Dance Between Biology, Mechanics, and Structure: A Systems-Based Approach to Developing Osteoarthritis Prevention Strategies

Abstract

Osteoarthritis (OA) is a leading cause of human suffering and disability for which disease-modifying treatments are lacking. OA occurs through complex and dynamic interplays between diverse factors over long periods of time. The traditional research and clinical focus on OA, the end stage disease, obscured understanding pathogenesis prior to reaching a common pathway defined by pain and functional deficits, joint deformity, and radiographic changes. To emphasize disease modification and prevention, we describe a multi-disciplinary systems-based approach encompassing biology, mechanics, and structure to define pre-osteoarthritic disease processes. Central to application of this model is the concept of “pre-osteoarthritis,” conditions where clinical OA has not yet developed. Rather, joint homeostasis has been compromised and there are potentially reversible markers for heightened OA risk. Key messages from this perspective are (i) to focus research onto defining pre-OA through identifying and validating biological, mechanical, and imaging markers of OA risk, (ii) to emphasize multi-disciplinary approaches, and (iii) to propose that developing personalized interventions to address reversible markers of OA risk in healthy joints may be the key to prevention. Ultimately, a systems-based analysis of OA pathogenesis shows potential to transform clinical practice by facilitating development and testing of new strategies to prevent or delay the onset of osteoarthritis.

INTRODUCTION

Osteoarthritis is an ancient disease that is evident in reptilian skeletons from the Mesozoic era,¹ and that is known to be a specific malady of paleolithic man.² While human and humanoid skeletons through the millennia show evidence for osteoarthritis, disease pathogenesis remains an enigma because it occurs through a complex interplay between diverse factors over long periods. Consequently, osteoarthritis continues to be one of the most common and disabling afflictions affecting modern man for which disease-modifying treatments are lacking.

The scientific method where new knowledge is obtained through objective evaluation of a testable hypothesis that then informs future experiments has transformed modern medicine. This level of rigor is easiest to obtain in highly controlled situations where a single phenomenon of interest can be isolated and repeatedly evaluated. Osteoarthritis, however, does not originate from a single faction such as an aberrant gene, and it is not the same disease process in all cases. Rather, it is an end-stage disease representing a common final pathway for a disease process that may be unique to each individual. As such, augmenting reductionist approaches with systems-based approaches will be critical to understanding the pathogenesis of osteoarthritis, a multi-factorial disease process with a long time frame of onset.

Given the dynamic interplay between multiple factors in human OA development, we propose adoption of a multi-disciplinary systems-based approach³ to translational and clinical research in delineating pre-osteoarthritic states. Central to application of this model is the concept of “pre-osteoarthritis,” conditions where there is heightened OA risk but where clinical disease has not yet developed.⁴ Rather then evaluating markers for OA, the focus on pre-OA involves identifying and validating biological, mechanical, and imaging markers of OA risk. The basic premises behind this approach are that (i) joint health depends upon the interplay over time between three broad categories of factors: Biology, Mechanics, and Structure (Fig. 1a), and that (ii) these factors do not generate or prevent disease in isolation. Rather, a continuously shifting balance of these factors over time ultimately determines whether joint health is maintained or whether the joint shifts into high-risk pre-osteoarthritic states and ultimately to irreversible clinical osteoarthritis (Fig. 1b).

Figure 1.

The Slot Machine System metaphor for joint health illustrates the role of OA risk in defining pre-osteoarthritis. (a) A system with “No Risk Factors” has a high probability of maintaining a “Healthy Joint” in response to “Activity” over time since the Biological, Mechanical, and Structural components of the system consistently fall within a large “Homeostasis Envelope.” (b) If the System includes a “Risk Factor” for OA (e.g., intra-articular fracture) where one of the system components (e.g., “biology” due to aging) moves out of the healthy envelope into an early disease state, this is accompanied by a reduction in the overall homeostasis envelope. This constitutes “pre-osteoarthritis” where the probability of maintaining joint health with activity over time is reduced both because one component is already out of homeostasis and because the envelope itself has shrunk.

The Biological Component includes factors that influence cell metabolism, levels of systemic inflammation and genetic etiologies.⁵ The Mechanical Component includes any factor that delivers a mechanical stimulus to the cell and spans the spectrum from the whole body (mechanics of ambulation) to the level of the local mechanical cell environment. The Structural Component includes factors that include joint alignment, bony change, cartilage morphology, and ligament properties. The absolute and relative health of these components determines a zone or envelope of homeostasis based on load verses frequency of loading of a certain shape, classically described by Dye in “the knee as a biologic transmission with an envelope of function.”⁶ Thus, the model implies that healthy joint homeostasis is maintained when each of the components operates within normal ranges.

Given the complexity of the system, the overall behavior cannot be uniquely defined. However, the probability of how the system will respond⁷ can be described using the metaphor of a “slot machine” where the potential for the system yielding a healthy response to activity depends on the Biological, Mechanical, and Structural components aligning within an envelope of a band that expands or contracts based on the interplay of these components within the joint. The slot machine metaphor both emphasizes the randomness of the system as well as its “responsiveness” to factors that are known to increase OA risk such as aging and joint trauma. While the specific output after each crank or push of the “play” button is based on a random generation of numbers or symbols, slot machines are programmed to pay a set percentage of winnings, known as the return to player, with the house keeping the remainder. The stochastic nature of the individual outputs reflect the random factors impacting each of the components (Biological, Mechanical, and Structural) that influence the development of OA. Meanwhile, the payout percentage, which is predetermined yet modifiable, reflects OA risk. These factors are dynamic, continuously shifting within an envelope of homeostasis in response to activity over time in a manner that typically maintains joint health (Fig. 1a). For example, employing the slot machine metaphor, a 20 years old healthy woman of normal weight with a family history of OA may be playing a machine programmed with an OA “payout” or risk of 5% that slowly increases over time to 50% at age 65. If she sustains a joint injury, the machine is reprogrammed to increase its OA “payout” or risk to 50% by age 30. Specifically, the envelope of healthy homeostasis is reduced and with at least one of the components (e.g., mechanics) now out of the range of homeostasis, a high-risk pre-osteoarthritic state ensues (Fig. 1b), that if not addressed, can progress to clinical osteoarthritis.

The traditional focus on OA, the end-stage disease, has obscured understanding disease pathogenesis prior to reaching a common pathway delineated by radiographic changes, joint deformity, pain, and functional deficits. To illustrate the power of this new approach in delineating potentially modifiable early events in OA pathogenesis, this article will discuss its application towards evaluating three conditions representing progressively earlier stages in potential OA disease development. These conditions are (i) Aging, where pre-OA and OA changes are prevalent, (ii) Anterior Cruciate Ligament (ACL) Injury, where individuals do not have OA but knee OA risk is elevated and disease modification through risk management may be achievable, and (iii) High Heel shoe wear, where kinematic changes associated with pre-OA and OA of the knee are immediately reversible by removing the heels. A systems-based approach illustrates that there are early markers of impending OA disease that appear well before disease onset, and that may even represent a potential disease initiating stimulus. Conversely, if the marker can be reversed through early treatment, then clinical OA may be delayed or even prevented. Knee flexion angle at heel strike (KFA_HS) in gait analysis may be one example of such a marker (Fig. 2).

Figure 2.

Alteration of Knee Flexion Angle at Heel Strike as a mechanical marker of OA risk. (a) Compared to young, healthy subjects, knee flexion during the heel strike phase of walking is increased in older subjects and in patients with knee OA.⁸ Knee flexion at heel strike is also increased compared to the contralateral side in patients after ACLR, and associated clinically with premature OA.⁹ Wearing high heels results in a similar increase in knee flexion at heel strike compared to the same person wearing flat shoes indicating complete reversibility in this group.¹⁰ The system metaphor (Fig. 1) helps to place the use and evaluation of a potential intervention in context. (b) In younger subjects the mechanical component (knee flexion) appears to be a promising target for intervention. (c) In older subjects there are biological changes that also need to be considered in assessing the effectiveness of potential interventions.

A popular view of Neanderthal man was that he walked with a crouched, bent knee posture. Subsequent analysis has shown that the reference specimen was from an older individual suffering from osteoarthritis, and that healthy Neanderthals walked upright.² In humans, those with established knee OA show a bent knee gait that translates into a measurable increase in KFA_HS. Of interest to the current discussion, gait analysis shows that KFA_HS is also increased in older individuals,⁸ in ACL injured subjects,⁹ and in healthy women after donning a pair of high heels¹⁰ (Fig. 2). Because both aging and ACL tear are known to substantially increase OA risk,^11–17 the increase in KFA_HS may be a potential mechanical marker for “pre-OA.”⁹ High heel wear has not been shown to increase OA risk, yet there is a similar alteration to gait mechanics to that of high OA risk and OA groups.¹³ In this discussion, we will show that while the mechanical marker is similar, the disease states are diverse, and the constellation of factors likely contributing to pathogenesis differs. As such, appropriate intervention strategies will also need to be tailored to each situation.

AGING

Aging is a key risk factor for OA and provides an excellent example of the stochastic and multi-factorial nature of OA development as only about half of individuals aged 45–75 develop clinical OA.¹⁵ The fact that many of the biological changes with aging can influence conditions such as neuromuscular changes or ligament and joint properties can confound isolating the nature of the pathway to OA associated with aging. As such, the majority of clinically diagnosed OA is idiopathic OA associated with “wear and tear” over time. It is this category of OA that exemplifies the need for a systems-based approach to understanding pathogenesis in order to tailor early interventions. Just as the aging process occurs as a continuum over time, so too, does the progression of the joint from healthy, to reversible pre-osteoarthritis, to early potentially modifiable disease, and then onto the classically described irreversible OA. The lines of demarcation are ill defined. In addition, disease progression as well as the relative weights of biology, mechanics, and structure varies between individuals, and within the same individual over time.

The biology of aging is complex, not well defined, and affects the joint tissues both directly and indirectly.^18,19 With age, chondrocytes decline both in absolute numbers and in the vigor and responsiveness of the remaining cells to mechanical and other external stimuli. The cartilage matrix stiffens with greater cross-linking between collagen fibrils which impede fluid flow and alter the critical dynamic between the collagen network and proteoglycans that afford articular cartilage it’s sophisticated functional properties. As such, the ability of even intact articular cartilage to mount an anabolic reparative response adequate enough to address tissue challenges resulting from activities of daily living decline. This results in a joint that has a reduced homeostatic envelope(Fig. 1b).⁶ When this occurs, the joint has lower reserve to deal with conditions of normal loading, much less added stress from other biological reasons such as increased inflammation, mechanical reasons such as altered gait mechanics, or structural reasons such as cartilage matrix changes in proteoglycan and collagen composition.

These seemingly diverse aberrations to biology, mechanics, and structure are interrelated and code-pendent. For example, altered gait mechanics of increased KFA_HS could be due to decreasing neuromuscular competence resulting from an aging nervous system, it could be due to joint contracture from prior injury or surgery, it could be due to chronic effusion from inflammation, or it could be due to other biological, structural, or combinations of reasons. At some point, the articular cartilage succumbs to this constellation of factors, breaks open, and begins to wear away. This process in turn triggers and aggravates biological responses of inflammation and ineffectual repair that further degrade structure and compromise mechanics. A downward vicious cycle progressing over time (typically measured in years if not decades) results in a clinical OA where it is virtually impossible to isolate cause and effect, or to divine an effective therapeutic strategy. This describes the challenges in studying established OA. We therefore propose that a systems-based approach be applied toward the study of populations with healthier joints that ideally have a modifiable and predominating OA risk factor. In other words, this model offers more clarity when applied to the “pre-osteoarthritic” joint and to evaluation of OA risk in normal joints.

PRE-OA AFTER ACL TEAR—AN OPPORTUNITY FOR DISEASE MODIFICATION?

Joint injuries result in numerous and varied changes to the mechanical, biological, and structural integrity of diarthrodial joints giving rise to a “pre-osteoarthritic” disease state. Post-traumatic osteoarthritis has been associated most strongly with intra-articular fractures. In this setting, there are immediate and substantial disruptions to the articular cartilage and the subchondral bone from the energy of the fracture itself.²⁰ Absent healing of the boney surfaces of the joint and the adjacent bone in anatomic alignment along with full neuromuscular recovery, joint mechanics are also permanently disrupted. Finally, bleeding and trauma incite an inflammatory response that further disrupts the biology of chondrocytes surviving the initial injury.^20,21 A systems-based analysis would show some degree of irreversible alteration of joint mechanics and cartilage structure in most cases involving intra-articular fracture. The initial inflammatory response appears to be transient although chondrocyte loss would have irreversible effects. With all components of the system altered to pre-OA levels, the ensuing osteoarthritis is highly progressive affecting the majority of patients within a decade.²² As further testimony to the multi-factorial processes in place, more rapid progression to OA has been observed with higher energy injuries where greater negative effects on mechanics, biology, and structure occur and in older joints where cellular senescence and neuromuscular decline reduce biological and mechanical reserve.^19,20,23,24 Currently, the modifiable elements involve operative restoration of joint contact surfaces as close to anatomic as possible, neuromuscular reconditioning, and biological therapies to temper inflammation and reduce chondrocyte loss. Several recent pre-clinical studies show promising results employing biological strategies to modulate inflammation and preserve chondrocyte health. These biological strategies will likely be most effective in lower energy and simpler injuries where the mechanical and structural insults are smaller.

The events following joint injuries that are less disturbing to all elements of the system than intra-articular fracture may present greater opportunities for disease modification. ACL tears are common knee injuries where studies show roughly half of afflicted persons develop OA approximately a decade later.¹⁷ While the data are sobering, reasons why the other half do not developed clinical OA within the same time frame may offer clues to disease modification. ACL injury occurs predominantly in young and healthy individuals who typically had no pre-existing significant medical or joint diseases prior to the injury.¹⁶ The injury is common in active and athletic people. Thus the biology, mechanics, and structure within the affected knee prior to injury for these patients were likely healthier than the population in general. After ACL tear, the biology is altered by an initial hemarthrosis and a marked inflammatory response that appears to resolve in many patients but not all.^25,26 Structurally, the articular cartilage remains essentially intact. As such, the most dramatic and consistent joint changes in the ACL deficient knee may be in the area of mechanics (Fig. 3a).

Figure 3.

The ACL Injured Knee shows strong potential for disease modification. (a) This is due to the relatively mild and potentially reversible deficits to biology, mechanics, and structure. The biological insult is mostly transient. Structurally, the articular cartilage generally appears grossly intact at the time of ACL surgery albeit with subsurface matrix injuries that new data shows may heal over time (Fig. 4).¹⁶ (b) Joint mechanics is altered and inconsistently restored after ACLR. As previously reported,³⁰ a more vertical orientation of the graft (dotted circle) is associated with a shift in the averaged tibial-femoral rotation outside of the normal range during walking while a more anatomic placement (solid circle) better restores knee kinematics. The system metaphor (Fig. 3a) suggests that improved restoration of mechanical markers after ACL injury may be a promising target for disease modification.

Kinematic changes at the knee after ACL injury have been implicated²⁷ as a factor in the cause of premature OA. Specifically, rotational kinematic changes have been reported^27–30 following ACL injury. These changes appear to be consistent with loss of ACL function where the rotational offset due to the normal “screw home” (external tibial rotation with knee extension) does not occur at the end of swing phase during walking in an ACL deficient knee. After ACL reconstruction, alterations in rotational motion of the knee frequently remain, with the tibia now tending to be more externally rotated throughout the stance phase of the walking cycle.³⁰ When analyzed in relation to graft orientation, the data from this study showed that the rotational offset appears related to a non-anatomic reconstruction (Fig. 3b). Similarly, differences in knee flexion at heel strike were also found⁹ in patients following ACL surgery where the reconstructed knee was more flexed than the healthy contralateral knee. While the reasons for decreased extension at heel strike were unknown, the side-to-side differences in knee extension reported in that study⁹ have been observed by others.³¹ Pertinent to this discussion, clinical studies show patients with extension deficits after ACL reconstruction developed significant joint space narrowing at 10–14 years after reconstruction.³¹

It would be difficult to interpret the relevance of the above observations without taking a systems view of the issue. Specifically, combining the kinematic changes with studies that show the morphological^8,32 and biological variation in articular cartilage suggest that if the kinematic changes are sufficient to move repetitive contact during walking to a new region of cartilage not conditioned for the new loading condition, then cartilage degradation can occur. These mechanical and structural changes constitute pre-OA that if not addressed early at reversible stages, can lead to clinical OA.

The concept of reversibility deserves further discussion. Biological states such as conditions of high inflammation can be reversed with therapies that reduce inflammation such as rest, ice, and a variety of anti-inflammatory medications. Some biological changes such as cellular senescence are not as well understood and therefore not currently considered reversible. Mechanical changes and deficits are generally considered to be reversible in many situations through neuromuscular training or surgery. While the goals of ACL reconstruction have been to reduce clinical instability and to restore joint kinematics, prior reconstruction techniques have not consistently returned joint kinematics to pre-injury levels.^30,33 Newer techniques of anatomic ACL reconstruction show promise in more closely restoring joint mechanics than nonanatomic techniques.³⁴ Thus, mechanical aberrations after ACL injury are considered modifiable to varying degrees depending on cause and severity. In contrast, structural changes to articular cartilage have generally been considered irreversible due to the notoriously poor healing potential of the tissue. However, new data in ACL injured subjects show there may also be a potential for structural reversibility of subsurface injuries to articular cartilage in settings where the biology and the mechanics are favorable.²¹

Injuries to articular cartilage after ACL injury are frequently subtle and difficult to ascertain by conventional clinical measures. By radiographic exam, structural MRI, and arthroscopy, the articular cartilage to the medial compartment typically appears intact at the time of ACL surgery. New, quantitative MRI techniques of T1rho and ultrashort echo-time enhanced (UTE) T2* mapping show signal abnormalities to the articular cartilage and menisci acutely after ACL injury.^21,35,36 The most consistent area of cartilage damage after ACL injury has been to the lateral compartment where a histopathological study and MRI studies show incident and persistent cartilage damage especially in areas overlying bone bruising and impaction injury to subchondral bone.^37,38 Yet, medial compartment OA is more widely seen in the post ACL injured knee,^38,39 suggesting that factors other than these acute structural changes impact more heavily on disease progression. Putting it together, the post-ACL injured knee can be considered to show a transient and relatively mild change to biology, a measurable alteration to mechanics, and a subtle change to cartilage structure requiring advanced imaging to uncover (Fig. 3b).

Analysis of this systems model would suggest that restoration of mechanics after ACL injury should reduce OA risk (Fig. 3b). The most direct effect would be on altered mechanics that would ameliorate generation of biological changes such as persistent inflammation from instability and eventual cartilage breakdown from altered contact pressures, inflammation, and instability. Loss of joint homeostasis is also reflected in the subchondral and metaphaseal bone.⁴⁰ Excess metabolic activity in pre-osteoarthritic and osteoarthritic joints after ACL injury has been demonstrated using Tc99m-MDP bone scan.^12,41,42 Dye’s work showing restoration of osseous homeostasis without the development of OA after ACL injury additionally supports potential use of Tc scintigraphy as a marker of joint homeostasis.⁴² Significantly, Daniel showed that decreasing functional demands across ACL injured knees was associated with improved bone scans and less osteoarthritis compared to ACL reconstructed subjects who returned to high demand sports.¹² The majority of studies to date have not, however, shown that reconstruction of the ACL reduces the incidence or rapidity of OA after ACL injury.¹² More recent work shows that commonly used methods of ACL reconstruction have not restored joint mechanics.⁹

In the past decade, studies of joint kinematics on more anatomic ACL reconstructions show that these newer techniques approximate normal joint mechanics more closely than less anatomic reconstructions.^34,43 A recent study using UTE-T2* mapping show signal elevations to the deep tissue of the medial femoral condylar articular cartilage and the posterior horn of the medial menisci appearing uninjured with conventional MRI and arthroscopy^21,36 that could be considered to represent signs of subsurface tissue “bruising.” Two years after anatomic ACL reconstruction, the UTE signal was similar to that of uninjured controls consistent with healing. This effect predominated in those with isolated ACL tears. Combined ACL and meniscus tears are common and affect approximately half of ACL injured patients.^16,44 The impact of meniscus tear on subsequent development of OA is high.⁴⁵ As such, meniscal tear can be considered an additional structural risk factor to be addressed with meniscus preservation where possible. While additional studies are needed, these studies support our hypothesis that identifying and addressing the predominant factor(s) perturbing the system may yield effective strategies to restore joint homeostasis and prevent or delay OA development.

GAIT ALTERATIONS AND HIGH HEELED SHOES—AN OPPORTUNITY FOR PREVENTION?

Prevention of OA relates to taking measures to maintain joint health. While ACL injured subjects represent a pre-OA group that had a healthy joint prior to the index knee injury, the injury status and associated factors negatively affecting joint homeostasis cannot be at present considered entirely reversible. Thus successful interventions for this group mainly serve to delay OA onset in a compromised joint as opposed to preventing disease onset in a healthy joint. If groups can be identified with healthy joints and completely reversible potential risk factors, then true prevention of OA may be achievable.

Walking confers functional mobility and is a key activity of daily living. Shoes have been shown to modify forces across the knee joint. Studies have shown that the adduction moment is increased in those who suffer from painful medial knee OA.^46,47 More recently, it has been shown that consistent wear of a variable stiffness shoe that is stiffer to the lateral aspect of the foot reduces both the adduction moment and symptoms of pain in human subjects with medial knee OA.⁴⁸ This study showing both a reduction in pain and in adduction moment suggests that load-modifying shoes may have disease-modifying effects if applied early enough in the disease process. Conversely, shoes that increase forces across the knee associated with OA may increase OA risk and accelerate OA development in those who already suffer from early disease.

Shoes with high heels were not originally intended for walking. They were first introduced to Europe in the 16th century by Persian warriors who wore heels to improve stirrup contact in order to fight better on horseback.⁴⁹ Intrigued, European royalty, such as the diminutive French King Louis the XIV, adopted the look. The practice soon spread to privileged upper class males who did not have to walk far or navigate the muddy streets of 17th century Europe, and then to upper class women. While heels fell out of favor after the French Revolution, they reappeared in women’s fashion in the mid-19th century. Today, it is estimated that more than 70% of women wear high heels, with nearly 40% wearing heels daily.⁵⁰ In contrast to horse-men and nobility, many women today walk, stand, and work for extended periods of time wearing high-heeled shoes.

Women are nearly twice as likely to suffer from knee OA then men, especially after age 50.⁵¹ Studies show that wearing high heels alters walking mechanics. While men and women showed similar knee biomechanics during barefoot walking,⁵² increased knee flexion in early stance similar to what has been observed in early OA has been observed^53,54 (Fig. 2). We have further shown that an increase in knee adduction moment occurs with increasing heel height.¹⁰ Because higher peak knee adduction moments have been associated with medial compartment OA progression, these data suggest an intriguing question: Does frequent and extensive walking in high heels increase OA risk over time? Unlike in aging or after ACL injury, the observed changes to gait mechanics in women with healthy knees is due solely to high heel shoe wear and reverses immediately upon transition to an athletic shoe.¹⁰ As such, current rates of high heel wear in women potentially offers us a unique opportunity to evaluate the effects of both positive and negative changes to gait mechanics on OA risk in healthy female cohorts.

Application of the systems model clarifies that joint biology, gait mechanics, and cartilage structure are likely to be normal in young, healthy, and normal weight women without a history of knee injury. When the same woman walks in high-heeled shoes, the gait alterations are similar to what has been observed in those with knee OA or with elevated risk of knee OA (Fig. 2). While this altered gait may remain within the zone of homeostasis for the knee if the subject does not need to walk far, she may experience a transient increase in OA risk with longer periods and greater distances spent walking in heels. With habitual walking in high heels over several years, the prospect that the mechanical change may initiate or aggravate an OA disease process increases. This is especially likely if a second factor such as exacerbation of mechanical perturbation with weight gain, biological changes of perimenopause, or a structural change from joint injury enters into play. These factors may collaborate to shrink the zone of homeostasis rendering the joint more vulnerable to even shorter periods of high heel wear.

Because the mechanical changes during gait are reversible by wearing flat or low-heeled shoes, the systems model clarifies that choosing not to wear high heels may be one potential true preventive treatment strategy in the young and healthy group. In the group with an additional risk factor, the same choice may reduce OA risk. In addition, if a modifiable secondary reason such as weight gain is also addressed, the systems model helps to potentially clarify a personalized preventive treatment plan to delay or prevent OA onset. While these scenarios are hypothetical, they illustrate the power a multi-disciplinary systems model in guiding the approach to studying and defining biological, mechanical, and structural markers for pre-OA that can then be translated into development of preventive and disease-modifying therapies.

CONCLUSIONS

The parable of the blind men, each touching a different part of an elephant and disagreeing on the descriptions illustrates the difficulty in accounting for the whole truth when evaluating complex, multi-faceted, and multi-dimensional entities such as osteoarthritis. In order to make new headway toward solving this age-old problem, acceptance and promotion of collaborative and holistic approaches to research in this area are critical. Central to application of this model is the concept of studying “pre-osteoarthritis” and conditions of altered joint homeostasis where measurable changes in each of these categories toward a higher OA risk category are defined early enough in the disease process that the pathological changes remain potentially reversible.⁴ Loss of joint homeostasis can occur in a variety of metabolically active tissues at the same time, and concurrently within the same joint. Besides standard and quantitative MRI and bone scans, other metabolic/molecular imaging techniques as well as biochemical, mechanical, and genetic biomarkers under development may prove helpful in defining loss and resolution of tissue/ joint homeostasis. This systems-based analysis may show likely therapeutic targets where one or more factors predominate, or assist in formulation of an effective multi-disciplinary approach to preventive therapy that is tailored to the needs of the individual patient. Finally, changes in any of the categories perturb the system as a whole to where positive or negative effects on OA disease progression may be synergistic and exceed the expected sum of the individual components. Ultimately, the goal is development of effective personalized OA risk management strategies to delay or prevent the onset of clinical osteoarthritis.

Figure 4.

Novel UTE-T2* mapping shows subsurface meniscus and articular cartilage structural changes due to injury that cannot be seen with conventional magnetic resonance imaging (reproduced from²¹). Left: UTE-T2* maps of the articular cartilage deep tissue (A, arrows) and meniscus (B) of a human subject after ACL tear, show a mottled pattern and higher UTE values than that seen in the uninjured control. Right: UTE-T2* maps of the articular cartilage (C, arrows) and meniscus (D) of the same subject two years after anatomic anterior cruciate ligament reconstruction, show return of the laminar pattern with lower UTE values (mapped to red), comparable to the uninjured control (Meniscal images shown in B and D were reproduced from¹⁶).