An Evidence-Based Systematic Review of Human Knee Post-Traumatic Osteoarthritis (PTOA): Timeline of Clinical Presentation and Disease Markers, Comparison of Knee Joint PTOA Models and Early Disease Implications

Abstract

Understanding the causality of the post-traumatic osteoarthritis (PTOA) disease process of the knee joint is important for diagnosing early disease and developing new and effective preventions or treatments. The aim of this review was to provide detailed clinical data on inflammatory and other biomarkers obtained from patients after acute knee trauma in order to (i) present a timeline of events that occur in the acute, subacute, and chronic post-traumatic phases and in PTOA, and (ii) to identify key factors present in the synovial fluid, serum/plasma and urine, leading to PTOA of the knee in 23–50% of individuals who had acute knee trauma. In this context, we additionally discuss methods of simulating knee trauma and inflammation in in vivo, ex vivo articular cartilage explant and in vitro chondrocyte models, and answer whether these models are representative of the clinical inflammatory stages following knee trauma. Moreover, we compare the pro-inflammatory cytokine concentrations used in such models and demonstrate that, compared to concentrations in the synovial fluid after knee trauma, they are exceedingly high. We then used the Bradford Hill Framework to present evidence that TNF-α and IL-6 cytokines are causal factors, while IL-1β and IL-17 are credible factors in inducing knee PTOA disease progresssion. Lastly, we discuss beneficial infrastructure for future studies to dissect the role of local vs. systemic inflammation in PTOA progression with an emphasis on early disease.

Articular Chondrocyte Phenotype Regulation through the Cytoskeleton and the Signaling Processes That Originate from or Converge on the Cytoskeleton: Towards a Novel Understanding of the Intersection between Actin Dynamics and Chondrogenic Function

“…In summary, IL-1β is considered to mediate its effects on the actin cytoskeleton through the small GTPases RhoA and Rac1 [70,221], whereas IL-6 induces actin polymerization [222] and both IL-6 and IL-8 are thought to signal through the Rho-ROCK pathway [223] ( Figure 6). Additionally, the connection between multiple pro-inflammatory cytokines, specifically TNF-α and IL-6, with actin cytoskeleton remodeling and SF formation, might prove relevant in the context of post-traumatic AC degeneration and clinical disease because our recent evidence-based systematic review identified TNF-α and IL-6 as causal factors in inducing post-traumatic OA (PTOA) [224].…”

Anti-Inflammatory Therapeutic Approaches to Prevent or Delay Post-Traumatic Osteoarthritis (PTOA) of the Knee Joint with a Focus on Sustained Delivery Approaches

“…The global prevalence of knee OA is 16% in individuals aged 15 and over and 23% in individuals aged 40 and over [ 2 ]. Post-traumatic osteoarthritis (PTOA) is a major cause of early knee OA [ 3 ] with 22–50% of people developing clinical symptoms of PTOA [ 4 , 5 , 6 , 7 , 8 , 9 , 10 ] within only a few years of an acute knee trauma [ 1 , 11 , 12 , 13 , 14 , 15 ] due to injuries such as intraarticular fracture, injury to the anterior cruciate ligament (ACL) alone or combined with medial collateral ligament or meniscus injuries [ 4 , 5 , 6 , 7 , 8 , 9 , 10 ]. This, as of yet, incurable, multifactorial chronic disease consists of multiple co-pathologies of the articular cartilage, synovial fluid, synovial membranes, and bone.…”

“…This, as of yet, incurable, multifactorial chronic disease consists of multiple co-pathologies of the articular cartilage, synovial fluid, synovial membranes, and bone. Importantly, it is also connected with systemic manifestations of the disease, in which inflammation plays a key causal role in inducing knee PTOA disease progression [ 3 ]. This systemic response begins within 1 week of knee trauma, leading to higher than normal levels of inflammatory and injurious biomarkers present in the synovial fluid, blood and urine, and can persist for many years after knee injury ( Figure 1 ).…”

“…This systemic response begins within 1 week of knee trauma, leading to higher than normal levels of inflammatory and injurious biomarkers present in the synovial fluid, blood and urine, and can persist for many years after knee injury ( Figure 1 ). A long-term continuous low-grade inflammation concomitant with the local presence of various immune system mediators including inflammatory cytokines, neutrophil and macrophage-associated factors, complement system activation products, cartilage-degrading proteolytic enzymes as well as ensuing mediators of articular cartilage degradation can endure for months to many years following knee trauma, indicative of early, progressive, and conceivably irreversible, damage to the cartilage tissue [ 3 ].…”

“…Considering the large role that inflammation plays in the pathogenesis of knee PTOA after knee trauma [ 3 ], there may be a window of opportunity, in which anti-inflammatory therapeutics are applied early following knee joint injury to prevent inflammation and the downstream effects that lead to PTOA of the knee ( Figure 1 ). This review focuses on identifying the optimal timeframe of a potential application of local intra-articular (i.a.)…”