Long-term Effect of a Single Subcritical Knee Injury: Increasing the Risk of Anterior Cruciate Ligament Rupture and Osteoarthritis

Abstract

Background: Rupture of the anterior cruciate ligament (ACL) is a well-known risk factor for the development of posttraumatic osteoarthritis (PTOA), but patients with the “same injury” can have vastly different trajectories for the onset and progression of disease. Minor subcritical injuries preceding the critical injury event may drive this disparity through preexisting tissue pathologies and sensory changes. Purpose: To investigate the role of subcritical injury on ACL rupture risk and PTOA through the evaluation of pain behaviors, joint mechanics, and tissue structural change in a mouse model of knee injury. Study Design: Controlled laboratory study. Methods: Ten-week-old male C57BL/6J mice were allocated to naïve control and subcritical knee injury groups. Injury was induced by a single mechanical compression to the right hindlimb, and mice were evaluated using joint histopathology, anteroposterior joint biomechanics, pain behaviors (mechanical allodynia and hindlimb weightbearing), and isolated ACL tensile testing to failure at 1, 2, 4, or 8 weeks after injury. Results: Subcritical knee injury produced focal osteochondral lesions in the patellofemoral and lateral tibiofemoral compartments with no resolution for the duration of the study (8 weeks). These lesions were characterized by focal loss of proteoglycan staining, cartilage structural change, chondrocyte pathology, microcracks, and osteocyte cell loss. Injury also resulted in the rapid onset of allodynia (at 1 week), which persisted over time and reduced ACL failure load ( P = .006; mean ± SD, 7.91 ± 2.01 N vs 9.37 ± 1.01 N in naïve controls at 8 weeks after injury), accompanied by evidence of ACL remodeling at the femoral enthesis. Conclusion: The present study in mice establishes a direct effect of a single subcritical knee injury on the development of specific joint tissue pathologies (osteochondral lesions and progressive weakening of the ACL) and allodynic sensitization. These findings demonstrate a predisposition for secondary critical injuries (eg, ACL rupture) and an increased risk of PTOA onset and progression (structurally and symptomatically). Clinical Relevance: Subcritical knee injuries are a common occurrence and, based on this study, can cause persistent sensory and structural change. These findings have important implications for the understanding of risk factors of ACL injury and subsequent PTOA, particularly with regard to prevention and management strategies following an often underreported event.

Rodent models of knee osteoarthritis for pain research

“…However, these behavioural effects were deemed too small by the authors for pharmacological intervention. Similarly, the ACL rupture model in male mice has been reported to induce secondary mechanical hyperalgesia, transient changes in weight bearing 75 , and knee hyperalgesia (Randall-Selitto) 76 . Thus, due to the limited pain reports using males and females, current evidence does not place ACLT as a robust model for OA pain research.…”

Monocytes, Macrophages, and Their Potential Niches in Synovial Joints – Therapeutic Targets in Post-Traumatic Osteoarthritis?

“…Thus, obesity/HFD may be primary exposures that train heightened or specific OA inducing immune responses to a secondary stimulus such as injury (123,256). It is interesting to speculate that this may also be relevant in the context of prior even minor joint injuries increasing the risk and/or severity of ptOA following a critical/destabilizing injury such as anterior cruciate ligament (ACL) rupture (see Blaker et al, 2021 and references therein) (271).…”

Effect of isokinetic muscle strength training on knee muscle strength, proprioception, and balance ability in athletes with anterior cruciate ligament reconstruction: a randomised control trial

“…It causes tibial advancement and internal rotation, which cause knee instability and further damage to the meniscus and articular surface ( Kittl et al, 2016 ; Sonnery-Cottet et al, 2017 ). ACL fracture leads to the destruction of the mechanical structure of the knee ( Blaker et al, 2021 ; Tayfur et al, 2021 ). Knee-joint static stability can be restored by bone–patellar tendon–bone reconstruction, but the decline in postoperative joint muscle strength can cause dynamic knee joint instability ( Brophy et al, 2022 ; Takagi et al, 2022 ).…”