Streamlining quantitative joint-wide medial femoro-tibial histopathological scoring of mouse post-traumatic knee osteoarthritis models.

OBJECTIVES: Histological scoring remains the gold-standard for quantifying post-traumatic osteoarthritis (ptOA) in animal models, allowing concurrent evaluation of numerous joint tissues. Available systems require scoring multiple sections/joint making analysis laborious and expensive. We investigated if a single section allowed equivalent quantitation of pathology in different joint tissues and disease stages, in three ptOA models. METHOD: Male 10-12-week-old C57BL/6 mice underwent surgical medial-meniscal-destabilization, anterior-cruciate-ligament (ACL) transection, non-invasive-ACL-rupture, or served as sham-surgical, non-invasive-ACL-strain, or naïve/non-operated controls. Mice (n = 12/group) were harvested 1-, 4-, 8-, and 16-week post-intervention. Serial sagittal toluidine-blue/fast-green stained sections of the medial-femoro-tibial joint (n = 7/joint, 84 µm apart) underwent blinded scoring of 40 histology-outcomes. We evaluated agreement between single-slide versus entire slide-set maximum or median scores (weighted-kappa), and sensitivity/specificity of single-slide versus median/maximum to detect OA pathology. RESULTS: A single optimal mid-sagittal section showed excellent agreement with median (weighted-kappa 0.960) and maximum (weighted-kappa 0.926) scores. Agreement for individual histology-outcomes was high with only 19/240 median and 15/240 maximum scores having a weighted-kappa ≤0.4, the majority of these (16/19 and 11/15) in control groups. Statistically-significant histology-outcome differences between ptOA models and their controls detected with the entire slide-set were reliably reproduced using a single slide (sensitivity >93.15%, specificity >93.10%). The majority of false-negatives with single-slide scoring were meniscal and subchondral bone histology-outcomes (89%) and occurred in weeks 1-4 post-injury (84%). CONCLUSION: A single mid-sagittal slide reduced the time needed to score diverse histopathological changes by 87% without compromising the sensitivity or specificity of the analysis, across a variety of ptOA models and time-points.

Synovial fluid mitochondrial DNA concentration reflects the degree of cartilage damage after naturally occurring articular injury.

OBJECTIVE: To evaluate mitochondrial DNA (mtDNA) release from injured chondrocytes and investigate the utility of synovial fluid mtDNA concentration in early detection of posttraumatic osteoarthritis. METHOD: We measured mtDNA release using four models of osteoarthritis: in vitro interleukin-1ß stimulation of cultured equine chondrocytes, ex vivo mechanical impact of bovine cartilage explants, in vivo mechanical impact of equine articular cartilage, and naturally occurring equine intraarticular fracture. In our in vivo model, one group was treated with an intraarticular injection of the mitoprotective peptide SS-31 following cartilage injury. mtDNA content was quantified using qPCR. For naturally occurring cases of joint injury, clinical data (radiographs, arthroscopic video footage) were scored for criteria associated with degenerative joint disease. RESULTS: Chondrocytes released mtDNA in the acute time frame following inflammatory and mechanical cellular stress in vitro. mtDNA was increased in equine synovial fluid following experimental and naturally occurring injury to the joint surface. In naturally occurring posttraumatic osteoarthritis, we found a strong positive correlation between the degree of cartilage damage and mtDNA concentration (r = 0.80, P = 0.0001). Finally, impact-induced mtDNA release was mitigated by mitoprotective treatment. CONCLUSION: Changes in synovial fluid mtDNA occur following joint injury and correlate with the severity of cartilage damage. Mitoprotection mitigates increases in synovial fluid mtDNA suggesting that mtDNA release may reflect mitochondrial dysfunction. Further investigation of mtDNA as a potentially sensitive marker of early articular injury and response to mitoprotective therapy is warranted.

From Inflammation to Resolution: Specialized Pro-resolving Mediators in Posttraumatic Osteoarthritis.

PURPOSE OF REVIEW: To provide a comprehensive overview of the inflammatory response following anterior cruciate ligament (ACL) injury and to highlight the relationship between specialized pro-resolving mediators (SPMs) and inflammatory joint conditions, emphasizing the therapeutic potential of modulating the post-injury resolution of inflammation to prevent posttraumatic osteoarthritis (PTOA). RECENT FINDINGS: The inflammatory response triggered after joint injuries such as ACL tear plays a critical role in posttraumatic osteoarthritis development. Inflammation is a necessary process for tissue healing, but unresolved or overactivated inflammation can lead to chronic diseases. SPMs, a family of lipid molecules derived from essential fatty acids, have emerged as active players in the resolution of inflammation and tissue repair. While their role in other inflammatory conditions has been studied, their relationship with PTOA remains underexplored. Proinflammatory mediators contribute to cartilage degradation and PTOA pathogenesis, while anti-inflammatory and pro-resolving mediators may have chondroprotective effects. Therapies aimed at suppressing inflammation in PTOA have limitations, as inflammation is crucial for tissue healing. SPMs offer a pro-resolving response without causing immunosuppression, making them a promising therapeutic option. The known onset date of PTOA makes it amenable to early interventions, and activating pro-resolving pathways may provide new possibilities for preventing PTOA progression. Harnessing the pro-resolving potential of SPMs may hold promise for preventing PTOA and restoring tissue homeostasis and function after joint injuries.

Increased complications rates and inferior patient reported outcomes following total knee arthroplasty due to post-traumatic osteoarthritis with previous fracture treatment: a systematic review.

PURPOSE: This study aims to present the existing literature relating to patient-reported outcome measures (PROMs) and complications in patients undergoing total knee arthroplasty (TKA) due to posttraumatic osteoarthritis (PTOA) with prior fracture treatment around the knee compared with patients who underwent TKA because of primary osteoarthritis (OA). METHODS: A systematic review was undertaken and synthesised in accordance with the PRISMA guidelines by searching existing literature in the following databases: PubMed, Scopus, Cochrane Library and EMBASE. A search string according to the PECO was used. After analysing 2781 studies, 18 studies (5729 PTOA patients/149,843 OA patients) were included for a final review. An analysis revealed that 12 (67%) were retrospective cohort studies, four (22%) were register studies and the remaining two (11%) were prospective cohort studies. The mean Critical Appraisal Skills Programme (CASP) score was 23.6 out of 28, signifying studies of moderate quality. RESULTS: The most frequently reported outcome measure were postoperative complications, reported in all eighteen studies. Intraoperative complications were reported in ten (4165 PTOA/124.511 OA) and patient-reported outcome measures (PROMs) in six studies (210 PTOA/2768 OA). A total of nine different PROMs were evaluated. As far as PROMs were concerned, the scores were inferior for PTOA but did not differ statistically from OA, except for one study, which favoured the OA group. Across all studies, postoperative complications were higher in the PTOA group, reporting infections as the most common complication. Furthermore, a higher revision rate was reported in the PTOA group. CONCLUSION: PROM analysis suggests that both patient groups benefit from a TKA in terms of functional outcome and pain relief, however, patient-reported outcomes could be inferior for PTOA patients. There is consistent evidence for increased complication rates following PTOA TKA. Patients undergoing TKA due to PTOA after fracture treatment should be informed about the risk for inferior results and refrain from comparing their knee function to patients with TKA after OA. Surgeons should be aware of the challenges that PTOA TKA poses. LEVEL OF EVIDENCE: Level III.

Functional outcome of total knee arthroplasty following tibial plateau fractures: a systematic review.

BACKGROUND: Posttraumatic osteoarthritis (PTOA) following a tibial plateau fracture (TPF) is a debilitating disease which often affects a young and active patient population for whom good knee function is essential. Frequently, total knee arthroplasty (TKA) is the only surgical option. The aim of this systematic review was to evaluate functional outcome for TKA in PTOA patients, together with several secondary outcome parameters. METHODS: A systematic review according to the PRISMA guidelines was conducted. Studies were included that reported on patient-reported outcome measures, range of motion or objective functional analysis after TKA because of PTOA following TPF. RESULTS: After analyzing 105 studies, 5 were included for the final review. In total, 162 patients with a TKA for PTOA were included of whom 125 (77%) were managed operatively for their TPF. All studies reported improvements in functional outcome after TKA, with two studies showing no significant differences between PTOA patients and a matched cohort of primary OA patients. Reported complication and re-intervention rates were higher for TKA patients with PTOA. CONCLUSION: The results of this review indicate the TKA for PTOA after a TPF provides satisfactory functional outcome, with results similar to those of matched primary OA patients. TKA should, therefore, be considered a viable treatment option to improve function, but both patients and orthopedic surgeons should be aware of the higher complication rates in this patient population.

In vivo multimodal imaging of hyaluronan-mediated inflammatory response in articular cartilage.

OBJECTIVE: One driving factor in the progression to posttraumatic osteoarthritis (PTOA) is the perpetuation of the inflammatory response to injury into chronic inflammation. Molecular imaging offers many opportunities to complement the sensitivity of current imaging modalities with molecular specificity. The goal of this study was to develop and characterize agents to image hyaluronan (HA)-mediated inflammatory signaling. DESIGN: We developed optical (Cy5.5-P15-1) and magnetic resonance contrast agents (Gd-DOTA-P15-1) based in a hyaluronan-binding peptide (P15-1) that has shown anti-inflammatory effects on human chondrocytes, and validated them in vitro and in vivo in two animal models of PTOA. RESULTS: In vitro studies with a near infrared (NIR) Cy5.5-P15-1 imaging agent showed a fast and stable localization of Cy5.5-P15-1 on chondrocytes, but not in synovial cells. In vivo NIR showed significantly higher retention of imaging agent in PTOA knees between 12 and 72 h (n = 8, Cohen's d > 2 after 24 h). NIR fluorescence accumulation correlated with histologic severity in cartilage and meniscus (ρ between 0.37 and 0.57, P < 0.001). By using in vivo magnetic resonance imaging with a Gd-DOTA-P15-1 contrast agent in 12 rats, we detected a significant decrease of T1 on injured knees in all cartilage plates at 48 h (-15%, 95%-confidence interval (CI) = [-18%,-11%]) while no change was observed in the controls (-2%, 95%-CI = [-5%,+1%]). CONCLUSIONS: This study provides the first in vivo evidence that hyaluronan-related inflammatory response in cartilage after injury is a common finding. Beyond P15-1, we have demonstrated that molecular imaging can provide a versatile technology to investigate and phenotype PTOA pathogenesis, as well as study therapeutic interventions.

Synovial fluid concentrations of matrix Metalloproteinase-3 and Interluekin-6 following anterior cruciate ligament injury associate with gait biomechanics 6 months following reconstruction.

OBJECTIVE: To compare gait biomechanics 6 months following anterior cruciate ligament (ACL) reconstruction (ACLR) between patients with the highest and lowest concentrations of synovial fluid (SF) interleukin-6 (IL-6) and matrix metalloproteinase-3 (MMP-3), as well as compared to uninjured controls. DESIGN: SF concentrations of IL-6 and MMP-3 were collected 7 ± 4 days post injury in 38 ACL injured patients (55% female, 21±4yrs, 25.3 ± 5.2BMI). ACL injured individuals were stratified into the lowest and highest quartiles based on IL-6 (IL-6Lowest and IL-6Highest) and MMP-3 (MMP-3Lowest and MMP-3Highest) concentrations. Gait biomechanics were collected on the injured limb 6 months post-ACLR and in 38 uninjured controls (50% female, 21±3yrs, 23.8 ± 2.8BMI). Functional analyses of variance were used to compare vertical ground reaction force (vGRF), knee flexion angle (KFA), and internal knee extension moment (KEM) waveforms throughout stance phase of gait to determine the proportions of stance differing between limbs and groups. RESULTS: Compared to uninjured controls, IL-6High and MMP-3High ACL subgroups demonstrated lesser vGRF (largest differences: IL-6, 7.88%BW; MMP-3, 11.05%BW) during early-stance and greater vGRF (largest differences: IL-6, 6.21%BW; MMP-3, 5.85%BW) in mid-stance, lesser KFA (largest differences: IL-6, 3.11°; MMP-3, 3.72°) and lesser KEM (largest differences: IL-6, 0.96%BW•m; MMP-3, 1.07%BW•m) in early-stance, as well as greater KFA in mid-stance (largest differences: IL-6, 1.5°; MMP-3, 2.95°). CONCLUSIONS: High SF concentrations of a proinflammatory cytokine and a degradative enzyme early post-ACL injury are associated with aberrant gait biomechanics in the injured limb at 6 months post-ACLR (i.e., lesser vGRF, KFA and KEM) linked to posttraumatic osteoarthritis development.

Tibiofemoral articular cartilage composition differs based on serum biochemical profiles following anterior cruciate ligament reconstruction.

OBJECTIVE: Biochemical joint changes contribute to posttraumatic osteoarthritis (PTOA) development following anterior cruciate ligament reconstruction (ACLR). The purpose of this longitudinal cohort study was to compare tibiofemoral cartilage composition between ACLR patients with different serum biochemical profiles. We hypothesized that profiles of increased inflammation (monocyte chemoattractant protein-1 [MCP-1]), type-II collagen turnover (type-II collagen breakdown [C2C]:synthesis [CPII]), matrix degradation (matrix metalloproteinase-3 [MMP-3] and cartilage oligomeric matrix protein [COMP]) preoperatively to 6-months post-ACLR would be associated with greater tibiofemoral cartilage T1ρ relaxation times 12-months post-ACLR. DESIGN: Serum was collected from 24 patients (46% female, 22.1 ± 4.2 years old, 24.0 ± 2.6 kg/m2 body mass index [BMI]) preoperatively (6.4 ± 3.6 days post injury) and 6-months post-ACLR. T1ρ Magnetic Resonance Imaging (MRI) was collected for medial and lateral tibiofemoral articular cartilage at 12-months post-ACLR. A k-means cluster analysis was used to identify profiles based on biomarker changes over time and T1ρ relaxation times were compared between cluster groups controlling for sex, age, BMI, concomitant injury (either meniscal or chondral pathology), and Marx Score. RESULTS: One cluster exhibited increases in MCP-1 and COMP while the other demonstrated decreases in MCP-1 and COMP preoperatively to 6-months post-ACLR. The cluster group with increases in MCP-1 and COMP demonstrated greater lateral tibial (adjusted mean difference = 3.88, 95% confidence intervals [1.97-5.78]) and femoral (adjusted mean difference = 12.71, 95% confidence intervals [0.41-23.81]) T1ρ relaxation times. CONCLUSION: Profiles of increased serum levels of inflammation and matrix degradation markers preoperatively to 6-months post-ACLR are associated with MRI changes consistent with lesser lateral tibiofemoral cartilage proteoglycan density 12-months post-ACLR.

[Fractures of the carpal bones without the scaphoid bone]. / Frakturen der Handwurzel ohne Os scaphoideum.

With the exception of the relatively frequent fractures of the scaphoid bone, isolated fractures of individual carpal bones are rare. Because these injuries are uncommon and because of the complex anatomy and function of the carpus, treatment of carpal bone fractures can be challenging. Carpal bone fractures generally occur in young, sports active and professional patients, can be easily overlooked in plain radiographs and are frequently associated with ligamentous instability, neurovascular injuries and tendon lesions. Small posttraumatic alterations of the precisely aligned carpal structure can cause chronic pain and functional impairment. Therefore, if a wrist fracture is suspected a thorough clinical examination and appropriate differentiated imaging is always necessary, at the end of which a fracture can be excluded or an appropriate conservative or surgical treatment is initiated, with the aim of restoration of carpal anatomy and function.

A Mouse Noninvasive Intraarticular Tibial Plateau Compression Loading-Induced Injury Model of Posttraumatic Osteoarthritis.

This study sought to develop a noninvasive, reliable, clinically relevant, and easy-to-implement mouse model that can be used for investigation of the pathophysiology of PTOA and for preclinical testing of new therapies of PTOA. Accordingly, we have established a closed intraarticular tibial plateau compression loading-induced injury model of PTOA in C57BL/6J mice. In this model, a single application of a defined loading force was applied with an indenter to the tibial plateau of the right knee to create injuries to the synovium, menisci, ligaments, and articular cartilage. The limiting loading force was set at 55 N with the loading speed of 60 N/s. This loading regimen limits the distance that the indenter would travel into the joint, but still yields substantial compression loading energy to cause significant injuries to the synovium, meniscus, and articular cartilage. The joint injury induced by this loading protocol consistently yielded evidence for key histological hallmarks of PTOA at 5-11 weeks post-injury, including loss of articular cartilage, disorganization of chondrocytes, meniscal hyperplasia and mineralization, osteophyte formation, and degenerative remodeling of subchondral bone. These arthritic changes were highly reproducible and of a progressive nature. Because 50% of patients with meniscal and/or ligament injuries without intraarticular fractures developed PTOA over time, this intraarticular tibial plateau compression loading-induced injury model is clinically relevant. In summary, we have developed a noninvasive intraarticular tibial plateau compression loading-induced injury model in the mouse that can be used to investigate the pathophysiology of PTOA and for preclinical testing for new therapies.

Pathomechanisms of Posttraumatic Osteoarthritis: Chondrocyte Behavior and Fate in a Precarious Environment.

Traumatic injuries of the knee joint result in a wide variety of pathomechanisms, which contribute to the development of so-called posttraumatic osteoarthritis (PTOA). These pathogenetic processes include oxidative stress, excessive expression of catabolic enzymes, release of damage-associated molecular patterns (DAMPs), and synovial inflammation. The present review focuses on the underlying pathomechanisms of PTOA and in particular the behavior and fate of the surviving chondrocytes, comprising chondrocyte metabolism, regulated cell death, and phenotypical changes comprising hypertrophy and senescence. Moreover, possible therapeutic strategies, such as chondroanabolic stimulation, anti-oxidative and anti-inflammatory treatment, as well as novel therapeutic targets are discussed.

Fibular nailing for fixation of ankle fractures in patients at high risk of surgical wound infection.

BACKGROUND: Postoperative infection is a severe complication after operative treatment of ankle fractures, associated with age, comorbidities, and severe soft tissue injuries. We assessed the efficacy of intramedullary fibular nailing for treating ankle fractures in patients at high risk of wound complications. METHODS: 41 high-risk patients were included in the study. We retrospectively reviewed the medical records to assess the risk profile, the treatment data, and possible infections and re-operations. After a minimum of 2 years eight patients had died, three had advanced-staged dementia and two were lost to follow-up. Remaining 28 patients reported the functional outcome and QoL through patient-reported questionnaires. Radiographs and cone-beam computed tomography were performed, as well as range-of-motion was measured. RESULTS: No surgical wound infections were found. The mean Olerud-Molander score was 67 points (SD 28 [20-100]). The osteoarthritis stages and the range-of-motion were significantly different between the injured and uninjured ankles, but we detected no significant effect on the QoL. CONCLUSION: Intramedullary fibular fixation appeared to be a safe treatment choice for ankle fractures in high-risk patients. LEVEL OF EVIDENCE: IV.

Suppression of NF-κB activity via nanoparticle-based siRNA delivery alters early cartilage responses to injury.

Osteoarthritis (OA) is a major cause of disability and morbidity in the aging population. Joint injury leads to cartilage damage, a known determinant for subsequent development of posttraumatic OA, which accounts for 12% of all OA. Understanding the early molecular and cellular responses postinjury may provide targets for therapeutic interventions that limit articular degeneration. Using a murine model of controlled knee joint impact injury that allows the examination of cartilage responses to injury at specific time points, we show that intraarticular delivery of a peptidic nanoparticle complexed to NF-κB siRNA significantly reduces early chondrocyte apoptosis and reactive synovitis. Our data suggest that NF-κB siRNA nanotherapy maintains cartilage homeostasis by enhancing AMPK signaling while suppressing mTORC1 and Wnt/ß-catenin activity. These findings delineate an extensive crosstalk between NF-κB and signaling pathways that govern cartilage responses postinjury and suggest that delivery of NF-κB siRNA nanotherapy to attenuate early inflammation may limit the chronic consequences of joint injury. Therapeutic benefits of siRNA nanotherapy may also apply to primary OA in which NF-κB activation mediates chondrocyte catabolic responses. Additionally, a critical barrier to the successful development of OA treatment includes ineffective delivery of therapeutic agents to the resident chondrocytes in the avascular cartilage. Here, we show that the peptide-siRNA nanocomplexes are nonimmunogenic, are freely and deeply penetrant to human OA cartilage, and persist in chondrocyte lacunae for at least 2 wk. The peptide-siRNA platform thus provides a clinically relevant and promising approach to overcoming the obstacles of drug delivery to the highly inaccessible chondrocytes.

Quadriceps weakness associates with greater T1ρ relaxation time in the medial femoral articular cartilage 6 months following anterior cruciate ligament reconstruction.

PURPOSE: Quadriceps weakness following anterior cruciate ligament reconstruction (ACLR) is linked to decreased patient-reported function, altered lower extremity biomechanics and tibiofemoral joint space narrowing. It remains unknown if quadriceps weakness is associated with early deleterious changes to femoral cartilage composition that are suggestive of posttraumatic osteoarthritis development. The purpose of the cross-sectional study was to determine if quadriceps strength was associated with T1ρ relaxation times, a marker of proteoglycan density, of the articular cartilage in the medial and lateral femoral condyles 6 months following ACLR. It is hypothesized that individuals with weaker quadriceps would demonstrate lesser proteoglycan density. METHODS: Twenty-seven individuals (15 females, 12 males) with a patellar tendon autograft ACLR underwent isometric quadriceps strength assessments in 90°of knee flexion during a 6-month follow-up exam. Magnetic resonance images (MRI) were collected bilaterally and voxel by voxel T1ρ relaxation times were calculated using a five-image sequence and a monoexponential equation. Following image registration, the articular cartilage for the weight-bearing surfaces of the medial and lateral femoral condyles (MFC and LFC) were manually segmented and further sub-sectioned into posterior, central and anterior regions of interest (ROI) based on the corresponding meniscal anatomy viewed in the sagittal plane. Univariate linear regression models were used to determine the association between quadriceps strength and T1ρ relaxation times in the entire weight-bearing MFC and LFC, as well as the ROI in each respective limb. RESULTS: Lesser quadriceps strength was significantly associated with greater T1ρ relaxation times in the entire weight-bearing MFC (R2 = 0.14, P = 0.05) and the anterior-MFC ROI (R2 = 0.22, P = 0.02) of the ACLR limb. A post hoc analysis found lesser strength and greater T1ρ relaxation times were significantly associated in a subsection of participants (n = 18) without a concomitant medial tibiofemoral compartment meniscal or chondral injury in the entire weight-bearing MFC, as well as anterior-MFC and central-MFC ROI of the ACLR and uninjured limb. CONCLUSIONS: The association between weaker quadriceps and greater T1ρ relaxation times in the MFC suggests deficits in lower extremity muscle strength may be related to cartilage composition as early as 6 months following ACLR. Maximizing quadriceps strength in the first 6 months following ACLR may be critical for promoting cartilage health early following ACLR. LEVEL OF EVIDENCE: Prognostic level 1.

Clinically Asymptomatic Patients Show a High Bacterial Colonization Rate of Osteosynthetic Implants Around the Knee but Not the Hip.

BACKGROUND: Patients with osteosynthetic implants around the hip and knee show higher infection rates after joint arthroplasty. Our aim was to evaluate the bacterial colonization of any osteosynthetic implants around the hip and knee in patients without clinical signs of infection. METHODS: Consecutive patients with osteosynthetic implant removal because of related soft tissue irritations or before elective total joint arthroplasty of the hip and knee were prospectively included. Patients with signs of infection were excluded. Based on sonication fluid cultures, implants were classified according to microbial growth as negative (no growth), contaminated (nonsignificant growth), or colonized (significant growth). RESULTS: Sonication cultures were positive in 54 of 203 implants (27%), including 8 of 34 (24%) after orthopedic and 46 of 169 (27%) after traumatological surgery. Of 203 sonication cultures, 22 (11%) grew significant bacterial counts. Most common microorganisms were coagulase-negative staphylococci (46%). Implants around the knee showed a significantly higher rate of positive sonication cultures compared with those around the hip (14% vs 2%, P = .017). CONCLUSIONS: We detected high bacterial implant colonization rates regardless of the initial type of surgery. Predominant pathogens were staphylococci, the most common causative agents of periprosthetic joint infections. Positive sonication results do not necessarily lead to postoperative surgical complications and thus do not equal infection. It remains unclear if patients with evidence of bacterial implant colonization show a higher risk of periprosthetic joint infection after adjacent subsequent total joint arthroplasty. Nevertheless, surgeons should be aware of a significantly higher colonization rate of implants around the knee and take this into consideration when total knee arthroplasty is scheduled in patients with osteosynthetic devices.

Osteoarthritis: Trauma vs Disease.

Osteoarthritis (OA) is the most prevalent joint disease characterized by pain and degenerative lesions of the cartilage, subchondral bone, and other joint tissues. The causes of OA remain incompletely understood. Over the years, it has become recognized that OA is a multifactorial disease. In particular, aging and trauma are the main risk factors identified for the development of OA; however, other factors such as genetic predisposition, obesity, inflammation, gender and hormones, or metabolic syndrome contribute to OA development and lead to a more severe outcome. While this disease mainly affects people older than 60 years, OA developed after joint trauma affects all range ages and has a particular impact on young individuals and people who have highest levels of physical activity such as athletes. Traumatic injury to the joint often results in joint instability or intra-articular fractures which lead to posttraumatic osteoarthritis (PTOA). In response to injury, several molecular mechanisms are activated, increasing the production and activation of different factors that contribute to the progression of OA.In this chapter, we have focused on the interactions and contribution of the multiple factors involved in joint destruction and progression of OA. In addition, we overview the main changes and molecular mechanisms related to OA pathogenesis.

Subchondral screw abutment: does it harm the joint cartilage? An in vivo study on sheep tibiae.

PURPOSE: Subchondral screw abutment in osteosynthesis of joint fractures is an effective method to achieve sufficient screw grip. In this study we investigated if subchondral screw placement is possible without harming the overlying subchondral plate and joint cartilage iatrogenic. MATERIALS AND METHODS: A 3.5-mm conventional steel screw was placed in the tibia of ten sheep in distances between 1 and 7 mm beneath the joint cartilage. After a follow up of two and four months, evaluation of the subchondral bone and joint cartilage was performed by means of a histological osteoarthritis score, HRpQCT imaging and determination of the glycosaminoglycan content in the cartilage. The control group was the contralateral knee of the same animal. RESULTS: Histomorphometric evaluation of the Mankin osteoarthritis score revealed no significant difference compared to the control after two (p = 0.102) and four months (p = 0.429). No correlation between distance of the screw to the cartilage and histological scoring was found (p = 0.658, R2 = 0.04 after two months and p = 0.171, R2 = 0.18 after four months). HRpQCT measurements of the subchondral thickness between screw and cartilage after two (p = 0.05) and four months (p = 0.424) showed no significant difference. Mean glycosaminoglycan content in the treatment group compared to the control after two months (p = 0.25) and four months (p = 0.523) was not significant different. CONCLUSION: In conclusion subchondral screw abutment did not damage the joint cartilage after a two- and four-month follow up in this sheep model.

Antioxidative therapy in an ex vivo human cartilage trauma-model: attenuation of trauma-induced cell loss and ECM-destructive enzymes by N-acetyl cysteine.

OBJECTIVE: Mechanical trauma of articular cartilage results in cell loss and cytokine-driven inflammatory response. Subsequent accumulation of reactive oxygen (ROS) and nitrogen (RNS) species enhances the enzymatic degradation of the extracellular matrix (ECM). This study aims on the therapeutic potential of N-acetyl cysteine (NAC) in a human ex vivo cartilage trauma-model, focusing on cell- and chondroprotective features. DESIGN: Human full-thickness cartilage explants were subjected to a defined impact trauma (0.59 J) and treated with NAC. Efficiency of NAC administration was evaluated by following outcome parameters: cell viability, apoptosis rate, anabolic/catabolic gene expression, secretion and activity of matrix metalloproteinases (MMPs) and proteoglycan (PG) release. RESULTS: Continuous NAC administration increased cell viability and reduced the apoptosis rate after trauma. It also suppressed trauma-induced gene expression of ECM-destructive enzymes, such as ADAMTS-4, MMP-1, -2, -3 and -13 in a dosage- and time-depending manner. Subsequent suppression of MMP-2 and MMP-13 secretion reflected these findings on protein level. Moreover, NAC inhibited proteolytic activity of MMPs and reduced PG release. CONCLUSION: In the context of this ex vivo study, we showed not only remarkable cell- and chondroprotective features, but also revealed new encouraging findings concerning the therapeutically effective concentration and treatment-time regimen of NAC. Its defense against chondrocyte apoptosis and catabolic enzyme secretion recommends NAC as a multifunctional add-on reagent for pharmaceutical intervention after cartilage injury. Taken together, our data increase the knowledge on the therapeutic potential of NAC after cartilage trauma and presents a basis for future in vivo studies.

Elevated expression of periostin in human osteoarthritic cartilage and its potential role in matrix degradation via matrix metalloproteinase-13.

We investigated the role of periostin, an extracellular matrix protein, in the pathophysiology of osteoarthritis (OA). In OA, dysregulated gene expression and phenotypic changes in articular chondrocytes culminate in progressive loss of cartilage from the joint surface. The molecular mechanisms underlying this process are poorly understood. We examined periostin expression by immunohistochemical analysis of lesional and nonlesional cartilage from human and rodent OA knee cartilage. In addition, we used small interfering (si)RNA and adenovirus transduction of chondrocytes to knock down and up-regulate periostin levels, respectively, and analyzed its effect on matrix metalloproteinase (MMP)-13, a disintegrin and MMP with thrombospondin motifs (ADAMTS)-4, and type II collagen expression. We found high periostin levels in human and rodent OA cartilage. Periostin increased MMP-13 expression dose [1-10 µg/ml (EC50 0.5-1 µg/ml)] and time (24-72 h) dependently, significantly enhanced expression of ADAMTS4 mRNA, and promoted cartilage degeneration through collagen and proteoglycan degradation. Periostin induction of MMP-13 expression was inhibited by CCT031374 hydrobromide, an inhibitor of the canonical Wnt/ß-catenin signaling pathway. In addition, siRNA-mediated knockdown of endogenous periostin blocked constitutive MMP-13 expression. These findings implicate periostin as a catabolic protein that promotes cartilage degeneration in OA by up-regulating MMP-13 through canonical Wnt signaling.

Total Knee Arthroplasty for Posttraumatic Osteoarthritis: Is it Time for a New Classification?

BACKGROUND: Total knee arthroplasty (TKA) is often the best answer for end-stage, posttraumatic osteoarthritis after intra-articular and periarticular fractures about the knee. Although TKA in this setting is often considered more technically demanding, outcomes are typically worse for patients. This study examines the intraoperative differences and 30-day outcomes in posttraumatic vs primary TKA cohorts. METHODS: Patients undergoing TKA were selected from the National Surgical Quality Improvement Program database from 2010 to 2013. Patients were stratified on the basis of concurrent procedures and administrative codes indicating posttraumatic diagnoses. Thirty-day complications were recorded, and multivariate analyses were performed to determine whether posttraumatic arthritis was a risk factor for poor outcomes. RESULTS: A total of 67,675 primary and 674 posttraumatic TKAs were identified. Posttraumatic TKA patients were on average younger and healthier than the primary TKA population. The posttraumatic TKA group had higher rates of superficial surgical site infections and bleeding requiring transfusion. History of posttraumatic knee osteoarthritis was found to be an independent risk factor for prolonged operative time, increased length of hospital stay, and 30-day hospital readmission. CONCLUSION: We have demonstrated increased intraoperative times, heightened transfusion requirements and surgical site infections, and higher readmission rates after conversion TKA in the posttraumatic cohort. In contrast to total hip arthroplasty, current diagnosis and reimbursement schemes do not differentiate posttraumatic patients from primary osteoarthritis groups undergoing TKA. We believe that classification reform would improve medical documentation and improve patient care.