Mechanical Considerations in KOA and PTOA Pathogenesis

Mechanical Considerations in KOA and PTOA Pathogenesis: History

Please note this is an old version of this entry, which may differ significantly from the current revision.

Subjects: Orthopedics

Contributor:

Quinn T. Ehlen

Knee osteoarthritis (KOA) represents a prevalent and formidable challenge in the management and treatment of musculoskeletal disorders and exerts a substantial impact on global health, particularly in the context of the natural aging process. Post-traumatic osteoarthritis (PTOA) emerges as a distinct clinical manifestation within the realm of osteoarthritis and is interwoven within the landscape of sports injuries and trauma of the joints. Within the realm of sports, athletes are frequently exposed to joint injury and acute mechanical loading that sets the biological stage for the development of PTOA.

osteoarthritis
post-traumatic osteoarthritis
mechanical loading

1. Introduction

1.1. Knee Osteoarthritis

Knee osteoarthritis (KOA) represents a prevalent and formidable challenge in the management and treatment of musculoskeletal disorders and exerts a substantial impact on global health, particularly in the context of the natural aging process. The epidemiological footprint of KOA is extensive, as it emerges as one of the most common joint disorders worldwide, with models estimating a global prevalence of nearly 365 million affected individuals, with roughly 14 million of these in the United States alone [1,2]. Several studies have also noted the marked increase of KOA prevalence in elderly patients [3,4,5,6], which emphasizes the growing impact of this disease on aging individuals. The emergence of an increasingly at-risk population in terms of lifestyle, obesity, and age greatly contributes to the urgency of addressing osteoarthritis (OA) as a public health concern that demands a comprehensive foundational understanding in order to develop effective prevention and treatment strategies.

The pathophysiology of KOA highlights its degenerative nature and encompasses many intricate structural and biochemical changes within knee joints. Central to KOA is the progressive breakdown of articular cartilage in the joint over time, which normally provides cushioning and a mechanical buffer between the ends of the tibia and femur [7,8]. This process is amplified by alterations within the subchondral bone, which involves sclerosis and the formation of osteophytes [9]. Additionally, synovial inflammation further contributes to joint degradation [10]. Collectively, these pathological changes lead to the clinical manifestations of KOA, which are observed in a spectrum of symptoms that significantly impact affected individuals. Of these, knee pain, often worsened by movement, stands as a cardinal feature. Stiffness, usually after periods of inactivity, and a gradual reduction in the range of motion also contribute to the clinical presentation [11]. Importantly, these symptoms do not only affect physical well-being, but also pose a profound risk to an affected individual’s quality of life.

Various risk factors contribute to the development of KOA, which demonstrates the complexity of its etiology. Age emerges as a significant factor, with the incidence of KOA rising with advancing age [3,4,5,6]. Genetic predispositions also play a significant role in the progression of KOA, as twin studies have suggested a heritability of 50% or more [12,13]. Additionally, likely of greatest importance are mechanical factors, such as obesity, abnormal joint biomechanics or a history of traumatic injury, which impose a significant burden on joints and escalate the risk of KOA progression [14,15,16,17,18,19,20,21,22]. Furthermore, occupational stress, such as those incurred in physically demanding professions, has been demonstrated to increase the likelihood of OA development via wear and tear [23,24,25]. Thus, recognizing and mitigating these mechanical risk factors is integral to both preventative measures and the creation of personalized therapeutic approaches.

1.2. Post-Traumatic Osteoarthritis

Post-traumatic osteoarthritis (PTOA) emerges as a distinct clinical manifestation within the realm of osteoarthritis and is interwoven within the landscape of sports injuries and trauma of the joints. Within the realm of sports, athletes are frequently exposed to joint injury and acute mechanical loading that sets the biological stage for the development of PTOA [26,27,28]. The incidence of PTOA manifests across a wide spectrum of traumas, with a noted tenfold increase in likelihood of KOA following ligamentous or meniscal injuries [29,30]. However, there is considerable variability in the severity of PTOA observed, likely influenced by factors including the type of motion and loading stress applied, which is a primary focus of our discussion [31]. The nature of these injuries, often incurred during high-impact athletic activities, presents a unique challenge in the trajectory of PTOA development. The heightened forces and mechanical loading experienced during sports-related joint injuries contribute to a distinct pathophysiological profile of PTOA acutely, distinguishable radiologically [32], which differentiates it from primary KOA [33]. Trauma, as the primary instigator, sets in motion a series of events that alter joint mechanics and provoke long-term degenerative change [34]. Understanding the specific impact of sports-related injury and trauma on the disruption of joint health is paramount in unraveling the intricacies of PTOA development. It is still unknown how the field can use information about the inciting injury as a prognostic factor for PTOA severity.

The consequences of KOA and PTOA alike permeate beyond affected individuals alone, and greatly impact an aging, at-risk society. The impact on quality of life is profound, as influences on daily routines, recreational activities, and well-being have been observed within populations of OA patients [35]. Moreover, the socioeconomic burden associated with OA within the United States is substantial, accounting for roughly 1–2.5% of the gross national product, which encompasses healthcare costs, losses in productivity, and the strain on social support systems [36].

2. Mechanotransduction

The knee joint, in its healthy state, functions as a hinge joint, which enables vital movements like flexion and extension through the interaction of articular cartilage, synovial fluid, ligaments, and menisci that allow for smooth and continuous motion of the joint. Articular cartilage, the resilient tissue covering the ends of bones, distributes mechanical forces in order to promote frictionless movement. Ligaments provide stability, while the synovial fluid lubricates and nourishes the joint. Together, these components synergize to coordinate the typical physiological processes within the knee joint that allow for seamless motion and weight-bearing activities.

In the intricate milieu of KOA, the role of mechanical loading arises as a pivotal determinant in both the pathogenesis and recovery of the knee joint and is intricately linked to mechanotransduction processes. Mechanotransduction, described as the conversion of mechanical signals into biochemical responses, is paramount to understanding how mechanical loading influences the fate of articular cartilage. In the context of this review, it is critical to note that KOA pathogenesis is deeply involved with aberrations in mechanical loading, which disrupt the delicate balance of loading force required to maintain joint health. In the widely accepted pathological scenario [40,41,42,43,44,45], supramaximal mechanical forces act as a “trigger” for maladaptive responses in chondrocytes, the cells within articular cartilage [46]. Research conducted by Buckwalter and colleagues sheds light on the intricate relationship between mechanical loading and articular cartilage fate [46]. Their research emphasizes that both acute impact events and cumulative contact stress initiate the release of reactive oxygen species from mitochondria, leading to chondrocyte death and matrix degradation. Importantly, the study illuminates a substantial difference between PTOA primarily caused by acute intense joint injury and OA resulting from chronic joint instability or incongruity. Furthermore, the study describes the capacity of joints with advanced PTOA to remodel and improve with appropriate treatment, emphasizing the dynamic nature of the mechanotransduction processes involved in joint health and repair.

There is ample evidence in support of Buckwalter’s research [44,47,48,49,50,51], as it is well characterized that high-impact forces exerted on the joint lead to maladaptive responses in chondrocytes and subchondral bone. As a result, chondrocytes may exhibit increased production of matrix-degrading enzymes, leading to cartilage breakdown and the activation of several inflammatory pathway cascades [38,52,53]. In conjunction with their pathogenic effects, mechanotransduction pathways activated by beneficial or appropriate exercise and mechanical forces stimulate the synthesis of essential extracellular matrix components, which fosters an environment that is favorable to tissue repair and injury prevention [44,54,55,56,57,58,59]. While promising, the linkage between mechanical loading and KOA progression requires further investigation as a therapeutic option to understand how mechanical loading can induce beneficial regenerative responses in chondrocytes [60]. Through this interplay, well-regulated mechanical loading emerges as a key player in the preservation and restoration of joint health in the context of KOA and PTOA.

3. Mechanical Factors in PTOA

The mechanical aspects of PTOA pathogenesis involve complex interactions between joint biomechanics, tissue biology, and the body’s capacity for repair and maintenance of joint health. For example, disrupted joint biomechanics, as a result of trauma or sports injury, will disrupt the delicate balance surrounding mechanotransduction pathways. Altering either cartilage synthesis or degradation creates a mismatch that contributes to accelerated joint degeneration [61,62]. Additionally, progressive changes in load distribution within the joint due to aging or injury, whether it be from misalignment or other contributing factors, can result in abnormal stresses, leading to the breakdown of cartilage and inflammatory responses, as seen in PTOA and KOA alike [54,63,64]. Research has also elucidated several variables that contribute to PTOA progression, such as variations in flexion angles and resistance [29,30,65]. Therefore, it is crucial to understand that PTOA is complex and under active investigation.

Mechanical factors, such as the type of motion and loading stress incurred by the joint, significantly influence the severity of PTOA. Previous studies shed light on the complicated relationship between loading stress and PTOA progression. A previous study, utilizing rabbit models subjected to different impact loads, demonstrated that articular cartilage could tolerate single impact loads up to 45% of the joint fracture threshold without significant disruption or degradation [66]. These findings emphasize not only the resilience of articular cartilage, but also highlight the potential long-term consequences of acute mechanical injury and provide a reference point for quantifying “excessive” or supramaximal joint loading.

Previous studies by D’Lima et al. [67,68], focusing on knee joint forces and their impact on OA, underscore the critical role of factors like body weight, muscle contractions, and biomechanics in influencing knee forces. The research emphasizes that each additional kilogram in body weight is multiplied two or three times at the knee, contributing to increased joint loading and potentially accelerating arthritis progression. Malalignment of the lower extremity, as previously discussed, is also identified as a factor associated with the progression of osteoarthritis, which is thoroughly characterized [69,70]. D’Lima et al. [67] also examined knee forces during exercise and recreational activities after knee arthroplasty, providing valuable insights applicable to PTOA. Their study demonstrated, like others [71,72,73], that activities such as running, golf, and tennis were found to produce unexpectedly high forces, especially in the leading knee, emphasizing the need for careful consideration of post-traumatic joint health in athletes engaging in such activities. While the correlation between the increased forces incurred during high-load activities and KOA is unclear [74,75,76], it is evident that these activities do predispose an individual to injury of the knee [77,78], which can contribute to OA progression.

Furthermore, investigation into contact stresses in the knee joint during deep flexion activities by Thambyah and colleagues revealed significantly higher peak stresses, especially in the medial compartment, during squatting, a common resistance exercise [79]. The study raised concerns about the adequacy of articular cartilage to support high contact stresses during deep flexion and exemplifies the need to consider mechanical factors in common exercises as contributors to the development of PTOA.

Wallace and colleagues quantified patellofemoral joint reaction forces and stress during the squat maneuver and found that patellofemoral joint stress increases linearly with increasing knee flexion angle and joint force [80]. The addition of external resistance further elevated patellofemoral joint reaction force and stress. The study suggested that limiting terminal joint flexion angles and resistance loads could help minimize patellofemoral joint stress during squatting activities and may hinder osteoarthritis progression. These insights, among those previously discussed, emphasize the importance of considering specific motions and loading conditions in understanding the mechanical factors influencing the severity of PTOA, and exemplify the multifactorial nature of OA progression (Table 1).

Prior research, employing cadaver, in vivo, and in vitro animal cartilage, revealed that chondrocyte death can be triggered by impact stress as low as 18 MPa (megapascals). Furthermore, impact stress exceeding 30 MPa was observed to inflict surface damage on cartilage, ultimately contributing to cartilage degradation [34,81,82,83,84,85,86,87]. Patellofemoral joint stress linearly correlates with joint force [80], with the ratio of patellofemoral joint stress to force being about 2.3 MPa per body weight according to previous studies [79,88]. It suggests that exceeding eight times the body weight in patellofemoral joint forces may lead to potential cellular injury in articular cartilage by surpassing the critical threshold of 18 MPa. Joint forces are commonly quantified in terms of body weight (BW) in exercises (see next section) and can be used as a quantitative measure to evaluate various joint loading conditions to mitigate or prevent OA.

Table 1. Literature Review: Current research on mechanical factors contributing to PTOA and KOA progression, the therapeutic potential of mechanical loading, and quantification of mechanical forces in rehabilitation exercises that were utilized within this research.

Study Focus	Author, Year [Source]	Study Type	Number of Patients	Study Description
Impact of Athletics on Development of PTOA	Hootman et al., 2007 [26]	Epidemiological	182,000	Summarizing injury data to identify preventable risk factors for injury prevention strategies
	Golightly et al., 2009 [27]	Epidemiological	2528	Describes prevalence of KOA within retired football players
	Drawer et al., 2001 [28]	Epidemiological	500	Determines the prevalence of KOA within retired soccer players
	Kujala et al., 1995 [31]	Epidemiological	117	Analyzing the impact of increased mechanical loading during sport on KOA
	Swärd et al., 2010 [32]	Epidemiological	331	Compares radiographic structural changes of KOA and PTOA in athletes v non-athletes
	Boocock et al., 2009 [72]	Epidemiological	20	Investigates the effect of running on cartilage degeneration in athletes
	Thelin et al., 2005 [78]	Epidemiological	825	Analyzes the risk of KOA development in patients with sports participation and/or injury
	Shaw et al., 2004 [89]	Epidemiological	258	Evaluates the effect of triathlon training on likelihood of future injury
	Koplan et al., 1995 [90]	Epidemiological	535	Analyzes the impact of exercise on risk of knee injury and KOA development
	Piggot et al., 2009 [91]	Epidemiological	16	Analyzes the relationship between training load and injury in football players
	Satterthwaite 1999 [92]	Epidemiological	875	Investigates the impact of marathon running on prevalence of injuries in athletes
	Clausen et al., 2015 [93]	Epidemiological	326	Investigates the effect of previous knee injury on risk of future knee injury in soccer players
Mechanical Contributors to OA	Gillquist et al., 1999 [29]	Literature review	-	Summarizes the risk of ligamentous injury for osteoarthritis progression
	Hunter et al., 2005 [63]	Epidemiological	162	Analyzes the effect of malalignment in KOA progression
	Timmins et al., 2017 [75]	Systematic review	-	Determines the effect of running on development of KOA
	Schueller-Weidekamm et al., 2006 [94]	Epidemiological	26	Analyzes the long-term changes of the knee via MRI in former long-distance runners
	Bosomworth 2009 [76]	Systematic review	-	Analyzes the effect of exercise on risk of KOA
	D’Lima et al., 2008 [67]	Epidemiological	3	Investigates the effects of various activities on mechanical loading in the knee joint
	D’Lima 2006 [95]	Literature review	-	Synthesizes studies characterizing forces on the knee joint during various exercises
	Borelli et al., 2004 [66]	In vivo	-	Investigates the impact of varied loading conditions on knee cartilage in rabbit models
	Whittaker et al., 2022 [65]	Systematic review	-	Analyzes the effect of previous knee injury on PTOA progression
	Felson et al., 2013 [64]	Epidemiological	11,006	Characterizes the effect of malalignment on KOA progression
	Aljehani et al., 2022 [96]	Epidemiological	229	Investigates biomechanical predictors of KOA progression
	Driban et al., 2015 [97]	Epidemiological	4435	Analyzes the impact of knee pain or previous injury on the likelihood of future injury
	Lieberthal et al., 2015 [61]	Systematic review	-	Compiles evidence for the role of inflammation in joint injury and PTOA
	September et al., 2007 [98]	Literature review	-	Discusses risk factors and contributing elements to dysfunction in several joints
	He et al., 2020 [51]	In vivo	-	Evaluate effect of lessened mechanical loading on KOA in mouse model
	Fang et al., 2020 [52]	Systematic review	-	Summarize the biological underpinnings of the effect mechanical loading on KOA
	Schroder et al., 2019 [50]	In vitro *	5	Investigates the impact of mechanical loading on gene expression within chondrocytes in OA and non-OA patient samples
	Sharma et al., 2001 [69]	Epidemiological	237	Investigates the impact of alignment on KOA progression
	Tanamas et al., 2009 [70]	Systematic review	-	Analyzes the correlation between malalignment and KOA progression
	Neelapala et al., 2020 [99]	Systematic review	-	Summarizes current evidence on the effect of hip muscle weakness in KOA patients
	Zhu et al., 2020 [47]	In vivo	-	Analyzes the effect of mechanical loading on subchondral bone, cartilage, and KOA
	Robbins et al., 2011 [42]	Epidemiological	38	Evaluates the effect of increased mechanical loading of functional scores of KOA patients
	Milentijevic 2005 [34]	In vivo	-	Investigates the impact of loading stress on rabbit articular cartilage
	Roos et al., 1998 [30]	Epidemiological	123	Determining the effect of meniscal surgery/removal on osteoarthritis progression
Therapeutic Potential of Mechanical Loading	Frontera et al., 1988 [56]	Epidemiological	12	Analyzing the impact of strength-training regimen on muscle development
	Nebelung et al., 2012 [58]	In vitro *	8	Investigates gene expression of human chondrocytes following total knee replacement
	Veugelers et al., 2016 [100]	Epidemiological	45	Analyzes the impact of varied training loads on risk of future injury
	Baert et al., 2014 [101]	Systematic review	-	Investigates the impact of lateral wedge insoles in patients with KOA
	Fantini-Pagani 2011 [102]	Epidemiological	10	Analyzes the benefit of knee brace on minimizing force at the knee joint
	Robert-Lachaine 2022 [103]	Epidemiological	10	Investigates the impact of knee brace and orthoses in KOA treatment
	Barrios et al., 2010 [104]	Epidemiological	8	Investigates the effect of malalignment on KOA progression
	Jan et al., 2008 [105]	Epidemiological	102	Compares the effects of high and low load training regimens on KOA functional scores
	Kunduracilar 2018 [106]	Epidemiological	89	Investigates the effect of water training (low load bearing) on KOA progression
	Tagesson et al., 2008 [107]	Epidemiological	42	Analyzes the effect of quadriceps strengthening on KOA functional scores
	Heywood et al., 2019 [108]	Epidemiological	41	Analyzes variance in water v. land conditions while performing various exercises in KOA
	Vleck et al., 2010 [109]	Epidemiological	35	Investigates the effect of varied training regimens on risk of future injury
	Soligard et al., 2016 [110]	Literature review	-	Summarizes the impact of loading conditions on risk of injury, and injury prevention
Quantification of Mechanical Forces in Rehabilitation Exercises	Thambyah et al., 2005 [79]	In vitro *	5	Quantifies mechanical forces present at knee joint during walking
	Wong et al., 2011 [111]	In vitro *	4	Analyzes mechanical forces present on knee joint during various malalignment conditions
	Sasaki 2010 [112]	Computer model	-	Utilizes walking simulation to determine the muscles involved in walking
	Holyoak et al., 2019 [113]	In vivo	-	Quantifies mechanical forces during compression to elucidate beneficial loading range
	Glass et al., 2010 [114]	Systematic review	-	Analyzes the mechanical loading force of OKC and CKC exercises at the knee joint
	Bini 2017 [115]	Computer models	-	Utilizes computer simulated models to analyze forces on the knee joint during leg extension
	Escamilla et al., 1998 [116]	Epidemiological	10	Quantifies mechanical force at the knee joint during squat, knee extension, and leg press
	Escamilla 2001 [117]	Literature review	-	Discusses the mechanical forces incurred at the knee joint during the squat
	Schoenfeld 2020 [118]	Literature review	-	Summarizes the mechanical load incurred during the squat
	Perez et al., 2015 [119]	Literature review	-	Summarizes the mechanical load during various rehabilitation exercises
	Wallace et al., 2002 [80]	Epidemiological	15	Quantifies patellofemoral joint forces during the squat

* Denotes that in vitro samples were conducted on clinical patient samples.

4. The Goldilocks Zone

Establishing a Goldilocks zone of loading that preserves joint health while preventing or mitigating joint injury is an essential step for developing strategies to prevent and treat PTOA (Figure 1). As delineated by Sokoloff’s excellent aphorism in 1969 [120], “cartilage can survive in a large range of solicitations, but below or beyond, it will suffer”, illuminating the ideal range of mechanical loading is pivotal for optimizing joint health and the management of PTOA. Studies have described, in-depth and through varied language [121,122], what we are referring to as the Goldilocks zone. A 2016 International Olympic Committee (IOC) publication [110] critically analyzed the effects of underloading and overloading on athlete injury and performance. Within their discussion, the IOC cites evidence demonstrating the counterbalance between the increased risk of injury in athletes training with sub-competition loads [89,91,92,109], and the increased risk of injury with sustained, high-intensity loads [26,90,94,123,124]. Interestingly, however, the IOC also cites evidence demonstrating a beneficial effect of high-intensity loading on injury prevention [91,100,109,125]. This, in essence, demonstrates that high-intensity loading in the Goldilocks zone could prevent joint injury and damage, whereas exhibiting opposite effects outside the zone. Therefore, integrating the current knowledge from mechanobiology studies of knee joints into rehabilitation programs allows us to define the Goldilocks zone as a guide for the development of targeted exercises that optimize beneficial mechanical forces, fostering tissue repair and functional improvement.

Figure 1. The Goldilocks zone for mechanical stimulation.

This schematic depicts the factors of mechanical load that can stimulate the knee joint. On one end of the spectrum, less frequent repetitive movements performed over long periods of time, such as standing or slow walking with inadequate biomechanics, abnormal joint loading (injury) or excess load (obesity), can cause chronic degradation resulting in OA [44]. On the other end of the spectrum, acute movements with high force can cause acute injury and induce PTOA. Movements that occur with minimal load, regardless of frequency, do not provide an adequate stimulus to induce chondral regeneration. We propose that in the middle lies a Goldilocks zone (in green color) with therapeutic potential. Applying a mechanical load ranging from approximately 0.25 BW to 8 BW at a frequency range of 0.1–3 Hz and with proper joint biomechanics can be used to induce chondral regeneration without risk of further injury [119,126,127].

This entry is adapted from the peer-reviewed paper 10.3390/bioengineering11020110

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