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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
J Orthop Res. Author manuscript; available in PMC Jun 1, 2012.
Published in final edited form as:
PMCID: PMC3082940



Even with current treatments of acute joint injuries, more than 40% of people who suffer significant ligament or meniscus tears, or articular surface injuries, will develop osteoarthritis. Correspondingly, 12% or more of all patients with lower extremity osteoarthritis have a history of joint injury. Recent research suggests that acute joint damage that occurs at the time of an injury initiates a sequence of events that can lead to progressive articular surface damage. New molecular interventions, combined with evolving surgical methods, aim to minimize or prevent progressive tissue damage triggered by joint injury. Seizing the potential for progress in the treatment of joint injuries to forestall OA will depend on advances in: (1) quantitative methods of assessing the injury severity, including both structural damage and biologic responses, (2) understanding of the pathogenesis of post-traumatic OA, taking into account potential interactions among the different tissues and the role of post-traumatic incongruity and instability, and (3) application of engineering and molecular research to develop new methods of treating injured joints. This paper highlights recent advances in understanding of the structural damage and the acute biological response following joint injury, and it identifies important directions for future research.


Osteoarthritis (OA) is the most common joint disease and among the most important causes of pain, disability and economic loss in all populations. The physical impairment caused by OA of a single lower extremity joint is equivalent to that caused by end-stage kidney disease or heart failure.1 A substantial fraction (~12%) of the overall burden of disease of OA arises secondary to joint trauma.2 With the best current care of significant joint injuries, the risk of post-traumatic OA (PTOA) ranges from about 20% to more than 50%.3

Research in the area of PTOA spans a spectrum from basic in vitro culture work, to experiments with explanted tissues, to animal modeling, to human clinical assessment. Relating findings from these different research settings presents many challenges. The translation of bench results into clinically validated treatment approaches is a core challenge in orthopaedic research. The central theme of ongoing research is that acute-impact joint injuries initiate a sequence of biologic events that cause the progressive joint degeneration that leads to PTOA. Considerable evidence is emerging from explant tissue and animal studies that new molecular interventions can mitigate or arrest these adverse events and thus, promote joint healing. These findings remain to be confirmed in vivo in human joints, but they offer hope for a paradigm shift in the acute management of articular joint injury. Joint surface incongruity and instability that follow some joint injuries play a critical role in PTOA, a problem that also needs attention. The time course over which clinically measurable OA develops is highly variable, ranging from two to five years in the case of certain articular fractures, to decades for less severe joint injuries, and that is another problem that requires attention. Here we begin by briefly touching upon the incidence and impact of PTOA, introducing the evidence linking joint injuries and PTOA, highlighting recent laboratory advances in understanding the structural damage and acute biological response following joint injury, and finally identifying important directions for future research.

Incidence and Impact of Post-Traumatic OA

OA occurs frequently in people who suffer a significant joint injury. A study of 1321 former medical students4 found that 14% of those who had a knee injury during adolescence and young adulthood developed knee OA, compared with 6% of those who did not have a knee injury. Follow up of people who suffered knee ligamentous and meniscal injuries demonstrated that they had a ten-fold increased risk of OA as compared with those who did not have a joint injury.5,6 Other studies showed that at least one in four patients develop OA after acetabular fractures,7 that between 23% and 44% of patients develop knee OA after articular fractures of the knee,8 and that >50% of patients with fractures of the distal tibial articular surface develop OA.9 Taken together these data indicate that a significant ligamentous or capsular injury increases the risk of OA as much as 10-fold and that most articular fractures increase the risk of OA more than 20-fold.

These reports confirm that joint injury increases the risk of OA, but they do not provide an estimate of the burden of PTOA. A study of patients presenting with disabling hip, knee, and ankle OA showed that 1.6% of patients with hip OA, 9.8% of patients with knee OA, and 79.5% of patients with ankle OA had a verified history of one or more joint injuries.2 Extrapolation from this patient population indicates that the number of patients in the United States with disabling PTOA of the hip, knee, or ankle approaches six million and accounts for approximately 12% of annual societal expenditures for OA, or about three billion dollars.2 Adding to this burden is the fact that, unlike most other forms of OA, PTOA often affects younger adults for whom joint replacement or joint fusion are not desirable treatments.

Joint Injuries that Cause Post-Traumatic OA

A common feature of joint injuries that is proposed to cause PTOA is the sudden application of mechanical force (impact) to the articular surface. The extent of mechanical damage to any structure is a function of the intensity of the impact. Studies on explanted joints show that higher energy impact also causes greater local tissue damage, as measured experimentally by the proportion of cells releasing reactive oxygen species, chondrocyte death, and matrix disruption.10,11 Different levels of applied impact energy cause different types of articular surface injury, with different repair responses and healing potential: (1) damage to cells and/or matrices that does not include macroscopic structural disruption of cartilage or bone, (2) damage to cells and/or matrices along with macroscopic structural disruption of articular cartilage without displaced bone fracture (these injuries may be associated with microfractures of the calcified cartilage and in some instances of the subchondral or trabecular bone), and (3) displaced fractures of the articular surface extending through cartilage and bone.12,13 Low-energy injuries, including joint contusions, dislocations, and ligamentous injuries, commonly cause the first two types of articular surface damage, while higher energy injuries cause displaced intra-articular fractures.9,14

Animal models of articular fracture offer a means to investigate injuries that lead to PTOA. This body of work includes impact loading of whole joints without fracture, as well as direct impact loading of the articular surface following arthrotomy.1517 These studies generally mirror the results of impaction of cartilage explants and of ex vivo human joints,18 though they require much higher stresses to reproduce the injury in an intact joint. Other investigators examined the effects of an intra-articular osteotomy with varying degrees of articular displacement, but without articular loading or cartilage impaction, finding that inter-fragmentary compression may enhance articular fracture repair, and that remodeling of the articular surface can occur on a limited basis.1921 A third area of investigation has involved the creation of an intra-articular fracture via in vivo loading of the joint. Recent investigations suggest that articular fracture causes significant chondrocyte death at the fracture.22 Furthermore, in animal models, such an injury leads to the development of osteoarthritis-like changes in the cartilage, bone, synovium, and other joint tissues.23,24 These changes are associated with rapid changes in serum and synovial fluid concentrations of cartilage biomarkers and pro-inflammatory cytokines.2326

Techniques to characterize joint injuries in humans are increasingly available, although no general consensus on how to interpret the resulting measures has emerged. More work is needed to establish methods of measuring injury severity and to understand how to use this information to guide therapy and improve clinical outcomes. Currently, surgeons treating patients with joint injuries have limited ability to assess the extent of the injury to the articular surface or other joint tissues. Plain radiographic and CT studies of articular fractures can demonstrate the disruption of the joint surface and the degree of fracture fragment displacement.2729 MRI can demonstrate articular cartilage disruption or subchondral bone injuries, but only recently have investigators begun to define the relationships between MRI studies and changes in articular cartilage structure, composition, and mechanical properties.30 Although a variety of synovial fluid markers may provide insight into the biologic response of joints to injury,31,32 currently no biomarkers exist to clinically monitor the development and progression of PTOA or the efficacy of surgical or pharmacological treatment.

Quantitative assessment of the energy absorbed by the joint surfaces in patients with articular fractures provides one method of evaluating severity of injury.3336 The basic idea -grounded in principles of engineering fracture mechanics - is that the mechanical energy absorbed in producing a fracture is converted to surface energy of the fracture fragments. CT scans, acquired routinely for many articular fractures, provide the opportunity to directly measure de novo interfragmentary surface area, from which surface energy can be quantified. For studying PTOA, the primary utility of fracture energy is as a metric of the cartilage-injurious energy pulse that must have crossed the articular surface to create the bony fracture. Using this method, objective CT-based measures of fracture severity that meaningfully reflect the traumatic mechanical insult to the joint and risk of PTOA are obtained. For example, tibial plafond fracture patients with low energy (less severe) injuries have little or no risk of OA within two years of injury, even though they have displaced fractures of the articular surface, while patients with high energy (more severe) injuries develop OA within two years (Fig. 1). These observations show that, at least for injuries that disrupt the articular surface, the risk for rapid onset of PTOA is closely related to the energy delivered to the joint at the time of injury and the resulting severity of articular surface damage.9,14 It remains to be established what the longer term implications are regarding acute fracture severity and the eventual development of PTOA many years later in the remainder of those joints.

Figure 1
CT-based fracture severity metric values are shown for 20 tibial plafond fracture patients. This metric combines normalized values of overall fracture energy and the energy released at the articular surface into a single measure of fracture severity. ...

Experimental Models of Impact-Induced Cartilage Damage

Impact injuries not surprisingly cause cell and matrix damage. However, it is increasingly clear that injuries also initiate progressive tissue damage. Improvements in treating joint injuries are limited by lack of information concerning biologic mediators that cause this progressive damage.37 A variety of experimental models have provided insight in this area.

Recent in vitro studies showed that impact injury stimulates release of oxygen free radicals from chondrocytes, which leads to progressive chondrocyte damage and matrix degradation.38,39 To test the hypothesis that superoxide released by damaged components of the mitochondrial electron transport chain causes a significant fraction of impact-induced chondrocyte death, fresh osteochondral samples were exposed to rotenone, an agent that suppresses the release of superoxide from mitochondria, for varying periods of time from before until after impact. Rotenone treatment significantly inhibited superoxide at impact sites (Fig. 2), strongly suggesting that mitochondrial dysfunction could be responsible for chondrocyte mortality in joint injuries that involve blunt trauma to articular surfaces. Other in vitro explant studies show that cartilage impact causes release of fibronectin fragments, which stimulate cell damage and matrix degradation.40

Figure 2
Chondrocyte viabilities are shown for explants exposed to rotenone for varying periods of time from before until after impact (the hours before and after are labeled on the horizontal axis). Black columns are for impact sites; white columns for nonimpact ...

Joint injuries cause striking alterations in synovial fluid levels of compounds that may contribute to joint degeneration, including pro-inflammatory cytokines and mediators such as tumor necrosis factor alpha (TNF-α), interleukin (IL)-1, nitric oxide, and matrix metalloproteinases (MMPs).11,4143 Hypotheses concerning the relationships between joint injuries and the biological events that lead to progressive joint degeneration (Fig. 3) can not be tested in patients. Therefore, it is essential to perform studies in survival animal models that allow investigation of the mechanical and biological events that initiate PTOA and interventions that can decrease the risk of joint degeneration.

Figure 3
Factors involved in the development of PTOA after injury. The clinical manifestation of PTOA depends upon a number of factors at the cellular and molecular, joint, and systemic levels. Currently, surgical intervention primarily occurs at the joint or ...

Researchers studied the progression of PTOA following closed articular fractures in the tibial plateaus of skeletally mature adult male mice (28–35g, C57BL/6).23,44 The fractures were not reduced or stabilized. Modified Mankin grades demonstrated significant degenerative changes in experimental limbs at 8 weeks, and by 50 weeks, severe cartilage loss was observed (Fig. 4). One advantage of a mouse model is the ability to study mechanisms that are potentially involved in PTOA through the use of genetically modified or inbred strains. For example, the MRL/MpJ strain is an inbred mouse that demonstrates a heightened wound healing response,45 including increased repair of osteochondral defects.46 The regenerative healing characteristics of the MRL/MpJ strain have been attributed to decreased production of pro-inflammatory cytokines such as IL-1 and TNF-α during repair.47 These cytokines have also been implicated in the pathogenesis of OA.

Figure 4
Histologic sections of control (left) and experimentally fractured (right) mouse knee joints at 8 (A,B) and 50 (C,D) wks following fracture. By 8 wks, severe loss of safranin O staining for proteoglycan was evident in (B) the experimental tibial (T) and ...

In a recent study, the response of MRL/MpJ mice following induction of articular fractures with the above protocol was compared to that of C57BL/6 mice. Animals were euthanized at 4 and 8 weeks following fracture. Despite the lack of fracture reduction or fixation, the MRL/MpJ strain did not progress to PTOA like the C57BL/6 strain and did not show increased degeneration in the experimental limb when compared to the control limb. Furthermore, analyses of the synovial fluid and synovium showed an intense inflammatory response in C57BL/6 mice that was absent in the MRL/MpJ mice.48 These findings suggest that genetic factors, possibly associated with the suppression of an inducible inflammatory response that is characteristic of MRL/MpJ mice, may be protective against PTOA. A more thorough understanding of these mechanisms may thus provide new insights into the development of molecular therapeutics that can prevent or slow disease progression following joint injury.

Biologic Targets for Preventing Post-Traumatic Joint Degeneration

The vast majority of research in disease-modifying OA drugs has focused on mid- to late-term forestallment of joint degeneration.49,50 However, in the case of PTOA, the clear precipitating event presents a unique opportunity to intervene early in the acute post-traumatic period.

Acute joint trauma causes three overlapping phases of cartilage injury and response to injury over the course of the first week or two after trauma (Fig. 5): (1) an early phase is characterized by cell death/apoptosis and inflammation (e.g., elevation of caspases, pro-inflammatory cytokines, nitric oxide, reactive oxygen species, basic fibroblast growth factor, MMPs, aggrecanases, and release of matrix fragments); (2) an intermediate phase follows, when a potential balance between catabolic and anabolic responses may exist (catabolic responses subside and anabolic responses are initiated); and (3) a late phase with a limited repair/remodeling/matrix formation (activation of anabolic growth factors). An understanding of these overlapping phases provides a basis for identifying potential biologic targets for intervention to prevent later joint degeneration.

Figure 5
This conceptual framework depicts the immediate cellular responses to acute joint trauma and facilitates the identification of targets for early interventions. Catabolic and anabolic processes are involved in the response to the injury and overlap with ...

Increasing evidence exists that biologic interventions can decrease chondrocyte damage induced by mechanical stress,11,41 suggesting that limiting progressive chondrocyte damage after joint injury is possible. The work of D’Lima and co-workers shows that caspase inhibition can decrease mechanically induced chondrocyte apoptosis,41 and Haut and colleagues reported that P188 surfactant can limit chondrocyte necrosis following impact loading.51 Martin and coworkers demonstrated that anti-oxidants applied within hours of injury prevent progressive mechanically-induced chondrocyte damage and matrix degradation.11,38,52 In addition, in vitro studies showed that blocking the effects of the fibronectin pathways activated by cartilage impact injury also prevent progressive cell damage and matrix degradation.53 Treatments that decrease early loading of injured articular surfaces might also minimize extension of tissue damage and accelerate healing, by decreasing the inflammatory response and limiting cartilage degradation.42

A series of investigations were focused on acute injury limited to the cartilage surface,5457 both in vitro on the intact bovine and human cartilage and in vivo in sheep and canine femoral condyles.5861 These models involve articular cartilage impaction that produces immediate matrix disruption and cell death, but the evolution of the lesion is slow enough to provide an opportunity to study the response of chondrocytes to injury and for applying therapeutic interventions and determining their effect. A single ex vivo impact to human cartilage resulted in cell death at the impaction site, immediate release of inflammatory cytokines (mostly IL-6 and TNF-α), radial progression of apoptosis to adjacent non-impacted area, and progressive cartilage degeneration within the impacted and immediately adjacent non-impacted areas.58

In studies performed in fresh ankle cartilage explants obtained from human organ and tissue donors, a single dose of the surfactant P188 promoted cell survival (Fig. 6), delayed or inhibited the expansion of apoptosis, and thus protected cartilage integrity to a much higher extent than specific inhibitors of caspase-3 and −9.57 Multiple treatments with P188 were not superior to a single dose. In addition to its known stabilizing effect on cellular membranes, P188 also either inhibits or blocks stress-related p38 mitogen-activated protein (MAP) kinase signaling, apoptosis-related glycogen synthase kinase 3 (GSK3) activation, and inflammation-related IL-6 signaling.58 These findings suggest that P188 alone or in combination with growth factors may have the potential to prevent development of PTOA. But the choice of a growth factor is extremely critical. For instance, insulin-like growth factor-I and P188 were somewhat effective individually, but their combination showed no synergy.62

Figure 6
Quantitative assessment of cell survival between impacted samples of human ankle cartilage treated with a single (▲) dose or multiple ([triangle]) doses of P-188 (8μg/ml) and non-treated controls (■). The single dose was administered ...

More recent work focused on the combined effect of P188 and the bone morphogenetic protein OP-1 in vitro, since OP-1 was shown in multiple in vitro and in vivo studies,54 including an in vivo sheep model,56 to exhibit a chondroprotective effect in forestalling PTOA when administered immediately or within 3 to 4 weeks after injury. As for synergies between P188 and OP-1, both inhibit IL-6 activity/signaling, but through relatively distinct mechanisms. In data being prepared for publication, OP-1 inhibited gene expression of IL-6 and other chemokines. Other areas of synergism could be through the ability of both factors to inhibit apoptosis, though again they likely act through distinct mechanisms.56,57

Future Research Directions

As detailed above, recent research suggests that acute joint damage that occurs at the time of an injury initiates a sequence of events that can lead to progressive articular surface damage. New acute interventions, combined with evolving surgical methods, aim to minimize or prevent progressive tissue damage triggered by joint injury. Despite these exciting new opportunities for intervention, significant barriers must be overcome for these opportunities to yield new clinical approaches. Future work must create a path through which therapeutic approaches can be evaluated for efficacy in humans by establishing criteria for stratifying individuals in accordance with clinically relevant factors like severity of joint injury. Ultimately, understanding the healing period will help improve treatment of patients with joint injuries. Thus, a common theme of the following list of future research directions is that they embrace emerging technologies that are providing ways in which to monitor the health of the joint tissues during the subsequent healing period:

  1. Improved quantitative methods for assessing the severity of joint injuries. Without the ability to measure the severity of a joint injury in humans it will be difficult to assess the effects of treatments intended to decrease the risk of PTOA. Further progress in the use of CT-assessed articular fracture energy to define PTOA risk will be important in advancing treatment of articular fractures and understanding of the relationships between acute impact applied to a joint surface and the risk of OA. This approach will also make possible studies on the importance and roles of initial injury severity versus residual joint incongruity in causing OA. The majority of joint injuries do not involve articular fractures; rather, as discussed above, they consist of damage at the level of the cells and matrices often associated with ligamentous, meniscal, or joint capsule damage.
  2. Animal models that simulate human joint injuries and therefore allow study of the effects of biologic and surgical interventions. In the absence of these models, rigorous studies of interventions that have the potential to decrease the risk of OA can not be performed. Ideally, animal models would allow study of both biologic and surgical treatments. Animal models should also make it possible to optimize the treatment courses and combinations of treatments for specific types of joint injuries.
  3. Registries of patients with joint injuries, clinical studies of PTOA risk factors, and prospective controlled clinical trials to determine the efficacy of treatments of joint injuries. The establishment of registries to follow patients with articular injuries over time would make it possible to identify factors predictive of PTOA development, as well as to further establish the burden of disease. Clinical studies are needed to define the role of patient variables including body mass, muscle strength, genetic differences, and activity levels in PTOA. Finally, because PTOA may not develop for many years after joint injury, clinical trials must be designed so that they can be completed in a relatively short time. Fortunately, the time course over which clinically measurable OA develops is highly variable, and can be as short as from two to five years in the case of certain articular fractures. For injuries in which the timeframe is much longer, treatment advances may require further development of measures of joint injury severity and early joint healing and biomarkers predictive of the risk of OA.
  4. Improved methods for the assessment of joint health in the period following initial treatment to better define the nature of the observed damage and to better understand the implications in terms of future joint health. Joint injuries initiate a healing or repair response that may decrease the risk of OA. These responses are poorly understood because of the limited ability to evaluate joint healing in humans. New imaging methods and biomarkers would help. Important issues related to joint healing and the development of OA following injuries that do not disrupt the articular surface include the extent to which these injuries heal spontaneously, factors or treatments that promote or impede healing, and the role of repeated injuries due to joint instability. Issues that need study in patients with intra-articular fractures include: the extent to which repair tissue, cartilaginous tissue, and bone remodel over time, the type and quality of repair tissue that will prevent development of progressive joint degeneration, and the factors which promote functional joint repair.
  5. Studies of the relationships between residual joint incongruity/instability and OA. Many joint injuries leave residual articular surface incongruity and joint instability, problems that expose the joint to repeated injuries with normal use, thereby increasing the risk of OA. The current inability to objectively measure joint incongruity and instability in humans has made it difficult to define their relationships to PTOA.
  6. It has long been appreciated that PTOA is a failure of the joint as a system, made up of many different tissues with intricately linked biological relationships. Determination of the interaction among various joint tissues (e.g., cartilage, bone, ligament, joint capsule, meniscus) and their respective roles in disease progression is critical to advances in the treatment of PTOA. For example, mediators released from the synovium may influence articular cartilage and bone, and bone remodeling may have an important role in preventing or causing PTOA.


We would like to acknowledge the invaluable contributions of Markus Wimmer, Thomas Brown, Bridgette Furman, Mark Hurtig, J. Lawrence Marsh, and Thaddeus Thomas to this work. Portions of the work discussed in this manuscript were supported by the NIH (NIAMS AR39239, AR46601, AR48182, AR48852, AR48939, AR50245, AR55533, and NIA AG15768), NFL Charities, the Ciba-Geigy Endowed Chair of Biochemistry at Rush University, Dr. Jorge Galante’s fellowship, the Arthritis Foundation, the AO Foundation (Switzerland), OREF, the World Arthrosis Organization, Orthopaedic Trauma Association, and the VA.


Presented as a workshop at the 56th Annual Meeting of the ORS on March 9, 2010 in New Orleans, LA.


1. Saltzman CL, Zimmerman MB, O’Rourke M, et al. Impact of comorbidities on the measurement of health in patients with ankle osteoarthritis. J Bone Joint Surg Am. 2006;88:2366–2372. [PubMed]
2. Brown TD, Johnston JC, Saltzman CL, et al. Posttraumatic osteoarthritis: a first estimate of incidence, prevalence, and burden of disease. J Orthop Trauma. 2006;20:739–744. [PubMed]
3. Dirschl DR, Marsh JL, Buckwalter JA, et al. Articular fractures. J Am Acad Orthop Surg. 2004;12:416–423. [PubMed]
4. 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;133:321–328. [PubMed]
5. Gillquist J, Messner K. Anterior cruciate ligament reconstruction and the long-term incidence of gonarthrosis. Sports Med. 1999;27:143–156. [PubMed]
6. Roos H, Lauren M, Adalberth T, et al. Knee osteoarthritis after meniscectomy: prevalence of radiographic changes after twenty-one years, compared with matched controls. Arthritis Rheum. 1998;41:687–693. [PubMed]
7. Laird A, Keating JF. Acetabular fractures: a 16-year prospective epidemiological study. J Bone Joint Surg Br. 2005;87:969–973. [PubMed]
8. Weigel DP, Marsh JL. High-energy fractures of the tibial plateau. Knee function after longer follow-up. J Bone Joint Surg Am. 2002;84:1541–1551. [PubMed]
9. Marsh JL, Weigel DP, Dirschl DR. Tibial plafond fractures. How do these ankles function over time? J Bone Joint Surg Am. 2003;85:287–295. [PubMed]
10. Beecher BR, Martin JA, Pedersen DR, et al. Antioxidants block cyclic loading induced chondrocyte death. Iowa Orthop J. 2007;27:1–8. [PMC free article] [PubMed]
11. Martin JA, Buckwalter JA. Post-traumatic osteoarthritis: the role of stress induced chondrocyte damage. Biorheology. 2006;43:517–521. [PubMed]
12. Buckwalter JA. Articular cartilage injuries. Clin Orthop Relat Res. 2002;402:21–37. [PubMed]
13. Buckwalter JA, Brown TD. Joint injury, repair, and remodeling: roles in post-traumatic osteoarthritis. Clin Orthop Relat Res. 2004;423:7–16. [PubMed]
14. Buckwalter JA, Saltzman C, Brown T. The impact of osteoarthritis: implications for research. Clin Orthop Relat Res. 2004;427:S6–15. [PubMed]
15. Borrelli J, Jr, Tinsley K, Ricci WM, et al. Induction of chondrocyte apoptosis following impact load. J Orthop Trauma. 2003;17:635–641. [PubMed]
16. Borrelli J, Jr, Zhu Y, Burns M, et al. Cartilage tolerates single impact loads of as much as half the joint fracture threshold. Clin Orthop Relat Res. 2004;426:266–273. [PubMed]
17. Thompson RC, Jr, Oegema TR, Jr, Lewis JL, Wallace L. Osteoarthrotic changes after acute transarticular load. An animal model. Journal of Bone & Joint Surgery - American Volume. 1991;73:990–1001. [PubMed]
18. Tochigi Y, Buckwalter JA, Martin JA, et al. Distribution and progression of chondrocyte damage in a whole-organ model of human ankle intra-articular fracture. J Bone Joint Surg Am. 2011 (in Press) [PMC free article] [PubMed]
19. Llinas A, McKellop HA, Marshall GJ, et al. Healing and remodeling of articular incongruities in a rabbit fracture model. J Bone Joint Surg Am. 1993;75:1508–1523. [PubMed]
20. Mitchell N, Shepard N. Healing of articular cartilage in intra-articular fractures in rabbits. J Bone Joint Surg Am. 1980;62:628–634. [PubMed]
21. Trumble T, Verheyden J. Remodeling of articular defects in an animal model. Clin Orthop Relat Res. 2004;423:59–63. [PubMed]
22. Backus JD, Furman BD, Swimmer T, et al. Cartilage viability and catabolism in the intact porcine knee following transarticular impact loading with and without articular fracture. J Orthop Res. 2010 Nov 4; [Epub ahead of print] [PMC free article] [PubMed]
23. Furman BD, Strand J, Hembree WC, et al. Joint degeneration following closed intraarticular fracture in the mouse knee: a model of posttraumatic arthritis. J Orthop Res. 2007;25:578–592. [PubMed]
24. Olson SA, Connolly EA, Smith S, et al. Development of an animal model of acetabular fractures. Clin Orthop Relat Res. 2004;423:64–73. [PubMed]
25. Seifer DR, Furman BD, Guilak F, et al. Novel synovial fluid recovery method allows for quantification of a marker of arthritis in mice. Osteoarthritis Cartilage. 2008;16:1532–1538. [PMC free article] [PubMed]
26. Ward BD, Furman BD, Huebner JL, et al. Absence of posttraumatic arthritis following intraarticular fracture in the MRL/MpJ mouse. Arthritis Rheum. 2008;58:744–753. [PubMed]
27. Dirschl DR, Adams GL. A critical assessment of factors influencing reliability in the classification of fractures, using fractures of the tibial plafond as a model. J Orthop Trauma. 1997;11:471–476. [PubMed]
28. Jupiter JB. Complex Articular Fractures of the Distal Radius: Classification and Management. J Am Acad Orthop Surg. 1997;5:119–129. [PubMed]
29. Trumble TE, Culp RW, Hanel DP, et al. Intra-articular fractures of the distal aspect of the radius. Instr Course Lect. 1999;48:465–480. [PubMed]
30. Burstein D, Gray M. New MRI techniques for imaging cartilage. J Bone Joint Surg Am. 2003;85(Suppl 2):70–77. [PubMed]
31. Lohmander LS, Ionescu M, Jugessur H, Poole AR. Changes in joint cartilage aggrecan after knee injury and in osteoarthritis. Arthritis Rheum. 1999;42:534–544. [PubMed]
32. Carlson CS, Guilak F, Vail TP, et al. Synovial fluid biomarker levels predict articular cartilage damage following complete medial meniscectomy in the canine knee. J Orthop Res. 2002;20:92–100. [PubMed]
33. Beardsley C, Marsh JL, Brown T. Quantifying comminution as a measurement of severity of articular injury. Clin Orthop Relat Res. 2004;423:74–78. [PubMed]
34. Beardsley CL, Anderson DD, Marsh JL, Brown TD. Interfragmentary surface area as an index of comminution severity in cortical bone impact. J Orthop Res. 2005;23:686–690. [PMC free article] [PubMed]
35. Anderson DD, Mosqueda T, Thomas T, et al. Quantifying tibial plafond fracture severity: absorbed energy and fragment displacement agree with clinical rank ordering. J Orthop Res. 2008;26:1046–1052. [PMC free article] [PubMed]
36. Thomas TP, Anderson DD, Mosqueda TV, et al. Objective CT-based metrics of articular fracture severity to assess risk for posttraumatic osteoarthritis. J Orthop Trauma. 2010;24:764–769. [PMC free article] [PubMed]
37. Olson SA, Guilak F. From articular fracture to posttraumatic arthritis: a black box that needs to be opened. J Orthop Trauma. 2006;20:661–662. [PubMed]
38. Martin JA, McCabe D, Walter M, et al. N-acetylcysteine inhibits post-impact chondrocyte death in osteochondral explants. J Bone Joint Surg Am. 2009;91:1890–1897. [PMC free article] [PubMed]
39. Goodwin W, McCabe D, Sauter E, et al. Rotenone prevents impact-induced chondrocyte death. J Orthop Res. 2010;28:1057–1063. [PMC free article] [PubMed]
40. Ding L, Stroud NJ, McCabe D, et al. A single blunt impact to cartilage activates MAP kinases and NF-kappa-B radially from the impact zone within 24 hours. 55th Annual Meeting of the Orthopaedic Research Society. Paper#1085.2009.
41. D’Lima DD, Hashimoto S, Chen PC, et al. Prevention of chondrocyte apoptosis. J Bone Joint Surg Am. 2001;83(Suppl 2):25–26. [PubMed]
42. Green DM, Noble PC, Bocell JR, Jr, et al. Effect of early full weight-bearing after joint injury on inflammation and cartilage degradation. J Bone Joint Surg Am. 2006;88:2201–2209. [PubMed]
43. Guilak F, Fermor B, Keefe FJ, et al. The role of biomechanics and inflammation in cartilage injury and repair. Clin Orthop Relat Res. 2004;423:17–26. [PubMed]
44. Furman BD, Olson SA, Guilak F. The development of posttraumatic arthritis after articular fracture. J Orthop Trauma. 2006;20:719–725. [PubMed]
45. Clark LD, Clark RK, Heber-Katz E. A new murine model for mammalian wound repair and regeneration. Clin Immunol Immunopathol. 1998;88:35–45. [PubMed]
46. Fitzgerald J, Rich C, Burkhardt D, et al. Evidence for articular cartilage regeneration in MRL/MpJ mice. Osteoarthritis Cartilage. 2008;16:1319–1326. [PubMed]
47. Kench JA, Russell DM, Fadok VA, et al. Aberrant wound healing and TGF-beta production in the autoimmune-prone MRL/+ mouse. Clin Immunol. 1999;92:300–310. [PubMed]
48. Furman BD, Huebner JL, Seifer DR, et al. MRL/MpJ mouse shows reduced intra-articular and systemic inflammation following articular fracture. 55th Annual Meeting of the Orthopaedic Research Society. Paper#; 2009. p. 1120.
49. Pelletier JP, Martel-Pelletier J. DMOAD developments: present and future. Bull NYU Hosp Jt Dis. 2007;65:242–248. [PubMed]
50. Hellio Le Graverand-Gastineau MP. OA clinical trials: current targets and trials for OA. Choosing molecular targets: what have we learned and where we are headed? Osteoarthritis Cartilage. 2009;17:1393–1401. [PubMed]
51. Rundell SA, Baars DC, Phillips DM, Haut RC. The limitation of acute necrosis in retro-patellar cartilage after severe blunt impact to the in vivo rabbit patello-femoral joint. J Orthop Res. 2005;23:1363–1369. [PubMed]
52. Ramakrishnan P, Hecht BA, Pedersen DR, et al. Oxidant conditioning protects cartilage from mechanically induced damage. J Orthop Res. 2010;28:914–920. [PMC free article] [PubMed]
53. Ding L, Heying E, Nicholson N, et al. Mechanical impact induces cartilage degradation via mitogen activated protein kinases. Osteoarthritis Cartilage. 2010;18:1509–1517. [PMC free article] [PubMed]
54. Chubinskaya S, Hurtig M, Rueger DC. OP-1/BMP-7 in cartilage repair. Int Orthop. 2007;31:773–781. [PMC free article] [PubMed]
55. Chubinskaya S, Kawakami M, Rappoport L, et al. Anti-catabolic effect of OP-1 in chronically compressed intervertebral discs. J Orthop Res. 2007;25:517–530. [PubMed]
56. Hurtig M, Chubinskaya S, Dickey J, Rueger D. BMP-7 protects against progression of cartilage degeneration after impact injury. J Orthop Res. 2009;27:602–611. [PubMed]
57. Pascual Garrido C, Hakimiyan AA, Rappoport L, et al. Anti-apoptotic treatments prevent cartilage degradation after acute trauma to human ankle cartilage. Osteoarthritis Cartilage. 2009;17:1244–1251. [PMC free article] [PubMed]
58. Bajaj S, Shoemaker T, Hakimiyan AA, et al. Protective effect of P188 in the model of acute trauma to human ankle cartilage: the mechanism of action. J Orthop Trauma. 2010;24:571–576. [PMC free article] [PubMed]
59. Lewis JL, Deloria LB, Oyen-Tiesma M, et al. Cell death after cartilage impact occurs around matrix cracks. J Orthop Res. 2003;21:881–887. [PubMed]
60. Oegema TR, Jr, Lewis JL, Thompson RC., Jr Role of acute trauma in development of osteoarthritis. Agents Actions. 1993;40:220–223. [PubMed]
61. Thompson RC, Jr, Vener MJ, Griffiths HJ, et al. Scanning electron-microscopic and magnetic resonance-imaging studies of injuries to the patellofemoral joint after acute transarticular loading. J Bone Joint Surg Am. 1993;75:704–713. [PubMed]
62. Natoli RM, Athanasiou KA. P188 reduces cell death and IGF-I reduces GAG release following single-impact loading of articular cartilage. J Biomech Eng. 2008;130:041012. [PubMed]
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