

11. Goldring MB, Goldring SR. Osteoarthritis. J Cell Physiol. 2007;213(3):626–634. [PubMed]

12. Aigner T, Zhu Y, Chansky HH, et al. Reexpression of type IIA procollagen by adult articular chondrocytes in osteoarthritic cartilage. Arthritis Rheum. 1999;42(7):1443–1450. [PubMed]

13. Sandell LJ, Aigner T. Articular cartilage and changes in arthritis. An introduction: cell biology of osteoarthritis. Arthritis Res. 2001;3(2):107–113. [PMC free article] [PubMed]

14. Fukui N, Ikeda Y, Ohnuki T, et al. Regional differences in chondrocyte metabolism in osteoarthritis: A detailed analysis by laser capture microdissection. Arthritis Rheum. 2008;58(1):154–163. [PubMed]

15. Visco DM, Johnstone B, Hill MA, et al. Immunohistochemical analysis of 3-B-(-) and 7-D-4 epitope expression in canine osteoarthritis. Arthritis Rheum. 1993;36(12):1718–1725. [PubMed]

16. Aigner T, Kim HA, Roach HI. Apoptosis in osteoarthritis. Rheum Dis Clin North Am. 2004;30(3):639–653. xi. [PubMed]

17. Kuhn K, D'Lima DD, Hashimoto S, et al. Cell death in cartilage. Osteoarthritis Cartilage. 2004;12(1):1–16. [PubMed]

18. Burr DB, Radin EL. Microfractures and microcracks in subchondral bone: are they relevant to osteoarthrosis? Rheum Dis Clin North Am. 2003;29(4):675–685. [PubMed]

19. Burr DB. The importance of subchondral bone in the progression of osteoarthritis. J Rheumatol Suppl. 2004;70:77–80. [PubMed]

20. Mansell JP, Bailey AJ. Abnormal cancellous bone collagen metabolism in osteoarthritis. J Clin Invest. 1998;101(8):1596–1603. [PMC free article] [PubMed]

21. Sanchez C, Deberg MA, Bellahcene A, et al. Phenotypic characterization of osteoblasts from the sclerotic zones of osteoarthritic subchondral bone. Arthritis Rheum. 2008;58(2):442–455. [PubMed]

22. Felson DT, Chaisson CE, Hill CL, et al. The Association of Bone Marrow Lesions with Pain in Knee Osteoarthritis. Ann Intern Med. 2001;134(7):541–549. [PubMed]

23. Felson DT, McLaughlin S, Goggins J, et al. Bone marrow edema and its relation to progression of knee osteoarthritis. Ann Intern Med. 2003;139(5 Pt 1):330–336. [PubMed]

24. Haywood L, McWilliams DF, Pearson CI, et al. Inflammation and angiogenesis in osteoarthritis. Arthritis Rheum. 2003;48(8):2173–2177. [PubMed]

25. Ayral X, Pickering EH, Woodworth TG, et al. Synovitis: a potential predictive factor of structural progression of medial tibiofemoral knee osteoarthritis -- results of a 1 year longitudinal arthroscopic study in 422 patients. Osteoarthritis Cartilage. 2005;13(5):361–367. [PubMed]

26. van Beuningen HM, van der Kraan PM, Arntz OJ, et al. Transforming growth factor-beta 1 stimulates articular chondrocyte proteoglycan synthesis and induces osteophyte formation in the murine knee joint. Lab Invest. 1994;71(2):279–290. [PubMed]

27. Spector TD, Hart DJ, Nandra D, et al. Low-level increases in serum C-reactive protein are present in early osteoarthritis of the knee and predict progressive disease. Arthritis Rheum. 1997;40(4):723–727. [PubMed]

28. Livshits G, Zhai G, Hart DJ, et al. Interleukin-6 is a significant predictor of radiographic knee osteoarthritis: The Chingford study. Arthritis Rheum. 2009;60(7):2037–2045. [PMC free article] [PubMed]

29. Felson DT. Risk factors for osteoarthritis: understanding joint vulnerability. Clinical orthopaedics and related research. 2004;(427 Suppl):S16–21. [PubMed]

30. McAlindon TE, Felson DT, Zhang Y, et al. Relation of dietary intake and serum levels of vitamin D to progression of osteoarthritis of the knee among participants in the Framingham Study. Ann Intern Med. 1996;125(5):353–359. [PubMed]

31. Chaganti RK, Parimi N, Cawthon P, et al. Association of 25-hydroxyvitamin D with prevalent osteoarthritis of the hip in elderly men: the osteoporotic fractures in men study. Arthritis Rheum. 2010;62(2):511–514. [PMC free article] [PubMed]

32. Gelber AC, Hochberg MC, Mead LA, et al. Joint injury in young adults and risk for subsequent knee and hip osteoarthritis. Ann Intern Med. 2000;133(5):321–328. [PubMed]

33. Roos H, Adalberth T, Dahlberg L, et al. Osteoarthritis of the knee after injury to the anterior cruciate ligament or meniscus: the influence of time and age. Osteoarth Cartilage. 1995;3(4):261–267. [PubMed]

34. Pai YC, Rymer WZ, Chang RW, et al. Effect of age and osteoarthritis on knee proprioception. Arthritis Rheum. 1997;40(12):2260–2265. [PubMed]

35. Rosenthal AK. Calcium crystal deposition and osteoarthritis. Rheum Dis Clin North Am. 2006;32(2):401–412. vii. [PubMed]

36. Englund M, Guermazi A, Gale D, et al. Incidental meniscal findings on knee MRI in middle-aged and elderly persons. N Engl J Med. 2008;359(11):1108–1115. [PMC free article] [PubMed]

37. Englund M, Guermazi A, Roemer FW, et al. Meniscal tear in knees without surgery and the development of radiographic osteoarthritis among middle-aged and elderly persons: The Multicenter Osteoarthritis Study. Arthritis Rheum. 2009;60(3):831–839. [PMC free article] [PubMed]

38. Hill CL, Seo GS, Gale D, et al. Cruciate ligament integrity in osteoarthritis of the knee. Arthritis Rheum. 2005;52(3):794–799. [PubMed]

39. Strocchi R, De Pasquale V, Facchini A, et al. Age-related changes in human anterior cruciate ligament (ACL) collagen fibrils. Italian journal of anatomy and embryology = Archivio italiano di anatomia ed embriologia. 1996;101(4):213–220. [PubMed]

40. Felson DT, Neogi T. Osteoarthritis: is it a disease of cartilage or of bone? Arthritis Rheum. 2004;50(2):341–344. [PubMed]

41. Lo GH, Hunter DJ, Nevitt M, et al. Strong association of MRI meniscal derangement and bone marrow lesions in knee osteoarthritis: data from the osteoarthritis initiative. Osteoarthritis Cartilage. 2009;17(6):743–747. [PMC free article] [PubMed]

42. Hunter DJ, Gerstenfeld L, Bishop G, et al. Bone marrow lesions from osteoarthritis knees are characterized by sclerotic bone that is less well mineralized. Arthritis Res Ther. 2009;11(1):R11. [PMC free article] [PubMed]

43. Baranyay FJ, Wang Y, Wluka AE, et al. Association of bone marrow lesions with knee structures and risk factors for bone marrow lesions in the knees of clinically healthy, community-based adults. Semin Arthritis Rheum. 2007;37(2):112–118. [PubMed]

44. Felson DT, Anderson JJ, Naimark A, et al. The prevalence of chondrocalcinosis in the elderly and its association with knee osteoarthritis: the Framingham Study. J Rheumatol. 1989;16(9):1241–1245. [PubMed]

45. Doherty M, Dieppe P. Clinical aspects of calcium pyrophosphate dihydrate crystal deposition. Rheum Dis Clin North Am. 1988;14(2):395–414. [PubMed]

46. Richette P, Bardin T, Doherty M. An update on the epidemiology of calcium pyrophosphate dihydrate crystal deposition disease. Rheumatology (Oxford) 2009 [PubMed]

47. Neame RL, Carr AJ, Muir K, et al. UK community prevalence of knee chondrocalcinosis: evidence that correlation with osteoarthritis is through a shared association with osteophyte. Ann Rheum Dis. 2003;62(6):513–518. [PMC free article] [PubMed]

48. Nalbant S, Martinez JA, Kitumnuaypong T, et al. Synovial fluid features and their relations to osteoarthritis severity: new findings from sequential studies. Osteoarthritis Cartilage. 2003;11(1):50–54. [PubMed]

49. Liu-Bryan R, Pritzker K, Firestein GS, et al. TLR2 signaling in chondrocytes drives calcium pyrophosphate dihydrate and monosodium urate crystal-induced nitric oxide generation. J Immunol. 2005;174(8):5016–5023. [PubMed]

50. Punzi L, Ramonda R, Sfriso P. Erosive osteoarthritis. Best practice & research. 2004;18(5):739–758. [PubMed]

51. Vlychou M, Koutroumpas A, Malizos K, et al. Ultrasonographic evidence of inflammation is frequent in hands of patients with erosive osteoarthritis. Osteoarthritis Cartilage. 2009 [PubMed]

52. Aigner T, Hemmel M, Neureiter D, et al. Apoptotic cell death is not a widespread phenomenon in normal aging and osteoarthritis human articular knee cartilage: a study of proliferation, programmed cell death (apoptosis), and viability of chondrocytes in normal and osteoarthritic human knee cartilage. Arthritis Rheum. 2001;44(6):1304–1312. [PubMed]

53. Dowthwaite GP, Bishop JC, Redman SN, et al. The surface of articular cartilage contains a progenitor cell population. J Cell Sci. 2004;117(Pt 6):889–897. [PubMed]

54. Alsalameh S, Amin R, Gemba T, et al. Identification of mesenchymal progenitor cells in normal and osteoarthritic human articular cartilage. Arthritis Rheum. 2004;50(5):1522–1532. [PubMed]

55. Horton WE, Jr., Feng L, Adams C. Chondrocyte apoptosis in development, aging and disease. Matrix Biol. 1998;17(2):107–115. [PubMed]

56. Vignon E, Arlot M, Patricot LM, et al. The cell density of human femoral head cartilage. Clin Orthop. 1976;121(121):303–308. [PubMed]

57. Adams CS, Horton WE., Jr Chondrocyte apoptosis increases with age in the articular cartilage of adult animals. Anat Rec. 1998;250(4):418–425. [PubMed]

58. Taniguchi N, Carames B, Ronfani L, et al. Aging-related loss of the chromatin protein HMGB2 in articular cartilage is linked to reduced cellularity and osteoarthritis. Proc Natl Acad Sci U S A. 2009;106(4):1181–1186. [PMC free article] [PubMed]

59. Martin JA, Buckwalter JA. Telomere erosion and senescence in human articular cartilage chondrocytes. J Gerontol A Biol Sci Med Sci. 2001;56(4):B172–179. [PubMed]

60. Hayflick L. Intracellular determinants of cell aging. Mech Ageing Dev. 1984;28(2-3):177–185. [PubMed]

61. Itahana K, Campisi J, Dimri GP. Mechanisms of cellular senescence in human and mouse cells. Biogerontology. 2004;5(1):1–10. [PubMed]

62. Campisi J. Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors. Cell. 2005;120(4):513–522. [PubMed]

63. Dai SM, Shan ZZ, Nakamura H, et al. Catabolic stress induces features of chondrocyte senescence through overexpression of caveolin 1: possible involvement of caveolin 1-induced down-regulation of articular chondrocytes in the pathogenesis of osteoarthritis. Arthritis Rheum. 2006;54(3):818–831. [PubMed]

64. Campisi J, d'Adda di Fagagna F. Cellular senescence: when bad things happen to good cells. Nat Rev Mol Cell Biol. 2007;8(9):729–740. [PubMed]

65. Wu W, Billinghurst RC, Pidoux I, et al. Sites of collagenase cleavage and denaturation of type II collagen in aging and osteoarthritic articular cartilage and their relationship to the distribution of matrix metalloproteinase 1 and matrix metalloproteinase 13. Arthritis Rheum. 2002;46(8):2087–2094. [PubMed]

66. Hollander AP, Pidoux I, Reiner A, et al. Damage to type II collagen in aging and osteoarthritis starts at the articular surface, originates around chondrocytes, and extends into the cartilage with progressive degeneration. J Clin Invest. 1995;96(6):2859–2869. [PMC free article] [PubMed]

67. Aurich M, Poole AR, Reiner A, et al. Matrix homeostasis in aging normal human ankle cartilage. Arthritis Rheum. 2002;46(11):2903–2910. [PubMed]

68. Martin JA, Ellerbroek SM, Buckwalter JA. Age-related decline in chondrocyte response to insulin-like growth factor-I: the role of growth factor binding proteins. J Orthop Res. 1997;15(4):491–498. [PubMed]

69. Loeser RF, Shanker G, Carlson CS, et al. Reduction in the chondrocyte response to insulin-like growth factor 1 in aging and osteoarthritis: studies in a non-human primate model of naturally occurring disease. Arthritis Rheum. 2000;43(9):2110–2120. [PubMed]

70. Messai H, Duchossoy Y, Khatib A, et al. Articular chondrocytes from aging rats respond poorly to insulin-like growth factor-1: an altered signaling pathway. Mech Ageing Dev. 2000;115(1-2):21–37. [PubMed]

71. Dore S, Pelletier JP, DiBattista JA, et al. Human osteoarthritic chondrocytes possess an increased number of insulin-like growth factor 1 binding sites but are unresponsive to its stimulation. Possible role of IGF-1-binding proteins. Arthritis Rheum. 1994;37(2):253–263. [PubMed]

72. Fortier LA, Miller BJ. Signaling through the small G-protein Cdc42 is involved in insulin-like growth factor-I resistance in aging articular chondrocytes. J Orthop Res. 2006;24(8):1765–1772. [PMC free article] [PubMed]

73. Boehm AK, Seth M, Mayr KG, et al. Hsp90 mediates insulin-like growth factor 1 and interleukin-1beta signaling in an age-dependent manner in equine articular chondrocytes. Arthritis Rheum. 2007;56(7):2335–2343. [PubMed]

74. Loeser RF, Shanker G. Autocrine stimulation by insulin-like growth factor 1 and insulin-like growth factor 2 mediates chondrocyte survival in vitro. Arthritis Rheum. 2000;43(7):1552–1559. [PubMed]

75. Chubinskaya S, Kumar B, Merrihew C, et al. Age-related changes in cartilage endogenous osteogenic protein-1 (OP-1). Biochim Biophys Acta. 2002;1588(2):126–134. [PubMed]

76. Loeser RF, Im HJ, Richardson B, et al. Methylation of the OP-1 promoter: potential role in the age-related decline in OP-1 expression in cartilage. Osteoarthritis Cartilage. 2009;17(4):513–517. [PMC free article] [PubMed]

77. Blaney Davidson EN, Scharstuhl A, Vitters EL, et al. Reduced transforming growth factor-beta signaling in cartilage of old mice: role in impaired repair capacity. Arthritis Res Ther. 2005;7(6):R1338–1347. [PMC free article] [PubMed]

78. van der Kraan PM, Blaney Davidson EN, van den Berg WB. A role for age-related changes in TGFbeta signaling in aberrant chondrocyte differentiation and osteoarthritis. Arthritis Res Ther. 2010;12(1):201. [PMC free article] [PubMed]

79. Hudelmaier M, Glaser C, Hohe J, et al. Age-related changes in the morphology and deformational behavior of knee joint cartilage. Arthritis Rheum. 2001;44(11):2556–2561. [PubMed]

80. Ding C, Cicuttini F, Scott F, et al. Association between age and knee structural change: a cross sectional MRI based study. Ann Rheum Dis. 2005;64(4):549–555. [PMC free article] [PubMed]

81. Buckwalter JA, Roughley PJ, Rosenberg LC. Age-related changes in cartilage proteoglycans: quantitative electron microscopic studies. Microsc Res Tech. 1994;28(5):398–408. [PubMed]

82. Dudhia J, Davidson CM, Wells TM, et al. Age-related changes in the content of the C-terminal region of aggrecan in human articular cartilage. Biochem J. 1996;313(Pt 3):933–940. [PMC free article] [PubMed]

83. Bayliss MT, Osborne D, Woodhouse S, et al. Sulfation of chondroitin sulfate in human articular cartilage. The effect of age, topographical position, and zone of cartilage on tissue composition. J Biol Chem. 1999;274(22):15892–15900. [PubMed]

84. Wells T, Davidson C, Morgelin M, et al. Age-related changes in the composition, the molecular stoichiometry and the stability of proteoglycan aggregates extracted from human articular cartilage. Biochem J. 2003;370(Pt 1):69–79. [PMC free article] [PubMed]

85. Grushko G, Schneiderman R, Maroudas A. Some biochemical and biophysical parameters for the study of the pathogenesis of osteoarthritis: a comparison between the processes of ageing and degeneration in human hip cartilage. Connect Tissue Res. 1989;19(2-4):149–176. [PubMed]

86. Verzijl N, Bank RA, TeKoppele JM, et al. AGEing and osteoarthritis: a different perspective. Curr Opin Rheumatol. 2003;15(5):616–622. [PubMed]

87. Verzijl N, DeGroot J, Thorpe SR, et al. Effect of collagen turnover on the accumulation of advanced glycation endproducts. J Biol Chem. 2000;275:39027–39031. [PubMed]

88. 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(4):1207–1215. [PubMed]

89. Bank RA, Bayliss MT, Lafeber FP, et al. Ageing and zonal variation in post-translational modification of collagen in normal human articular cartilage. The age-related increase in non-enzymatic glycation affects biomechanical properties of cartilage. Biochem J. 1998;330(Pt 1):345–351. [PMC free article] [PubMed]

90. Verzijl N, DeGroot J, Ben ZC, et al. Crosslinking by advanced glycation end products increases the stiffness of the collagen network in human articular cartilage: a possible mechanism through which age is a risk factor for osteoarthritis. Arthritis Rheum. 2002;46(1):114–123. [PubMed]

91. Chen AC, Temple MM, Ng DM, et al. Induction of advanced glycation end products and alterations of the tensile properties of articular cartilage. Arthritis Rheum. 2002;46(12):3212–3217. [PubMed]

92. DeGroot J, Verzijl N, Bank RA, et al. Age-related decrease in proteoglycan synthesis of human articular chondrocytes: the role of nonenzymatic glycation. Arthritis Rheum. 1999;42(5):1003–1009. [PubMed]

93. Solomon A, Murphy CL, Kestler D, et al. Amyloid contained in the knee joint meniscus is formed from apolipoprotein A-I. Arthritis Rheum. 2006;54(11):3545–3550. [PubMed]

94. Harman D. Aging: A theory based on free radical and radiation chemistry. J Gerontol. 1956;11:298–300. [PubMed]

95. Studer R, Jaffurs D, Stefanovic-Racic M, et al. Nitric oxide in osteoarthritis. Osteoarthritis Cartilage. 1999;7(4):377–379. [PubMed]

96. Hiran TS, Moulton PJ, Hancock JT. Detection of superoxide and NADPH oxidase in porcine articular chondrocytes. Free Radic Biol Med. 1997;23(5):736–743. [PubMed]

97. Tiku ML, Shah R, Allison GT. Evidence linking chondrocyte lipid peroxidation to cartilage matrix protein degradation: Possible role in cartilage aging and the pathogenesis of osteoarthritis. J Biol Chem. 2000;275:20069–20076. [PubMed]

98. Jallali N, Ridha H, Thrasivoulou C, et al. Vulnerability to ROS-induced cell death in ageing articular cartilage: the role of antioxidant enzyme activity. Osteoarthritis Cartilage. 2005;13(7):614–622. [PubMed]

99. Del Carlo M, Jr., Loeser RF. Increased oxidative stress with aging reduces chondrocyte survival: Correlation with intracellular glutathione levels. Arthritis Rheum. 2003;48(12):3419–3430. [PubMed]

100. Ruiz-Romero C, Calamia V, Mateos J, et al. Mitochondrial dysregulation of osteoarthritic human articular chondrocytes analyzed by proteomics: A decrease in mitochondrial superoxide dismutase points to a redox imbalance. Mol Cell Proteomics. 2008 [PMC free article] [PubMed]

101. Aigner T, Fundel K, Saas J, et al. Large-scale gene expression profiling reveals major pathogenetic pathways of cartilage degeneration in osteoarthritis. Arthritis Rheum. 2006;54(11):3533–3544. [PubMed]

102. Loeser RF, Carlson CS, Carlo MD, et al. Detection of nitrotyrosine in aging and osteoarthritic cartilage: Correlation of oxidative damage with the presence of interleukin-1beta and with chondrocyte resistance to insulin-like growth factor 1. Arthritis Rheum. 2002;46(9):2349–2357. [PubMed]

103. Davies CM, Guilak F, Weinberg JB, et al. Reactive nitrogen and oxygen species in interleukin-1-mediated DNA damage associated with osteoarthritis. Osteoarthritis Cartilage. 2008;16(5):624–630. [PMC free article] [PubMed]

104. Grishko VI, Ho R, Wilson GL, et al. Diminished mitochondrial DNA integrity and repair capacity in OA chondrocytes. Osteoarthritis Cartilage. 2009;17(1):107–113. [PMC free article] [PubMed]

105. Yudoh K, Nguyen T, Nakamura H, et al. Potential involvement of oxidative stress in cartilage senescence and development of osteoarthritis: oxidative stress induces chondrocyte telomere instability and downregulation of chondrocyte function. Arthritis Res Ther. 2005;7(2):R380–391. [PMC free article] [PubMed]

106. 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(46):31972–31981. [PMC free article] [PubMed]

107. Zushi S, Akagi M, Kishimoto H, et al. Induction of bovine articular chondrocyte senescence with oxidized low-density lipoprotein through lectin-like oxidized low-density lipoprotein receptor 1. Arthritis Rheum. 2009;60(10):3007–3016. [PubMed]

108. Henrotin YE, Bruckner P, Pujol JP. The role of reactive oxygen species in homeostasis and degradation of cartilage. Osteoarthritis Cartilage. 2003;11(10):747–755. [PubMed]

109. Nelson KK, Melendez JA. Mitochondrial redox control of matrix metalloproteinases. Free Radic Biol Med. 2004;37(6):768–784. [PubMed]

110. Kurz B, Jost B, Schunke M. Dietary vitamins and selenium diminish the development of mechanically induced osteoarthritis and increase the expression of antioxidative enzymes in the knee joint of STR/1N mice. Osteoarthritis Cartilage. 2002;10(2):119–126. [PubMed]

111. Nakagawa S, Arai Y, Mazda O, et al. N-acetylcysteine prevents nitric oxide-induced chondrocyte apoptosis and cartilage degeneration in an experimental model of osteoarthritis. J Orthop Res. 2010;28(2):156–163. [PubMed]

112. Martin JA, McCabe D, Walter M, et al. N-acetylcysteine inhibits post-impact chondrocyte death in osteochondral explants. J Bone Joint Surg Am. 2009;91(8):1890–1897. [PMC free article] [PubMed]

113. McAlindon TE, Jacques P, Zhang Y, et al. Do antioxidant micronutrients protect against the development and progression of knee osteoarthritis? Arthritis Rheum. 1996;39(4):648–656. [PubMed]