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.

Keywords: Bradford Hill; IL-17; IL-1β; IL-6; TNF-α; acute; articular cartilage; cartilage; cartilage repair; chondrocyte; chronic; clinical; complement; early PTOA; early disease; immunomodulation; in vitro models; inflammation; inflammatory cytokines; injury; knee joint; knee trauma; osteoarthritis; post-traumatic osteoarthritis; subacute; synovial fluid.

Figure 1

PTOA development after knee joint injury. Following knee joint injury, an immediate acute phase of inflammation occurs which continues for up to 2 weeks and is typically followed by a subacute phase, lasting up to 1.5 months, exhibited by a primary high wave of inflammatory cytokines that decrease over time but remain higher than uninjured controls. Likewise, other mediators, including complement components, neutrophil and macrophage-associated factors, MMPs, degradative proteolytic enzymes and ECM fragments increase in the synovial fluid, while lubricin decreases, all indicative of early, and possibly irreversible, damage to the cartilage tissue. When inflammation is not resolved, cartilage degradation continues to be associated with a low-grade chronic phase of inflammation characterized by decreased, but higher than normal, levels of pro-inflammatory cytokines IL-6, TNF-α and IL-17. Although these inflammatory mediators are lower than what may be observed in OA or RA patients, this sustained low-grade inflammation is still clearly present, significantly higher than healthy controls, and correlates with degenerative effects, all of which promote joint pathology. A long-term inflammatory status persists, leading to a systemic effect (presence of biomarkers in the blood and/or uninjured knee) accompanied with alterations in joint function leading to PTOA. This figure was composed based on all of the clinical data discussed in this review that measured the concentrations of these markers at the (mean) time or range of times (using the data of multiple studies) post-injury showing, with the exception of lubricin which was decreased, significantly high levels of these markers at the indicated time points.

Figure 2

The effects of injury and/or inflammatory cytokines in in vivo models and ex vivo and in vitro models using tissue and chondrocytes from non-0A (healthy) articular cartilage. A (−) sign indicates a decrease and a (+) sign an increase. (a) In vivo models effects showing the effects of intra-articular injection of IL-1β [69,70], TNF-α [71], or IL-17 [69,70] alone, blood-induced injury [73], intra-articular (I.A.) acute tibial plateau fracture [87,88,89,90,91,92], or ACLT which includes data from the non-invasive ACL rupture single tibial compression overload model and invasive ACLT model [96,97,98,99,100,101]. The * indicates the corresponding model that showed an increase of that marker in the serum (S). (b) Ex vivo cartilage explant models using non-0A (healthy) tissue showing the effects of blood-induced injury [76,77,78], mechanical injury using a single injurious compression without the addition of any pro-inflammatory cytokines [93,141,143,144,206,207], inflammatory cytokines IL-1α alone [144,149,155,156] or combined with injury* [144,148], IL-1β alone [147,152], TNF-α alone [144,145,146,147] or combined with injury* [143,144,145,146], IL-17A alone [150], and TNF-α/IL-6/sIL-6R alone [143,146,154] or combined with injury* [144,148,154]. (c) In vitro chondrocyte models using cells isolated from non-OA (healthy) cartilage tissue showing the effects of IL-1α [157], IL-1β [159,160], TNF-α [166,167], IL-17 or IL-17F [172,175], IL-6 or IL-8 [160], and LIF [160,175].

Figure 2

The effects of injury and/or inflammatory cytokines in in vivo models and ex vivo and in vitro models using tissue and chondrocytes from non-0A (healthy) articular cartilage. A (−) sign indicates a decrease and a (+) sign an increase. (a) In vivo models effects showing the effects of intra-articular injection of IL-1β [69,70], TNF-α [71], or IL-17 [69,70] alone, blood-induced injury [73], intra-articular (I.A.) acute tibial plateau fracture [87,88,89,90,91,92], or ACLT which includes data from the non-invasive ACL rupture single tibial compression overload model and invasive ACLT model [96,97,98,99,100,101]. The * indicates the corresponding model that showed an increase of that marker in the serum (S). (b) Ex vivo cartilage explant models using non-0A (healthy) tissue showing the effects of blood-induced injury [76,77,78], mechanical injury using a single injurious compression without the addition of any pro-inflammatory cytokines [93,141,143,144,206,207], inflammatory cytokines IL-1α alone [144,149,155,156] or combined with injury* [144,148], IL-1β alone [147,152], TNF-α alone [144,145,146,147] or combined with injury* [143,144,145,146], IL-17A alone [150], and TNF-α/IL-6/sIL-6R alone [143,146,154] or combined with injury* [144,148,154]. (c) In vitro chondrocyte models using cells isolated from non-OA (healthy) cartilage tissue showing the effects of IL-1α [157], IL-1β [159,160], TNF-α [166,167], IL-17 or IL-17F [172,175], IL-6 or IL-8 [160], and LIF [160,175].