Post-Traumatic Osteoarthritis Following ACL Injury

Li-Juan Wang; Ni Zeng; Zhi-Peng Yan; Jie-Ting Li; Guo-Xin Ni


Arthritis Res Ther. 2020;22(57) 

In This Article

Suggested Mechanisms of PTOA After ACL Injury

Although accumulating evidence demonstrates that patients with ACL injury are predisposed to PTOA, the precise mechanism remains unclear.[6] Structural, biological, mechanical, and neuromuscular factors are thought to be involved in this process. The involvement of ACL injury in the development of OA may be associated with the mechanisms described in this section (Figure 1).

Figure 1.

Suggested mechanisms of PTOA after ACL injury. An up arrow (↑) indicates an increase and a down arrow (↓) indicates a decrease

Structural Factors

In addition to ACL, many other associated structures may be compromised during initial injury and secondary instability. Compared to patients with isolated ACL rupture, those with concomitant intra-articular injuries have a higher incidence of PTOA.[5] Injury to the articular cartilage (chondral injury), meniscus, ligamentous capsular structures, and subchondral bone[1–3,5,6] may contribute to the development of clinically significant OA.

Almost half of patients with ACL injury also suffer from articular cartilage damage of the medial and lateral femoral condyles.[3] Higher impact energy during the initial trauma causes more severe damage to the articular cartilage, with over 25 MPa initiating chondrocyte necrosis and apoptosis.[10] Increased chondrocyte expression of matrix-degrading enzymes and inflammatory cytokines caused by mechanical impact results in chondrocyte apoptosis.[1,3] As cartilage has a poor healing capacity, damage to the articular chondral surface may directly lead to OA development.[5]

One fourth to two thirds of ACL-injured knees have concomitant meniscal damage.[16] It seems that meniscus status is a critically important factor that may contribute to the progression of PTOA. Patients with meniscus tear are more likely to develop radiographic OA compared with patients with isolated ACL injury.[29] Damage to the meniscus decreases the capacity of the joint to attenuate energy. Besides, as a biologically active tissue, the meniscus may synthesize various soluble enzymes and inflammatory mediators in response to trophic trauma that may accelerate the degradation of adjacent cartilage.[3]

Notably, 80–90% of patients also show signs of subchondral bone (SB) injuries after ACL injury.[5] When bone marrow lesions are associated with the disruption of adjacent cortical bone and articular surface, they may result in osteocyte necrosis in the bone marrow, significant proteoglycan loss, chondrocyte injury, and matrix degeneration in the overlying cartilage. Subchondral damage is co-localized with bone remodeling, and the balance between bone resorption and formation is disturbed following ACL injury.[30,31] The alteration of SB mineralization may change the morphology of the SB plate, leading to abnormal mechanical loading on the articular cartilage.[31] These changes in the subchondral bone may initiate the progression to PTOA following ACL injury.

Biological Factors

Following the initial ACL trauma, various biological factors, together with the damage to associated structures, may trigger progressive joint degeneration. Low-grade synovial cellular infiltration, cytokine production, and inflammatory activation of joint tissue cells put patients at risk of progressive OA development.[11,32] Oxygen free radicals from chondrocytes released during impact injury may lead to progressive chondrocyte damage and matrix degradation. In addition, a large number of cytokines are produced immediately after injury with long-lasting effects, which may disturb homeostasis in the joint and lead to joint degeneration via various metabolic pathways, including inflammatory cytokines IL-1, IL-6, IL-8, IL-17, and TNF-α[3,5,12,33] and molecular biomarkers such as stromal cell-derived factor 1 (SDF-1) and cartilage extracellular matrix fragments.[3] For example, IL-1 downregulates the synthesis of cartilage extracellular matrix (ECM). IL-6 and IL-17 work synergistically with IL-1 to accelerate the breakdown of the ECM. TNF-α plays a role in the increased activity in the apoptotic caspase pathway. The increased levels of IL-1β, TNF-α, and IL-6 are associated with a decreased level of lubricin. Lubricin provides anti-adhesive and chondroprotective properties to the articular cartilage, and the decrease in synovial fluid lubricin following ACL injury increases the risk of degradation.[33] Moreover, these inflammatory biomarkers may stimulate angiogenesis, osteophyte formation, and catabolic enzyme expression.[14]

The alteration of gene expression in chondrocytes and the activation of various degradative enzymes, such as MMPs, during injury cause progressive cartilage loss.[1,34] Increased MMP levels contribute to the degradation of the articular ECM encompassing GAGs, proteoglycans, and collagen, triggering further activation of MMPs, which creates a positive feedback cycle.[1] The loss of proteoglycan and collagen in the articular cartilage is a significant alteration from which it is difficult for the tissue to recover.[13] Increased permeability of the ECM and water content in the articular cartilage induced by catabolic pathways results in alteration of the biochemical and biomechanical properties of the articular cartilage.[14]

Mechanical Factors

Mechanical pathways play a vital role in the progression of OA. After injury, an ACL may fail to maintain the joint as stably as before. Consequently, chronic changes in the static and dynamic loading of the knee may lead to the degradation of the cartilage and other joint structures.[5] Reasons that could contribute to abnormal mechanical loading of knee joints include damage to static stabilizing structures, proprioception loss of dynamic stabilizers such as quadriceps and hamstrings, psychological factors such as emotional distress caused by pain and fear of re-injury, residual muscle weakness and disuse atrophy,[1] joint derangement, and biomechanical variables.[35] Adaptive changes during ambulation due to mechanical factors may lead to the disruption of joint homeostasis.[36] Given that chondrocytes are very sensitive to mechanic environment alterations, abnormal mechanical loading caused by various factors could change chondrocyte metabolism, proteoglycan production, collagen fiber orientation, and MMP expression, lead to ECM degradation, alter the mechanical properties of the cartilage itself, and ultimately cause functional disability.[1,3]

Kinematic abnormalities and kinetic alteration following joint injury are associated with OA development.[37] Knee joint structures, such as the ACL, the medial collateral ligament, and the lateral collateral ligament, work synergistically to limit the motion of anterior tibial translation. In patients with ACL injury, load is distributed to other structures to compensate for ACL deficiency.[15]

Neuromuscular Factors

Impairment of neuromuscular functions may also contribute to the development of PTOA.[5,6] The alteration of neuromuscular feedback caused by persistent ligament laxity[14] and impaired muscle function[10] poses a risk of progressive degradation of structures within the joints. The ACL not only restricts tibiofemoral motion passively but also serves as a dynamic sensor transmitting afferent information to the central nervous system. The loss of joint mechanoreceptors within the ACL after traumatic injury results in altered information input, decreased motor output, and poor neuromuscular control.[38] Patients with ACL injury suffer from quadriceps and hamstring strength deficit due to disuse atrophy or arthrogenic muscle inhibition. As shock absorbers and dynamic stabilizers, the quadriceps distribute load across the articular surface and stabilize the knee joint.[38,39] When the quadriceps are weak, articular loading of the knee joint increases, which may initiate a degenerative process.[2,40]