The Role of Biomechanics and Inflammation in Cartilage Injury and Repair : Clinical Orthopaedics and Related Research®

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SECTION I: SYMPOSIUM: Articular Fractures

The Role of Biomechanics and Inflammation in Cartilage Injury and Repair

Guilak, Farshid PHD*†; Fermor, Beverley PHD*; Keefe, Francis J PHD; Kraus, Virginia B MD, PHD; Olson, Steven A MD*; Pisetsky, David S MD, PHD§∥; Setton, Lori A PHD*†; Weinberg, J Brice MD§∥

Editor(s): Olson, Steven A MD, Guest Editor; Marsh, J Lawrence MD, Guest Editor

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Clinical Orthopaedics and Related Research 423():p 17-26, June 2004. | DOI: 10.1097/01.blo.0000131233.83640.91
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Articular cartilage is the connective tissue that lines the ends of bones in all diarthrodial joints. This tissue serves important biomechanical functions in supporting and distributing forces generated during joint loading and provides a low-friction lubricating surface to prevent wear or degradation of the joint.102 Isolated cartilage lesions or intraarticular fractures may lead to progressive damage and degenerative joint conditions such as osteoarthritis (OA). Osteoarthritis manifests as a slowly progressing debilitating disease that affects one or more joints of the body. Clinical symptoms include pain, swelling, enlargement of the joints, and a decreased range of joint motion. Radiographic changes often are apparent and include joint space narrowing, osteophytes, cysts, and subchondral sclerosis. The primary pathologic changes of OA are fibrillation and loss of the articular cartilage, accompanied by thickening and remodeling of the subchondral bone. Osteoarthritis seems to be the common end point of numerous potentially independent pathologic processes that culminate in a loss of joint function.15,68,78,79,126

The development of these changes after joint injury generally has been termed posttraumatic arthritis and can be accelerated by factors such as a displaced intraarticular fracture. However, joint injury may involve additional factors that can contribute to the progression of OA, such as the initial impact(s) of the cartilage,105 soft tissue injuries and resulting joint instability,59,133 the quality of the reduction,83 or the introduction of blood in the joint.67 Furthermore, the incidence of OA after joint injury can depend considerably on which joint is affected.93 Considering the impact and consequences of posttraumatic arthritis, its etiology is not fully understood. It is now apparent that cartilage loss and joint destruction in OA can be influenced by a combination of genetic, age-related, and environmental factors such as soluble mediators (growth factors and cytokines) and biomechanical stress. Increasing evidence suggests that increased concentrations of inflammatory mediators, coupled with alterations in the mechanical environment of the cartilage, may influence the fate of the joint after injury. We review the potential roles of some of these modulators of cartilage physiology and their interactions in the health, injury, and repair of articular cartilage within the context of articular fractures and posttraumatic arthritis.

Mechanical Stress: A Regulator of Cartilage Health and Metabolism

Biomechanical factors play important roles in the health and function of the diarthrodial joint.64 For example, clinical data indicate that various exercises are safe and are not associated with an increased risk for joint disease.80 In fact, exercise has been shown to be an effective therapy for individuals with OA157 and has been strongly recommended in OA treatment guidelines by the American College of Rheumatology.7 Furthermore, obesity is a strong but potentially modifiable risk factor for OA incidence, progression, and disability.97 There is growing recognition that pain may lead patients with OA who are obese to alter how they perform physical activities so as to decrease load on joints and that efforts to avoid pain may set in motion vicious cycles that contribute to disability and pain.134 Individuals with OA are known to be less active than their age-matched peers, and efforts to avoid pain by decreasing activity may lead to a sedentary lifestyle that makes it difficult to lose weight.42

Although these effects could be related to altered gait and increased joint stresses secondary to increased body weight,96 there is also evidence that obesity leads to systemic inflammation29,154 that may interact with biomechanical factors to promote the progressive degradation of joint cartilage in joints of the hand.41 The benefits of exercise in an arthritic population include not only weight loss, but also decreased systemic inflammation, increased muscle strength, flexibility, energy, a sense of well-being, higher levels of self-efficacy, use of more active and adaptive coping strategies, enhanced quality of sleep, decreased blood pressure, and fewer heart attacks.104

Clinical and animal studies of joint loading have provided strong evidence that abnormal loads can lead to alterations in the composition, structure, metabolism, and mechanical properties of articular cartilage and other joint tissues.64 Abnormal loading may be caused by various factors such as obesity, immobilization, joint instability, overuse, or trauma. A recent study showed that there is considerable cartilage thinning caused by decreased joint loading subsequent to spinal cord injury.153 Conversely, obesity is strongly associated with OA,108 and a decrease of 5 kg of body weight can decrease the risk of OA by more than 50%.42 Altered joint loading attributable to instability or injury of the joint is now well known to be a major risk factor for the onset and progression of OA.17,68 Joint instability, induced by ligament transection50,118 or meniscectomy65,101 also may lead to joint degeneration. These procedures result in profound changes in joint tissues that mimic changes seen in early human OA, including increased hydration, collagen disruption, and matrix turnover accompanied by decreased tissue stiffness in tension, compression, and shear.2,20,35,39,59,95,125,131,133 Articular cartilage and synovial fluid from these models of OA show notable increases in various biomarkers85 that are correlated with histologic damage in the joint.19 Similarly, the presence of these biomarkers is increased in cartilage in a coronal step-off model of articular fracture,87 suggesting that common pathways may be responsible for the metabolic changes in these two models.

Cartilage Inflammation in OA

Although the role of inflammation in OA has been long debated,121 considerable evidence now confirms the role of proinflammatory cytokines and mediators in this disease,94 and their potential in various therapies (Table 1).46 For example, the catabolism of osteoarthritic cartilage is thought to involve the action of proinflammatory cytokines such as interleukin 1 (IL-1) and tumor necrosis factor alpha (TNF-α).51,94,156 Interleukin-1 down-regulates extracellular matrix (ECM) synthesis and up-regulates metalloprotease synthesis through production of nitric oxide (NO) in chondrocytes.113 Furthermore, IL-1 receptor antagonist (IL-1Ra) has been shown to be an effective therapeutic agent in animal models of arthritis and in human rheumatoid arthritis.37 After traumatic joint injury, a transient increase occurs in IL-1 and TNF-α concentrations in chondrocytes and articular cartilage.117

Table 1:
Several Major Effects of Primary Pro-Inflammatory Cytokines in Cartilage and Joint Physiology Are Listed

Of importance to an understanding of OA is the finding that inflammation and cartilage destruction may be separate pathogenic events; as such, therapeutic interventions for one aspect of the disease may or may not influence the other aspect. In this respect, IL-1 seems more potent in its ability to cause cartilage degradation, whereas TNF-α seems to be responsible for inflammatory events.148 The two isoforms of IL-1 (α and β) show similar potency, but IL-1α seems to be active in early synovial inflammation whereas IL-1β is the more dominant cytokine in advanced disease.150 Inhibition of nitric oxide synthase 2 (NOS2) and NO production prevents IL-1β-mediated suppression of proteoglycan and Type II collagen synthesis and increased expression of metalloproteases in chondrocytes, showing that NO acts as an endogenous mediator of the catabolic actions of IL-1β.

Other cytokines, such as IL-6 and IL-17 have been implicated in cartilage degradation and inflammation.148 Importantly, there is evidence for synergy in the interaction of these cytokines in the stimulation of cartilage breakdown127 and the production of inflammatory mediators.84 The mechanism of action of IL-1 may in fact be through the upregulation of IL-6.106 Human osteoarthritic cartilage releases sufficient IL-1 to upregulate chondrocyte production of IL-6.9 In vitro, human synoviocytes spontaneously release IL-6 in a manner that is increased by IL-1 and TNF-α.55 Interleukin 6 levels have been correlated with pain in the temporomandibular joint,137 and IL-6 synergizes with IL-1 to promote collagen degradation in cartilage.127

The Roles of NO and Prostaglandins in Cartilage

The action of these inflammatory cytokines seems to be regulated by the small proinflammatory mediators NO and prostaglandin E2 (PGE2).62,69,71 These mediators are elevated in the articular cartilage, synovium, and synovial fluid of osteoarthritic and rheumatoid joints3,24,38,53,62,69 and serve as potential therapeutic targets for OA.

Nitric oxide is a gaseous, short-acting signaling molecule with multiple important physiologic and pathologic functions.11,100,103 In the presence of oxygen, NO is converted rapidly (within seconds) to nitrite and nitrate, substances which generally are not bioactive.140 However, on reacting with O2, NO may form peroxynitrite (OONO), a toxic and reactive molecule. Nitric oxide is formed during the conversion of arginine to citrulline by the nitric oxide synthase (NOS) enzymes. There are three forms of NOS encoded by three different genes, NOS1, NOS2, and NOS3. Inducible NOS (iNOS or NOS2) was described initially in mononuclear phagocytes, and seems to be the primary NOS enzyme in chondrocytes.141 Nitric oxide synthase 2 can produce high levels of NO and most commonly is associated with inflammation in arthritic disorders.53 Inhibition of NO production using NOS2-specific inhibitors can considerably reduce disease progression in animal models of OA.24,38,114,143

The prostaglandins are important mediators of pain and inflammation in arthritis61 and are the prime target of most current therapies for OA. Prostaglandin E2 is a prostanoid synthesized by the cyclooxygenase (COX) enzymes that catalyze the conversion of arachidonic acid and oxygen to prostaglandin H2 (PGH2), the committed step in prostanoid biosynthesis. Increased prostaglandin synthesis is a cellular response to activation by proinflammatory stimuli,151 and nonsteroidal antiinflammatory drugs (NSAIDS) compete directly with arachidonic acid binding to the cyclooxygenase site and inhibit COX activity. Aspirin covalently modifies and irreversibly inhibits COX, whereas other NSAIDS such as ibuprofen and indomethacin act as reversible competitive inhibitors. Cyclooxygenase exists as three isoforms. Cyclooxygenase-1 is constitutive and exists in endothelium, stomach, kidney, and platelets, where it regulates some normal physiologic functions such as gastric mucosal cytoprotection, maintenance of renal blood flow, and function and platelet aggregation.26,155 Inducible COX (COX2) is the isoform associated with inflammatory responses and most likely is responsible for the elevated PGE2 levels in arthritis.1 Inducible–COX-specific inhibitors such as NS398 and celecoxib are time-dependent, reversible inhibitors of COX2, and display little inhibition of COX1. Cyclooxygenase-3 is a distinct isoenzyme of COX1 and has been shown to be the putative target for acetaminophen and several other analgesic or antipyretic drugs.22

Increased prostanoid synthesis and COX2 expression occur in arthritic cartilage, compared with nonarthritic cartilage.1 Prostaglandin E2 is a pleiotropic bioregulator with the ability to alter the expression of many target genes involved in the pathophysiology of arthritic diseases. Because cartilage is avascular, it is likely that effects of PGE2 are through paracrine and autocrine mechanisms. Cytokine stimulation of articular cartilage leads to PGE2 release because of increased COX2 activity.48,91 Prostaglandin E2 plays a role in the regulation of chondrocyte proliferation and synthesis of extracellular components.33 The effects of PGE2 are dose dependent and can have opposite effects on matrix biosynthesis depending on concentration.31,52 Prostaglandin E2 also can exert anticatabolic and antiinflammatory effects and can potently downregulate the expression and synthesis of inflammatory cytokines IL-1, and TNF-α, and NOS2, and metalloproteases 1 and 3.12,32,75,98

Cyclooxygenase 2 inhibitors have provided an alternative to nonspecific NSAIDs in the treatment of arthritis. They are effective therapeutic agents for OA and rheumatoid arthritis and also attenuate inflammation and hyperalgesia in several animal models of arthritis.6,151 Cyclooxygenase-2 expression is upregulated in various cell types by proinflammatory cytokines and downregulated by antiinflammatory cytokines and glucocorticoid hormones. Cyclooxygenase-2 is expressed in inflamed synovial tissue.13,25,30 Newer drugs that have high selectivity against COX2 such as celecoxib, rofecoxib, or valdecoxib have proven potent anti-inflammatory compounds with reduced side effects.36,115 However, because of the potential influence of prostaglandins on cartilage matrix turnover, the effect of COX2 inhibition on chondrocyte activity is unclear,77 particularly with respect to mechanical stress.

Furthermore, there is growing evidence that the COX enzymes, and particularly COX1, are integrally involved in bone repair,49 potentially by regulating the differentiation of mesenchymal stem cells into the osteoblast lineage.158 These recent findings support the notion that COX expression and prostanoid synthesis may play anabolic and catabolic effects on joint tissues. The role of these enzyme systems on the repair of articular fractures remains to be determined.

Importantly, there seems to be considerable interaction between the NOS and COX systems. Prostanoids can reduce NOS2 expression and NO production,92 and NO modulates PGE2 formation.130,152 Arginine analogs such as NG-monomethyl L-arginine (NMMA) may be antiinflammatory by inhibiting COX2 and NOS.129 Furthermore, aspirin (in high doses) can inhibit cyclooxygenase and NOS2.4 Modulation of NO levels or NOS expression may influence prostaglandin synthesis129,130 through the altered transcription of COX genes, modulation of COX activity, or modification of prostaglandin-metabolizing enzymes. In cartilage, NO apparently inhibits the stimulation of prostaglandin production by IL-1 or mechanical stress.21,44,45 Considerable interactions exist between mechanical stress and cytokines in the regulation of COX2 and NOS2 expression and PGE2 and NO production as they relate to inflammation (Fig 1).

Fig 1.:
This diagram shows pathways of interaction of mechanical stress and proinflammatory mediators. Increased concentrations of cytokines or alterations in the mechanical environment of the joint may activate COX2 and NOS2 in articular cartilage, increasing production of prostaglandins or NO.

Cartilage Injury and Inflammation

Injury to articular cartilage most often results from a single or repeated impact load. Impact loading (a rapid increase of force across the joint) can be expected to produce a highly nonuniform combination of tensile, compressive, and shear stresses and strains132 in addition to very high hydrostatic pressures through the cartilage layer.8 Impact loading can cause acute damage to the joint, but there is little evidence for progressive joint degeneration in the absence of articular fracture or repetitive loading.34,107,122,144 The effects of impact loading on chondrocyte activity in vivo have not been studied extensively, particularly with respect to the role of inflammatory mediators. However, a previous study showed the presence of synovial inflammation following repeated impact of the joint.89 Furthermore, there is evidence of the upregulation of arachidonic acid, IL-1, TNF-α, and the metalloprotease stromelysin (MMP-3) in cartilage after joint impact in the absence of articular fracture.117

Articular fractures can result in the rapid onset of posttraumatic arthritis, although the cellular basis of this response is not well defined. Displaced articular fractures result in physical disruption of articular cartilage and the underlying subchondral bone. It commonly is thought that articular impaction injury also must occur in this setting. However, little is known about the local inflammatory changes in the joint resulting after an articular fracture. In general, trauma increases local and systemic concentrations of proinflammatory cytokines such as IL-6 and IL-8.66,116 Increased circulating levels of cytokines after bodily trauma are predictive of injury severity and clinical outcome.47,63,142 Injury to the joints or skeleton can transiently increase the levels of proinflammatory cytokines locally70 and systemically.112 Such a systemic increase in inflammatory cytokines is thought to be closely related to a prolonged period of shock.112 Furthermore, short-term exposure of cartilage to blood (as would be expected after a displaced articular fracture) can induce chondrocyte apoptosis.67 However, it is not known whether a systemic increase in inflammatory cytokines has an effect on the outcome of an articular fracture.

It also is clear that a displaced fracture alters the loading environment of the joint.5,10,16,76,109,110 in a manner that can lead to posttraumatic arthritis.82,83 Data regarding physical or inflammatory changes are not known, and an understanding of the role of inflammation in the development of posttraumatic arthritis is still evolving. Nonetheless, inflammatory mediators and cytokines seem to play an important role in other models of OA based on altered joint loading, which may provide additional insight on the relationship between biomechanical factors and inflammation.

Additional information on the potential interaction of mechanical stress and joint inflammation comes from studies of rheumatoid arthritis. Physical activity for patients with rheumatoid arthritis has been controversial, especially for patients with active disease. With increasing numbers of controlled, blinded trials, evidence has emerged of the benefits of exercise on joint pain in the uninflamed joint. Exercise alters immune function in a way that seems helpful in regulating inflammation. Furthermore, there is evidence that patients can tolerate a program of regular moderate aerobic exercise, and such exercise substantially enhances physical performance without exacerbating either clinical or immunologic markers of the disease process.104,136 In other studies, training of the muscles acting over the swollen joints resulted in a considerable decrease in the number of swollen joints.90 In fact, high-intensity strength training now is thought to be feasible and safe in selected patients and leads to considerable improvements in strength, pain, and fatigue without exacerbating disease activity or joint pain.124

In an acutely inflamed joint, there still is controversy as to the benefits or detriment of mechanical stress (rest versus exercise). Historically, rest therapy and immobilization have been prescribed for the inflamed joint, often to prevent fatigue.138 Of particular interest is the finding that running exercise considerably increases cartilage destruction in the joints of hamsters that have been injected with lipopolysaccharide (LPS) to induce inflammation. This finding suggests that mechanical stress applied to cartilage in the presence of inflammation enhances the breakdown of the collagen matrix, and may increase further the inflammatory response by the release of cartilage breakdown products into the synovial fluid.135

These in vivo studies emphasize the relationship between mechanical loading and the health of the joint and suggest that the normal regulation of chondrocyte activity by mechanical factors may be influenced adversely by the presence of proinflammatory mediators and cytokines in the joint. Considered together, these studies suggest that a critical amount of joint loading and a specific pattern of joint loading are required for the normal homeostatic balance of cartilage anabolism and catabolism. The interactions of biomechanical and inflammatory mechanisms involved in the progression of cartilage degeneration are not known. Currently, there is considerable evidence to implicate the role of various cytokines, specifically IL-1, IL-6, and TNF-α, in these processes.149 One interpretation of the disuse and exercise studies is that the frequency of loading of articular cartilage influences the rate of matrix synthesis and breakdown. Conversely, studies of progressive joint degeneration present evidence that degenerative changes are initiated by hyperphysiologic magnitudes of loading or by alterations in the normal loading pattern of the joint because of joint instability or articular fracture. Considered together, these findings support the notion that altered patterns and magnitudes of stress in the joint after a displaced intraarticular fracture may play a role in posttraumatic arthritis.

Biomechanical Factors and Inflammation in Cartilage: In Vitro Studies

In vitro explant models of mechanical loading provide systems in which the biomechanical and biochemical environments of the chondrocytes can be better controlled, compared with the in vivo situation. Considerable research effort has been directed toward understanding the processes by which biophysical signals are converted to a biochemical signal by the chondrocyte population. Clarification of the specific biophysical factors and biologic signaling mechanisms in normal and inflamed cartilage would provide a better understanding of cartilage physiology and repair and also may yield new insights on the pathogenesis of posttraumatic OA. This information potentially could reveal new targets for disease prevention or treatment.

Explant models of cartilage loading have been used in numerous different loading configurations, including unconfined compression, indentation, tension, and osmotic and hydrostatic pressure.14,18,54,56–58,74,111,123,128,145 The general consensus of these studies is that static compression suppresses matrix biosynthesis, and cyclic and intermittent loading stimulate chondrocyte metabolism. These responses have been reported over a wide range of loading magnitudes, and exhibit a stress-dose dependency.60

Numerous in vitro studies have investigated supraphysiologic loading of cartilage using one impact load or repeated impact loads.27,40,72,73,88,119,146 These studies have shown acute changes in the biomechanical properties, metabolic activity, and cell viability of articular cartilage that are similar to those occurring with in vivo impact. These in vitro studies suggest that the rate and the magnitude of loading can have considerable effects on cartilage health and apoptosis, and that the effects on cell death and matrix loss after injury can vary considerably with depth in the cartilage layer.23,34,72,73,86,120

Mechanical stress also can influence NO production by chondrocytes,28,81 and increased IL-6, NO, PGE2, and proteoglycan synthesis occurs in isolated chondrocytes in response to fluid shear stress.99,139 Chondrocytes embedded in their own ECM show similar increases in the production of proinflammatory mediators with stress,43–45 although chondrocytes embedded in an agarose matrix show an opposite effect81 suggesting that interactions with the native ECM can influence this response. Other studies have shown that static and intermittent mechanical compression influences the synthesis of NO44 and PGE2 with considerable interaction between the NOS2 and COX2 pathways.21 In an in vitro model, intermittent compression of cartilage explants in the presence of the specific NOS2 inhibitor 1400W caused an additional increase in PGE2 production (40-fold increase compared with control), indicating that inducible NO has a negative feedback role in the prostanoid pathway in articular cartilage. Because the effects of mechanical loading are not additive with those of exogenous PGE2, investigators have hypothesized that prostanoids play a role in the degenerative and repair process in arthritis, where elevated intraarticular levels of PGE2 are present.147 These findings may have important implications regarding the pathogenesis of arthritis and the development of new physical and pharmacologic interventions for arthritis treatment.


There now is considerable evidence that proinflammatory mediators and cytokines contribute to cartilage injury and repair, particularly in the context of OA. There is also evidence that these mediators are involved in the events after cartilage injury and articular fracture that lead to posttraumatic arthritis. Changes in the mechanical environment, an important regulator of cartilage physiology, seem to play an important role in modulating the production of proinflammatory mediators in articular cartilage, whereas injury of the joint may lead to considerable increases in local concentrations of proinflammatory cytokines. Numerous different but interacting cytokines have been implicated in the inflammatory response of articular cartilage (Table 1), and several recent approaches for OA therapy have targeted these molecules.46 In vivo findings indicate that altered joint loading can cause deleterious cartilage changes similar to those of early OA, and these effects can be ameliorated by inhibition of inflammatory cascades. A more detailed understanding of the inflammatory changes occurring in joint tissues in response to traumatic injury may provide new insights into the mechanisms of disease progression in posttraumatic arthritis. Nonetheless, inflammation is an important aspect of tissue repair, and recent reports suggest that the COX enzymes are integrally involved in bone healing. Therefore, any therapeutic manipulation of inflammatory pathways after articular fracture should be approached with caution.

The biomechanical and biologic mechanisms involved in the transduction of mechanical loads to an intracellular response remain to be elucidated. In situ explant studies confirm that mechanical load may be a potent regulator of matrix metabolism and cell viability. Furthermore, mechanical stress can influence the production of the proinflammatory mediators NO and PGE2 through the activation of NOS2 and COX2, respectively, with considerable evidence of cross-talk between these pathways. These findings further support the potential of these pathways as therapeutic targets, but also suggest that agents such as COX2 inhibitors or NOS2 inhibitors that are designed to combat one inflammatory pathway may affect other pathways, particularly under physiologic loading conditions. Together, these findings suggest that additional knowledge of the interaction of inflammatory and biomechanical factors in regulating cartilage metabolism would be beneficial to understanding the onset and progression of posttraumatic arthritis.


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