Potential Roles of Inflammation on Post-Traumatic Osteoarthritis of the Ankle.

Post-traumatic osteoarthritis of the ankle (PTOA) is frequently observed following a debilitating consequence of intra-articular ankle fractures. Numerous risk factors contribute to the pathogenesis of PTOA, including articular incongruity, joint malalignment, and concomitant soft tissue damage. Despite attempts to restore joint anatomy and manage soft tissues to avoid long-term complications after intra-articular ankle fractures, the incidence of PTOA remains markedly elevated. Inflammatory processes triggered by intra-articular ankle fractures have emerged as potential instigators that expedite the progression of PTOA. Injury to the articular cartilage and subchondral bone may lead to the release of inflammatory mediators, which can contribute to cartilage degradation and bone resorption. This study provides a narrative review on the current knowledge concerning the association between inflammation and the development of PTOA following intra-articular ankle fractures. We also discuss novel therapeutic agents that target inflammatory pathways to impede the progression of post-traumatic osteoarthritis after intra-articular ankle fractures. These medication and interventions were summarized within this review article.

Pathogenesis of Posttraumatic Osteoarthritis of the Ankle.

Ankle osteoarthritis affects a significant portion of the global adult population. Unlike other joints, arthritis of the ankle often develops as a response to traumatic injury (intra-articular fracture) of the ankle joints. The full mechanism leading to posttraumatic osteoarthritis of the ankle (PTOAA) is poorly understood. These deficits in knowledge pose challenges in the management of the disease. Adequate surgical reduction of fractured ankle joints remains the gold standard in prevention. The purpose of this review is to thoroughly delineate the known pathogenesis of PTOAA, and provide critical updates on this pathology and new avenues to provide therapeutic management of the disease.

[Effectiveness comparison of open reduction and internal fixation for open and closed ankle Logsplitter fractures].

Objective: To investigate the effectiveness of open reduction and internal fixation on high-energy ankle Logsplitter injuries (a kind of transsyndesmotic ankle fracture dislocation), and compare the prognosis between open and closed Logsplitter fracture. Methods: The clinical data of 36 Logsplitter fractures treated with open reduction and internal fixation between April 2011 and May 2016 were retrospectively analyzed. Among them, 15 cases were open fracture and dislocation (open group) and 21 cases were closed fracture and dislocation (closed group). There was no significant difference between the two groups in gender, age, combined injury, injury to hospital admission time, and other general data ( P>0.05), with comparability. The wound healing, ankle mobility recovery, complications, and fracture healing were observed after operation. The ankle function was evaluated by the American Orthopaedic Foot and Ankle Society (AOFAS) score. Results: Both groups were followed up 12-29 months (mean, 19 months). There was no significant difference in the follow-up time between the open group and the closed group ( t=1.169, P=0.251). In the open group, there were 3 cases of postoperative infection, 3 cases of nonunion, and 5 cases of post-traumatic osteoarthritis; the above complications occurred in 1 case in the closed group; there was no significant difference in complications between the two groups ( P=0.41) except post-traumatic osteoarthritis ( P=0.02). At last follow-up, there was no significant difference in AOFAS score between the two groups ( t=1.981, P=0.056). According to AOFAS score criterion, the results were good in 10 cases and general in 5 cases in the open group, and good in 13 cases and general in 8 cases in the closed group, showing no significant difference ( P=0.45). There was no significant difference in the fracture healing time and ankle flexion, dorsal extension, varus, and valgus motion between the two groups ( P>0.05). Conclusion: Open reduction and internal fixation for open or closed Logsplitter fractures can achieve satisfactory results, improve fracture healing rate, effectively reduce the incidence of complications, and improve ankle function.

Sinomenine Regulates Inflammatory Response and Oxidative Stress via Nuclear Factor kappa B (NF-κB) and NF-E2-Related Factor 2 (Nrf2) Signaling Pathways in Ankle Fractures in Children.

BACKGROUND This study aimed to investigate the effects of SIN on ankle fracture and the underlying mechanisms in MG-63 cells. MATERIAL AND METHODS qRT-PCR and ELISA assay were used to detect the mRNA and protein levels of cytokines in peripheral blood of children with or without ankle fracture. The expression and activity of antioxidant and detoxifying enzymes were detected by ELISA assay. Pretreated MG-63 cells with/without SIN were stimulated with 1 µg/ml bradykinin (BK). A CCK-8 kit was used to detect the cell viability. The cytokines produced from MG-63 cells were detected by Western blotting and qRT-PCR. Moreover, Western blotting was used to detect the levels of p-p38 and p-NF-κB (p65), and the activation level of the Nrf2 signaling pathway was examined by qRT-PCR and Western blotting. RESULTS In this study, we found that compared with the healthy children, the mRNA and protein levels of interleukin (IL)-1ß, IL-6, and tumor necrosis factor-alpha (TNF-α) were significantly upregulated in children with ankle fracture. In addition, the expression and activity of antioxidant and detoxifying enzymes were imbalanced in children with ankle fracture. SIN treatment did not have a cytotoxic effect on MG-63 cells. SIN dose-dependently suppressed BK-induced upregulation of IL-1ß, IL-6, TNF-α, p-p38, and p-NF-κB (p65). Furthermore, SIN dramatically inhibited oxidative stress induced by BK via balancing the expression and activity of antioxidant and detoxifying enzymes and inhibited the activation of Nrf2 signaling. CONCLUSIONS SIN might be a potential agent for the treatment of ankle fracture through reducing inflammatory response and oxidative stress.

Amino Acid Profile of Synovial Fluid Following Intra-articular Ankle Fracture.

BACKGROUND: Post-traumatic osteoarthritis (PTOA) is a frequent complication in patients with a previous traumatic joint injury, and the pathophysiology is not well understood. The goal of this study was to characterize the biochemical signature of amino acids, peptides, and amino acid metabolites in ankle synovial fluid following intra-articular fracture. METHODS: Synovial fluid from both the injured and contralateral ankles of 19 patients with an intra-articular ankle fracture was obtained and analyzed via metabolic profiling. Follow-up analysis was performed after 6 months in 7 of these patients. RESULTS: Statistical comparisons between injured and contralateral ankles revealed that 19 of the 66 measured amino acids, peptides, and amino acid metabolites were significantly elevated at time of fracture. Metabolites associated with glutathione metabolism exhibited the most elevated mean-fold changes, indicating a possible role for oxidative stress in fractured ankles. None of the metabolites elevated at baseline were significantly elevated after 6 months, but 6 metabolites had mean-fold changes greater than 2.1 at this time point. Multiple metabolites also exhibited significant correlations ( r > 0.575) with matrix metalloproteinase-1 and -9. CONCLUSION: These results indicate the presence of amino acid metabolic products in the setting of ankle fracture and suggest that these changes in amino acid metabolism may be chronic and indicate a role for inflammation and collagen degradation in disease progression. CLINICAL RELEVANCE: Changes in amino acid metabolism following intra-articular fracture may contribute to the progression to PTOA. This knowledge may allow for the identification and early treatment of patients at risk of developing PTOA. LEVEL OF EVIDENCE: Level III, comparative series.

Lipid profile of human synovial fluid following intra-articular ankle fracture.

This study characterizes the metabolic profile of synovial fluid after intra-articular ankle fracture with an emphasis on changes in the lipid profile. Bilateral ankle synovial fluid from 19 patients with unilateral intra-articular ankle fracture was submitted for metabolic profiling. Contralateral ankle synovial fluid from each patient served as a matched control. Seven patients participated in a second bilateral synovial fluid collection after 6 months. Random forest classification, matched pairs t-tests (α < 0.01), repeated measures ANOVA with post-test contrasts (α < 0.01), correlation to cytokines and matrix metalloproteinases, and fracture and injury classification analyses yielded key lipid biomarkers in synovial fluid following intra-articular fracture. Free fatty acids, sphingomyelins, and lysolipids demonstrated significant elevation in fractured ankles at baseline. Fatty acids and sphingomyelins showed a significant decrease 6 months post-surgery. Random forest analysis showed predominantly fatty acids differentiating between groups. Significant correlations included fatty acids, sphingomyelins, and lysolipids with inflammatory cytokines and matrix metalloproteinases. Fracture classification showed increased fatty acids, lysolipids, and inositol metabolites as fracture severity increased. Fatty acid and sn-1 lysolipid elevation could be detrimental to the joint, as these strongly correlated with matrix metalloproteinases and TNF-α. This elevation also suggests involvement of phospholipase A2 , a potential target for therapeutic intervention. Together with elevated 2-hydroxyl fatty acids, these findings suggest elevated sn-1 lysolipids, sphingomyelins, and subsequent lipid metabolites in synovial fluid as biomarkers of ankle injury. Reversal of this signature after 6 months suggests temporary involvement of these metabolites in disease progression, although they may activate signaling pathways which drive progression to osteoarthritis. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:657-666, 2017.

Early intra-articular complement activation in ankle fractures.

Cytokine regulation possibly influences long term outcome following ankle fractures, but little is known about synovial fracture biochemistry. Eight patients with an ankle dislocation fracture were included in a prospective case series and matched with patients suffering from grade 2 osteochondritis dissecans (OCD) of the ankle. All fractures needed external fixation during which joint effusions were collected. Fluid analysis was done by ELISA measuring aggrecan, bFGF, IL-1 ß, IGF-1, and the complement components C3a, C5a, and C5b-9. The time periods between occurrence of fracture and collection of effusion were only significantly associated with synovial aggrecan and C5b-9 levels (P < 0.001). Furthermore, synovial expressions of both proteins correlated with each other (P < 0.001). Although IL-1 ß expression was relatively low, intra-articular levels correlated with C5a (P < 0.01) and serological C-reactive protein concentrations 2 days after surgery (P < 0.05). Joint effusions were initially dominated by neutrophils, but the portion of monocytes constantly increased reaching 50% at day 6 after fracture (P < 0.02). Whereas aggrecan and IL-1ß concentrations were not different in fracture and OCD patients, bFGF, IGF-1, and all complement components were significantly higher concentrated in ankle joints with fractures (P < 0.01). Complement activation and inflammatory cell infiltration characterize the joint biology following acute ankle fractures.