Etiology and Pathophysiology of Osteoarthritis

ABSTRACT

Acute or chronic insult, including normal wear and tear, age, obesity, and joint injury, may initiate an imbalance between matrix synthesis and matrix degradation in healthy cartilage that promotes chondral loss and prevents cartilage self-repair. The structure of healthy cartilage and the pathophysiological mechanisms of its degradation are described, followed by descriptions of endogenous and exogenous factors believed to be involved in the progressive course of osteoarthritis. Studies cited include research from the community of sports medicine.

Over the past decade, there has been a significant shift in the conceptualization of osteoarthritis etiology and pathogenesis. Sometimes oversimplified as the rejection of an old-fashioned “wear and tear” model in favor of a newer “inflammatory/molecular” model, this shift is actually more nuanced. Rather than discarding wear and tear as a causative factor, the evolving paradigm considers how insult and injury, along with other risk factors, induce and interact with mechanisms at the cell and molecular level in an active, progressive disease process.

Osteoarthritis is now conceived as the endpoint of a complex series of events rooted in factors that have been recognized as associated with osteoarthritis risk, in some cases, for many years. The new framework for osteoarthritis etiology permits us to classify these factors either as drivers of abnormal stresses on articular cartilage, including obesity, anatomic abnormalities, or trauma; or as drivers of aberrant cartilage physiology, including aging, genetic and metabolic factors, and inflammation (Figure 1). These sets of disease drivers induce biophysical and biochemical changes that culminate in cartilage breakdown.

Figure 1. Active bone morphogenetic proteins exist as dimers linked by a disulfide bond. Reprinted with permission from 2002 Medtronic Sofamor Danek, Basic Bone Biology.

In this review, we first briefly describe cartilage structure and the pathophysiological mechanisms responsible for cartilage destruction, introducing the major structural, enzymatic, and inflammatory “players” in osteoarthritis. These mechanisms, which are well understood, have provided the first set of targets for therapeutic approaches that extend beyond pain relief and surgical repair to true modification of the disease process. We then consider osteoarthritis etiology: how disease drivers interact in the development of chondropenia, a first step on the osteoarthritis continuum, and how they influence the balance between cartilage synthesis and degradation. We also address events at the cellular and molecular level, including the possible role of gap junctions in facilitating signal transduction that promotes disease progression.

Cartilage Structure and Osteoarthritis Pathophysiology

	Table
	Cartilage Components Water (65%-80%) Chondrocytes Collagen Other matrix proteins Hyaluronic acid Glycosaminoglycans/aggrecans Small proteoglycans

Human cartilage is a complex material synthesized and maintained by its living component, the chondrocyte. The remarkable biomechanical properties of cartilage are the consequence of interactions between water (which makes up 65% to 80% of cartilage) and matrix proteoglycans, matrix collagens, and other matrix components (Table). These interactions reflect not only the composition of cartilage, but also its biochemistry and organization.

The appreciation that cartilage is a dynamic, rather than a static, structure was central to the development of our current understanding of osteoarthritis pathophysiology. Healthy cartilage is in a state of balance between matrix synthesis and matrix degradation. The progressive course of osteoarthritis is the result of sustained imbalance between these two processes, favoring degradation.

A healthy cartilage matrix (Figure 2) consists of collagen fibrils through which proteoglycan complexes are intertwined. The backbone of each proteoglycan complex is a long molecule of hyaluronic acid, or hyaluronan, to which large glycosaminoglycan molecules known as aggrecans are attached by link proteins. The complete structure provides cartilage with its most important core biomechanical properties, compressibility and elasticity; the aggrecans are thought to be especially important determinants of these properties.^1,2

Two families of enzymes are important in matrix degradation, both in healthy cartilage and in osteoarthritis. Matrix metalloproteinases break down collagen, gelatin, and other proteinaceous components of the matrix. Aggrecanases, which degrade aggrecans, are complex proteins whose multiple domains account for their somewhat unwieldy family designation: a disintegrin and metalloproteinase with thrombospondin motif (ADAMTS).³ The increased breakdown of aggrecans by ADAMTS enzymes is one of the hallmarks of early osteoarthritis, and it contributes significantly to the loss of cartilage structure and function.^2,3

In healthy cartilage, the activity of degradative enzymes is balanced by that of synthetic enzymes; it is also regulated by specific enzyme inhibitors known as tissue inhibitors of matrix metalloproteinases. In the pathogenesis of osteoarthritis, this balance is tipped in favor of degradative activity. Perhaps the most important insight into osteoarthritis pathophysiology in the past decade has been the recognition of the role played by inflammatory cytokines and mediators released by synovial tissue and chondrocytes in the disruption of this balance.

Figure 2. Activation of SMAD proteins by binding of bone morphogenetic proteins to their receptors. Figure courtesy of Medtronic Sofamor Danek.

The most important of these mediators, at least initially, appear to be interleukin-1 (IL-1) and tumor necrosis factor (TNF-). Synthesis of IL-1ß and TNF-, as well as their membrane-bound receptors, is upregulated in osteoarthritis. These cytokines are potentiators of an inflammatory cascade, stimulating their own production and that of a range of proinflammatory cytokines such as IL-6, IL-8, IL-11, IL-17, and RANTES.^1,4 Taken together, the net effect of these cytokines on chondrocyte metabolism is to increase the synthesis of matrix metalloproteinases and aggrecanases, decrease the synthesis of tissue inhibitors of matrix metalloproteinases and other inhibitors of degradative enzymes, and reduce the rate of matrix synthesis.^1,4,5

IL-1ß and TNF- activity stimulates the release of nitric oxide, a molecule best known for its modulatory role in the cardiovascular system. In cartilage, nitric oxide appears to inhibit collagen and proteoglycan synthesis and increase the activity of matrix metalloproteinases. However, the most important long-term effect may be the induction of apoptosis of chondrocytes. Because chondrocytes are not regenerated, loss of chondrocyte mass and function further accelerates degradative processes.^4,6,7

Chondrocytes respond to the degradative consequences of the inflammatory cascade by increasing the rate at which they synthesize matrix components, and by releasing anti-inflammatory cytokines (IL-4, IL-10, IL-13). However, in osteoarthritis, the increased synthetic and anti-inflammatory activity of chondrocytes loses out to the increased degradative activity. First, increased synthetic activity is confined to deeper layers of cartilage, which allows the imbalance toward degradation to persist in the upper layer, near the synovial boundary. Ultimately, chondrocyte malfunction and apoptosis limit the response potential and hasten the progression of osteoarthritis.^4,5

Osteoarthritis Etiology and Onset of Chondropenia

Chondropenia is the progressive loss of cartilage structure and function over time; it is best viewed as an intermediate stage in a continuum that begins with acute or chronic injury to cartilage and culminates with osteoarthritis. At this point, researchers have yet to define fully the parameters and diagnostic criteria that characterize the onset of chondropenia, various stages of chondropenia itself, and the passage into osteoarthritis.

Although radiographic evidence of cartilage damage typically becomes apparent only with frank osteoarthritis, magnetic resonance imaging has shown promise in identifying proteoglycan loss and volume. In addition, the work of Kiviranta et al^8,9 in Finland has produced a probe-based technology capable of assessing the stiffness of cartilage arthroscopically. This technology is being extended experimentally to provide ultrasound assessment of cartilage thickness and structure.¹⁰ In the near future, it is hoped that these methodologies, along with others, will be combined to develop a consensus definition of chondropenia.

Much of the research supporting the chondropenia concept comes from sports medicine specialists, as the limits of cartilage capabilities and function are routinely tested among top athletes. The frequency of athletic injuries that induce cartilage lesions, especially to the knee, has enabled sports medicine to serve as a laboratory, illuminating the time course and events involved in osteoarthritis pathogenesis.

Extensive literature documents the relationship between knee injury and subsequent osteoarthritis; the initial demonstration came from Messner and Maletius¹¹ in a follow-up study of 28 young athletes 14 years after diagnosis of severe medial chondral damage in the knee. Although most of the subjects retained good knee function at follow-up, 12/28 (43%) had radiographic evidence of joint space narrowing.

Gelber et al¹² performed one of the most extensive studies of joint injury sequelae. The researchers tracked a cohort of 1321 former medical students (mean age at entry 22 years) enrolled in the Johns Hopkins Precursors Study over a mean follow-up of 36 years. Of the total cohort, 141 students experienced a joint injury (to the knee, hip, or both) before or after graduation; the cumulative incidence of osteoarthritis among these subjects was 13.9%, compared to 6% among subjects who reported no joint injuries (P=.0045). With regard to the development of osteoarthritis at the site of reported injury, the risk ratios vs. subjects with no site-specific injury were 5.17 (95%; CI, 3.07 to 8.71) for injuries to the knee and 3.50 (95%; CI, 0.84 to 14.69) for injuries to the hip.

More recently, a follow-up study was conducted on 103 Swedish female soccer players who had suffered an injury to the anterior cruciate ligament (ACL) between the ages of 14 and 28 (the risk of ACL injury among girls and women is 3 to 4 times that of male players). Twelve years after their injuries, more than half demonstrated radiographic or symptomatic signs of osteoarthritis, including persistent pain and functional limitation. Moreover, the risk of osteoarthritis was similar between women who had undergone reconstructive surgery and those who had not, which suggests that ACL repair (at least using technology of the time) has little or no effect on osteoarthritis progression.¹³

The time course of cartilage damage following acute injury has been investigated by Murrell et al¹⁴ in a study of 130 patients whose cartilage status was assessed while they underwent reconstructive ACL surgery. The degree of cartilage damage was 9 times greater and the degree of full-thickness cartilage loss was 2 times greater among patients whose injury had occurred >2 years before surgery compared to those whose injury had occurred <1 month before surgery. Meniscal loss was associated with a 3-fold increase in cartilage damage, regardless of time since injury. This study demonstrated the progressive nature of cartilage damage following acute injury.

Although much of the literature on the relationship between injury and cartilage loss is derived from studies that track patients following acute joint injuries, chronic joint problems have also been shown to lead to increased risk for osteoarthritis development and progression. Misalignment of the hip-knee-ankle axis at the knee joint has been shown to affect the course of osteoarthritis profoundly. In a recent 18-month follow-up study of 230 patients with knee osteoarthritis at baseline, varus misalignment increased the odds of medial osteoarthritis progression 4-fold, wereas valgus misalignment increased the odds of lateral osteoarthritis progression 5-fold.¹⁵

In a study of cadaveric knees, Guettler et al¹⁶ showed how a small degree of varus misalignment can create tremendous increase in localized pressures within the knee joint. A 3° varus angulation nearly doubled the peak contact pressure and medial joint force. Pressure increases were exacerbated when a 14-mm full-thickness chondral defect was created in the articular cartilage, and the greatest increase in pressure occurred at the intact rim of the defect. The presence of an intact meniscus helped ameliorate the pressure increase, consistent with the increased chondral damage observed with meniscal loss in the Murrell study.

Transduction of Acute/Chronic Joint Injury Into Chondropenia

The preceding studies suggest that chondral damage from acute or chronic insult may initiate a process of chondral loss in which the affected cartilage is unable to self-repair. A number of in vitro and in vivo investigations have shed light on the transduction of abnormal biomechanical stresses into processes leading to increased breakdown and reduced synthesis of cartilage.

Lohmander et al¹⁷ showed in a series of studies that acute injury to the cruciate ligament or meniscus results in profound, long-lasting alteration of cartilage regulatory mechanisms that paves the way toward progressive disease. Within the first day following trauma, the level of the matrix metalloproteinases stromelysin-1 in synovial fluid increased 25-fold, while the level of the tissue inhibitors of matrix metalloproteinases-1 also increased, but only 10-fold; this results in a molar excess of stromelysin. Levels remained higher than in matched controls for up to 18 years.

Direct evidence of cartilage breakdown following trauma exists. Levels of proteoglycan fragments, cleavage fragments from cartilage oligomeric matrix protein, and aggrecans in joint fluid increase significantly in the period immediately after injury. Although these levels decline over time, they remain elevated for many years. Levels of both degradative enzymes and breakdown products increase in the contralateral knee as well, which suggests that at least some components of response to acute injury are systemic as well as local. In addition, levels of enzymes and breakdown products appear to return to normal more quickly in patients who have mild knee symptoms following injury, compared with patients with more severe symptoms. The latter observation suggests that robust repair and restorative mechanisms may be important modulators of the transition from acute injury to progressive disease.^18-20

Other studies have revealed that some degree of mechanical stress is essential to maintaining the integrity of articular cartilage. Animal studies have shown that joint immobilization induces significant deterioration of matrix composition, including loss of proteoglycans and aggrecans^21,22; these changes are persistent with abnormalities still clearly detectable 1 year after remobilization.²³

In contrast, experiments on cartilage explants have shown that cyclic dynamic compression within typical biomechanical ranges stimulates biosynthesis by chondrocytes.²⁴ In an experimental system using chondrocytes cultured in agarose constructs, dynamic compression inhibits release of the inflammatory mediators nitric oxide and prostaglandin-E2.²⁵ In isolated human chondrocytes, cyclic strain also produces cartilage-enhancing effects, including an increase in cell proliferation.²⁶

However, once compression or other biomechanical stress reaches levels considered injurious, degradative responses once again predominate. In cartilage explants, injurious compression leads to chondrocyte apoptosis and proteoglycan degradation.^27,28 Compared to uninjured chondrocytes, chondrocytes in cartilage exposed to injurious compression have a greater response to exogenous cytokines (TNF- and IL-1), with increased loss of proteoglycans and increased synthesis of certain matrix metalloproteinases.²⁸

Whether chondrocytes respond to a given biomechanical stress by building cartilage or by degrading it appears to depend on the nature, intensity, and duration of the stimulus, which suggests a “dose-response” relationship for some stimuli. For example, when beagles were exercised by walking 4 km/day on a treadmill, articular cartilage thickness and proteoglycan content increased. However, increasing the workload to 20 km/day reversed these changes and led to a 6% reduction in thickness and an 11% reduction in proteoglycan content from baseline.²⁹

With regard to compressive stimuli, the transition from cartilage-enhancing to cartilage-degrading responses depends not only on the peak compressive force, but also on the rate at which it is applied.³⁰ In addition, animal studies have shown that the age of cartilage tissue plays a role, with significantly greater rates of apoptosis occurring in immature cartilage.³¹ This suggests that patients who incur joint injury at a young age may be a priority for disease intervention approaches.

Modulators of Chondropenia

A number of endogenous and exogenous factors, some of which are established risk factors, are considered to be potential modulators of the progressive course of chondropenia into osteoarthritis. Osteoarthritis has long been recognized as primarily a disease of the elderly, with prevalence rising sharply after age 55; the strong age dependence of osteoarthritis has been regarded as perhaps the most important evidence supporting the wear and tear model.^32,33

At least two mechanisms seem to be involved in the age dependence of osteoarthritis. The first is the observed accumulation of advanced glycation endproducts with increased age. High levels of accumulation of advanced glycation endproducts have been shown to reduce synthesis of proteoglycans and degradation of human cartilage in vitro, reducing matrix turnover and, potentially, overall repair and healing capability.³⁴ Experimental induction of increased accumulation of advanced glycation endproduct levels in canine models confirmed these observations and also led to greater osteoarthritis severity and progression than in control animals.³⁵

The second mechanism, possibly interrelated with the first, is chondrocyte senescence. A number of metabolic and physiologic changes have been associated with aging in chondrocytes, including altered regulation of nitric oxide release, reduced response to IGF-1, reduced proliferative capacity and glycosaminoglycan production following induction by cytokines, increased production of ß-galactosidase, and reduced telomere length.^36-39 Older chondrocytes also produce an altered spectrum of aggrecan aggregates, characterized by fewer aggrecans per hyaluronic acid chain and reduced sulfate incorporation.⁴⁰

Obesity has also been shown to be a strong risk factor for osteoarthritis. Body mass index was an independent predictor of knee osteoarthritis incidence among a population of Finnish farmers, with a relative risk of 1.4 for each standard deviation increase (3.8 kg/m²).⁴¹ In women with unilateral knee osteoarthritis, obesity was also a strong risk factor for both progression in the affected knee and osteoarthritis development in the contralateral knee.⁴² Compared with normal-weight women, obese women with knee osteoarthritis had significantly poorer quality of life and functional scores following knee arthroscopy and were significantly more likely to experience recurrence of knee pain.⁴³

Given the association between injurious compression and pathological chondrocyte changes, it is not surprising that obese people have a higher risk of knee osteoarthritis. However, obesity has also been shown to increase the risk of osteoarthritis in non-weight bearing joints (the carpometacarpal and distal interphalangeal joints of the hand).^44,45 These observations suggest that increased body fat may promote osteoarthritis development not only through increased loading, but also through metabolic factors. It is encouraging that in a recent study exercise, both alone and combined with dietary restriction, produced both weight loss and functional improvement in obese patients with knee osteoarthritis.⁴⁶

The prevalence of osteoarthritis is generally higher in women than in men; however, much of this difference appears to be attributable to increased osteoarthritis incidence among women after meno-pause.^32,47,48 This has led to speculation that estrogen may be chondroprotective; chondrocytes from a range of mammalian species including humans bear estrogen receptors.^49,50 In vitro experiments have suggested a biphasic response to estrogen in chondrocytes stimulated with IL-1ß, with effects tending toward chondroprotection at low estrogen concentration and tending toward cartilage degradation at higher estrogen concentrations.⁵¹ In surgically menopausal monkeys, estrogen replacement therapy increases production of insulin-like growth factor-1 binding proteins and proteoglycans.⁵²

Studies of postmenopausal women have produced equivocal results with regard to the effects of estrogen replacement therapy. One study showed that women receiving hormone replacement therapy had greater cartilage volume than those not receiving therapy.⁵³ However, in a substudy of the Heart and Estrogen/Progestin Replacement Study conducted on women with heart disease, estrogen replacement therapy was not shown to be associated with reductions in the proportion of women with frequent knee pain, in pain severity, or in disability.⁵⁴ Other studies have supported this lack of association,^55,56 and one even found increased incidence of osteoarthritis among hormone replacement therapy recipients.⁵⁷ These results, the pleiotropic, multi-sytemic effects of estrogen replacement therapy, and disappointing safety results from the Women’s Health Initiative studies call for extreme caution in considering the therapeutic use of estrogen to reduce risk or progression of osteoarthritis.

The nutraceutical glucosamine, a popular over-the-counter remedy for osteoarthritis, may possess disease-modifying characteristics. Glucosamine treatment of normal human articular chondrocytes in vitro prevents their activation by IL-1ß, inhibiting the release of nitric oxide. In addition to nitric oxide suppression (achieved by preventing increase in the expression of nitric oxide synthase), glucosamine treatment also prevented IL-1ß–induced release of the inflammatory cytokine IL-6.⁵⁸

In a rabbit model, 8 weeks of oral glucosamine treatment increased the glycosaminoglycan content of injured, but not normal, cartilage without affecting the collagen content. The authors suggest that oral glucosamine may be particularly useful in situations in which glucosamine content is limiting, including rapid replacement of cartilage proteoglycans following injury.⁵⁹ It is unclear at this point whether such treatment could potentially arrest or ameliorate posttraumatic degradative changes in cartilage.

Intra-articular injection of various forms of hyaluronic acid (viscoelastic supplementation) has been found to reduce osteoarthritis pain and is now recommended by the American College of Rheumatology for treatment of osteoarthritis patients unresponsive to oral non-steroidal anti-inflammatory drugs and/or cyclooxygenase-2 inhibitors, or as an alternative to such treatment.⁶⁰ However, the pain relief provided by hyaluronic acid supplementation extends well beyond the in vivo lifetime of injected hyaluronic acid, which suggests a role for other possibly disease-modifying mechanisms.^1,60

A detailed consideration of the actions of hyaluronic acid is beyond the scope of this review. However, both in vitro and in vivo studies have suggested that intra-articular hyaluronic acid has significant activity that extends beyond simple shock absorption, including direct modification of nociceptive pathways; enhancement of matrix structure and prevention from damage; suppression of inflammatory mediator (TNF-, IL-1ß, nitric oxide, prostaglandins); and prevention of cartilage degradation following injury.¹ Future studies should help characterize potential additional roles for hyaluronic acid supplementation, such as treatment following injury, not only in osteoarthritis but during the course of chondropenia.

The Role of Gap Junctions

Gap junctions are specialized connections between cells in a tissue. Structurally, each gap junction consists of a number (from a few to hundreds) of individual hexagonal channels, each formed by 6 molecules of a structural protein known as connexin. The importance of gap junctions is that they provide an avenue for immediate passage of materials (and potentially, communication) between adjacent cells, without the need to negotiate the cell membrane. Gap junctions permit the passage of ions and molecules up to a molecular weight of approximately 1000 daltons.^61,62

Several recent studies have shown that intercellular communication facilitated by gap junctions may play an important role in the early development of osteoarthritis. Synovial tissue from patients with osteoarthritis has been found to have 4 times the number of gap junctions as that from unaffected patients. In addition, the level of the gap junction protein connexin 43 was 50% higher in osteoarthritis synovial tissue than in control synovium.⁶³ Treatment of synovial tissue with agents that inhibit the formation of gap junctions has been found to prevent the release of matrix metalloproteinases following induction by IL-1ß.⁶² These results suggest that communication via gap junctions may be an important facilitator of the cartilage-degrading tissue response following injury.

Conclusion

Healthy articular cartilage is essential to normal joint function; good joint health is central not only to high-end athletic pursuits, but also to activities of daily living and to overall quality of life. It has become clear that the degradation of cartilage observed in osteoarthritis is the result of a long-term disease process involving interactions between chronic or acute joint injury and a variety of exogenous and endogenous modulatory factors.

Recent research on osteoarthritis pathogenesis has helped illuminate the tremendous complexity of cartilage biology and osteoarthritis disease progression and has already helped identify potential targets for disease intervention. Continued improvements in our understanding of osteoarthritis biology can be expected to produce new treatment modes, to refine existing approaches, and to characterize patients in whom these advances can be most productively applied.

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Authors

From Pepperdine University, Santa Monica Orthopedic and Sports Medicine Group, Santa Monica, Calif, and Lousiana State University Health Sciences Center, Shreveport, La.