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Background: Sport-related ankle sprains (SASs) are prevalent in adolescents (ages 10-19), increasing the risk of developing posttraumatic osteoarthritis (PTOA). Although early ankle osteoarthritis (OA) is not well defined, OA eventually includes alterations in bone mineral density (BMD), structural changes, and soft tissue pathology. This study examined the impact of SAS sustained in adolescent sport on bone and soft tissue structural outcomes 3-15 years postinjury. Methods: Participants (n = 10) with prior unilateral SAS in adolescent sport (HxAI) were compared to age- and sex-matched controls. To assess injury-related pathologies and BMD, 1.5-tesla (T) extremity magnetic resonance imaging (MRI) and computed tomography scans were used. Semiquantitative scores for injury patterns and OA features from MRI scans were summed and compared between groups. The talus, calcaneus, navicular, and 5% distal tibia were segmented, and BMD was measured for each bone. Results: All HxAI participants exhibited MRI injury pathology (median 2; IQR 1-6), whereas only 1 of 10 controls showed pathology (median 0; IQR 0-0), χ2(1, n = 20) = 16.36, P <.001. Both the injured and uninjured ankles in HxAI displayed injury pattern pathology. Additionally, 3 of 10 injured ankles and 2 of 10 uninjured ankles in the HxAI group (median 0; IQR 0-3), but none of the controls (median 0; IQR 0-0), exhibited OA features. In the HxAI group, talus BMD was lower in the injured ankle (502.4 ± 67.9 g/cm3) compared with the uninjured ankle (515.6 ± 70.1 g/cm3) (F = 13.33, P =.002), with no significant BMD differences at the calcaneus, navicular, or 5% distal tibia. No differences were observed between the ankles of the control group. Conclusion: The presence of injury pattern pathology, structural changes, and reduced talus BMD suggest that degenerative changes may occur in individuals as early as 3-15 years following ankle injury. [ABSTRACT FROM AUTHOR]

Background: Posttraumatic osteoarthritis (PTOA) is directly associated with early acute articular cartilage injury. Inhibition of cartilage destruction immediately following joint damage can effectively slow or prevent PTOA progression. Therefore, we sought to determine intervention targets and therapeutic strategies in the acute stage of cartilage injury. The benefits of chronic intermittent hypobaric hypoxia (CIHH) extend to various body tissues, but its impact on acute cartilage injury remains unclear. We selected PTOA initiation as the therapeutic window and administered CIHH treatment immediately following cartilage injury initiation to investigate its protective effect on cartilage and molecular mechanism changing with time-varying. Methods: The non-invasive PTOA mouse model was established by applying a single rapid specific impact force to the right knee's tibial plateau, initiating load-induced PTOA development, closely resembling the pathological changes in human diseases. Following loading, we inhibited cartilage destruction by treating mice immediately in a hypobaric chamber with a hypobaric hypoxia mimic at 5000 m altitude. Cohorts of mice subjected to distinct experimental conditions were monitored for 3, 7, 14 or 28 days. Safranin O-Fast Green staining, Immunohistochemistry, immunofluorescence, ELISA, and western blotting were performed to evaluate the therapeutic effects of CIHH on cartilage in vivo. The nuclear translocation of NF-κB p65 and Nrf2 were detected by immunofluorescence. Results: The results showed that inhibiting cartilage destruction using CIHH immediately following acute articular cartilage injury initiation delayed the progression of PTOA, decreased the Mankin score and suppressed the expression of proinflammatory factors, including iNOS, NO, TNF-α, and IL-1β. Meanwhile, immediate CIHH treatment reduced levels of the catabolic enzymes ADAMTS5 and MMP13 in the cartilage matrix, reversed degradation of Collagen II and COMP, and inhibited oxidative stress by decreasing ROS levels. Moreover, CIHH suppressed NF-κB signaling by activating the Nrf2 in vivo studies. Conclusion: Our study demonstrated that immediate CIHH treatment following cartilage injury initiation can attenuate load-induced cartilage damage by activating Nrf2/HO-1 and inhibiting the NF-κB p65 signalling pathways to counteract oxidative stress and inflammatory reactions, enhance the metabolic balance of the cartilage matrix and delay cartilage degeneration. This treatment may represent a potential therapeutic strategy for limiting PTOA progression. [ABSTRACT FROM AUTHOR]

Posttraumatic osteoarthritis (PTOA) commonly develops following anterior cruciate ligament (ACL) injuries, affecting around 50% of individuals within 10–20 years. Recent studies have highlighted early changes in subchondral bone structure after ACL injury in adolescent or young adult mice, which could contribute to the development of PTOA. However, ACL injuries do not only occur early in life. Middle‐aged and older patients also experience ACL injuries and PTOA, but whether the aged subchondral bone also responds rapidly to injury is unknown. This study utilized a noninvasive, single overload mouse injury model to assess subchondral bone microarchitecture, turnover, and material properties in both young adults (5 months) and early old age (22 months) female C57BL/6JN mice at 7 days after injury. Mice underwent either joint injury (i.e., produces ACL tears) or sham injury procedures on both the loaded and contralateral limbs, allowing evaluation of the impacts of injury versus loading. The subchondral bone response to ACL injury is distinct for young adult and aged mice. While 5‐month mice show subchondral bone loss and increased bone resorption postinjury, 22‐month mice did not show loss of bone structure and had lower bone resorption. Subchondral bone plate modulus increased with age, but not with injury. Both ages of mice showed several bone measures were altered in the contralateral limb, demonstrating the systemic skeletal response to joint injury. These data motivate further investigation to discern how osteochondral tissues differently respond to injury in aging, such that diagnostics and treatments can be refined for these demographics. [ABSTRACT FROM AUTHOR]

Collaboration between military and civilian investigators is necessary to develop strategies for optimizing treatments to diminish the sequelae of non–battle-related musculoskeletal injuries, which are highly prevalent among servicemembers. The 2024 Extremity War Injuries Symposium provided a forum whereby a diverse group of clinicians and researchers could develop strategies for optimizing treatments and diminishing the sequelae of conditions that are highly prevalent among active individuals. Key points were as follows: 1. The value of collaborations between military and civilian investigators cannot be overemphasized. These synergies can leverage the capabilities of established infrastructures in order to answer important questions pertaining to short-term outcomes—for example, warrior readiness of anterior cruciate ligament reconstructions among servicemembers and long-term posttraumatic osteoarthritis (PTOA) outcomes among civilian cohorts. 2. Current and future prospective trials will inform future treatment decisions related to multiligamentous knee injuries and glenohumeral instability. 3. Novel approaches to addressing PTOA in the acute postinjury period will need longitudinal surveillance to measure their impact on improving clinical outcomes and diminishing residual functional deficits. [ABSTRACT FROM AUTHOR]

Abstract Background Posttraumatic osteoarthritis (PTOA) is directly associated with early acute articular cartilage injury. Inhibition of cartilage destruction immediately following joint damage can effectively slow or prevent PTOA progression. Therefore, we sought to determine intervention targets and therapeutic strategies in the acute stage of cartilage injury. The benefits of chronic intermittent hypobaric hypoxia (CIHH) extend to various body tissues, but its impact on acute cartilage injury remains unclear. We selected PTOA initiation as the therapeutic window and administered CIHH treatment immediately following cartilage injury initiation to investigate its protective effect on cartilage and molecular mechanism changing with time-varying. Methods The non-invasive PTOA mouse model was established by applying a single rapid specific impact force to the right knee’s tibial plateau, initiating load-induced PTOA development, closely resembling the pathological changes in human diseases. Following loading, we inhibited cartilage destruction by treating mice immediately in a hypobaric chamber with a hypobaric hypoxia mimic at 5000 m altitude. Cohorts of mice subjected to distinct experimental conditions were monitored for 3, 7, 14 or 28 days. Safranin O-Fast Green staining, Immunohistochemistry, immunofluorescence, ELISA, and western blotting were performed to evaluate the therapeutic effects of CIHH on cartilage in vivo. The nuclear translocation of NF-κB p65 and Nrf2 were detected by immunofluorescence. Results The results showed that inhibiting cartilage destruction using CIHH immediately following acute articular cartilage injury initiation delayed the progression of PTOA, decreased the Mankin score and suppressed the expression of proinflammatory factors, including iNOS, NO, TNF-α, and IL-1β. Meanwhile, immediate CIHH treatment reduced levels of the catabolic enzymes ADAMTS5 and MMP13 in the cartilage matrix, reversed degradation of Collagen II and COMP, and inhibited oxidative stress by decreasing ROS levels. Moreover, CIHH suppressed NF-κB signaling by activating the Nrf2 in vivo studies. Conclusion Our study demonstrated that immediate CIHH treatment following cartilage injury initiation can attenuate load-induced cartilage damage by activating Nrf2/HO-1 and inhibiting the NF-κB p65 signalling pathways to counteract oxidative stress and inflammatory reactions, enhance the metabolic balance of the cartilage matrix and delay cartilage degeneration. This treatment may represent a potential therapeutic strategy for limiting PTOA progression.

Abstract Acute cartilage injuries, such as intra-articular fractures and blunt impacts, frequently result in chondrocyte death and extracellular matrix (ECM) degradation, significantly elevating the risk of post-traumatic osteoarthritis (PTOA). Despite advances in treatment, no effective therapies currently exist to fully cure PTOA or halt its progression. This study explores the protective effects of the dietary fatty acid eicosapentaenoic acid (EPA) on human primary chondrocytes (HPCs) and cartilage explants exposed to mechanical overload and blunt trauma. HPCs were isolated and subjected to mechanical stretching using BioFlex six-well culture plates, while cartilage explants were subjected to impact loading via a customized drop tower. EPA was incorporated into the culture medium, followed by assays to evaluate cell viability, calcium (Ca²⁺) influx, apoptosis, reactive oxygen species (ROS) levels, and collagen type II alpha (Col-2a) expression. EPA treatment markedly decreased chondrocyte mechanical sensitivity, as demonstrated by enhanced cell viability and reduced lactate dehydrogenase (LDH) release. Furthermore, EPA inhibited Piezo1 activation, leading to lower intracellular Ca²⁺ concentrations, decreased apoptosis, and diminished ROS levels. In cartilage explants, EPA improved chondrocyte viability, minimized structural damage, and sustained higher Col-2a expression compared to the blunt trauma group. These results indicate that EPA effectively shields chondrocytes and cartilage explants from mechanical overload-induced damage by inhibiting Piezo1 activation and mitigating Ca²⁺ influx, apoptosis, and oxidative stress. The findings suggest that EPA supplementation could offer a promising strategy for preventing PTOA progression following acute cartilage injuries. Further research is warranted to assess the clinical applications of EPA and confirm its efficacy in larger animal models and human trials.

Abstract Posttraumatic osteoarthritis (PTOA) is closely related to the inflammatory response caused by mechanical injury and leads to joint degeneration. Herein, we aimed to evaluate the role and underlying mechanism of NUMB in PTOA progression. Anterior cruciate ligament transection (ACLT)-induced rats and interleukin (IL)-1β-treated chondrocytes were used as in vivo and in vitro models of PTOA, respectively. The NUMB overexpression plasmid (pcDNA-NUMB) was administered by intra-articular injection to PTOA model rats, and safranin O-fast green staining, the Osteoarthritis Research Society International (OARSI) scoring system, and HE staining were used to evaluate the severity of cartilage damage. The secretion of inflammatory cytokines (TNF-α, IL-1β, and IL-6) and chondrocyte-specific markers (MMP13 and COL2A1) was detected via ELISA. Cell viability and apoptosis were evaluated by MTT and TUNEL assays. NUMB was expressed at lower levels in ACLT-induced PTOA rats and in IL-1β-treated chondrocytes than in control rats and cells. NUMB overexpression enhanced cell viability and reduced cell apoptosis, inflammation and cartilage degradation in chondrocytes stimulated by IL-1β. NUMB bound to BTRC to promote p-IκBα expression, resulting in NF-κB pathway inactivation. BTRC overexpression reversed the promoting effect of NUMB overexpression on cell viability and the inhibitory effects of NUMB overexpression on apoptosis, inflammation and cartilage degradation in IL-1β-induced chondrocytes. In addition, overexpression of NUMB alleviated articular cartilage damage by repressing inflammation and cartilage degradation in ACLT-induced PTOA rats. Our data indicated that NUMB regulated PTOA progression through the BTRC/NF-κB pathway, which may be a viable therapeutic target in PTOA.

Acute cartilage injuries, such as intra-articular fractures and blunt impacts, frequently result in chondrocyte death and extracellular matrix (ECM) degradation, significantly elevating the risk of post-traumatic osteoarthritis (PTOA). Despite advances in treatment, no effective therapies currently exist to fully cure PTOA or halt its progression. This study explores the protective effects of the dietary fatty acid eicosapentaenoic acid (EPA) on human primary chondrocytes (HPCs) and cartilage explants exposed to mechanical overload and blunt trauma. HPCs were isolated and subjected to mechanical stretching using BioFlex six-well culture plates, while cartilage explants were subjected to impact loading via a customized drop tower. EPA was incorporated into the culture medium, followed by assays to evaluate cell viability, calcium (Ca²⁺) influx, apoptosis, reactive oxygen species (ROS) levels, and collagen type II alpha (Col-2a) expression. EPA treatment markedly decreased chondrocyte mechanical sensitivity, as demonstrated by enhanced cell viability and reduced lactate dehydrogenase (LDH) release. Furthermore, EPA inhibited Piezo1 activation, leading to lower intracellular Ca²⁺ concentrations, decreased apoptosis, and diminished ROS levels. In cartilage explants, EPA improved chondrocyte viability, minimized structural damage, and sustained higher Col-2a expression compared to the blunt trauma group. These results indicate that EPA effectively shields chondrocytes and cartilage explants from mechanical overload-induced damage by inhibiting Piezo1 activation and mitigating Ca²⁺ influx, apoptosis, and oxidative stress. The findings suggest that EPA supplementation could offer a promising strategy for preventing PTOA progression following acute cartilage injuries. Further research is warranted to assess the clinical applications of EPA and confirm its efficacy in larger animal models and human trials. [ABSTRACT FROM AUTHOR]

Background: Posttraumatic osteoarthritis (PTOA) arises secondarily to joint trauma and is driven by catabolic inflammatory pathways. Alpha-2-macroglobulin (α2M) is a naturally occurring proteinase inhibitor found in human serum and synovial fluid that binds proteases as well as proinflammatory cytokines involved in the pathogenesis of PTOA. Purpose: (1) To investigate the therapeutic potential of intra-articular α2M injections during the acute stages of PTOA by inhibiting inflammatory pathways driven by the cytokines expressed by the synovium in a large preclinical Yucatan minipig model and (2) to determine if 3 intra-articular α2M injections have greater chondroprotective effects compared with 1 intra-articular injection. Study Design: Controlled laboratory study. Methods: A total of 48 Yucatan minipigs were randomized into 4 groups (n = 12 each): (1) modified intra-articular drilling (mIAD) and saline (mIAD + saline), (2) mIAD and 1 intra-articular α2M injection (mIAD +α2M-1), (3) mIAD and 3 α2M injections (mIAD +α2M-3), and (4) sham control. Surgical hindlimbs were harvested at 15 weeks after surgery. Cartilage degeneration, synovial changes, inflammatory gene expression, and matrix metalloproteinase levels were evaluated. Gait asymmetry was measured before and after surgery using a pressure-sensing walkway system. Results: Macroscopic lesion areas and microscopic cartilage degeneration scores were lower in the mIAD +α2M-1 and mIAD +α2M-3 groups compared with the mIAD + saline group (P <.05) and similar to those in the sham group (P >.05). Synovial membrane scores of the mIAD +α2M-1 and mIAD +α2M-3 groups were lower than that of the mIAD + saline group (P <.05) and higher than that of the sham group (P <.05). Interleukin-1 beta, nuclear factor kappa B, and tumor necrosis factor alpha mRNA expression in the synovium and matrix metalloproteinase-1 levels in synovial fluid were significantly lower in the mIAD +α2M-1 and mIAD +α2M-3 groups compared with the mIAD + saline group (P <.05). No significant differences were observed between the mIAD +α2M-1 and mIAD +α2M-3 groups for all measured outcomes. There were early changes in gait (P <.05) between preoperative and postoperative time points for the mIAD + saline, mIAD +α2M-1, and mIAD +α2M-3 groups that normalized by 15 weeks. Conclusion: Animals receiving early α2M treatment exhibited less cartilage damage, milder synovitis, and lower inflammation compared with animals with no α2M treatment. These results exemplify the early anti-inflammatory effects of α2M and provide evidence that intra-articular α2M injections may slow the progression of PTOA. Clinical Relevance: In patients presenting with an acute joint injury, an early intervention with α2M may have the potential to reduce cartilage degeneration from catabolic pathways and delay the development of PTOA. [ABSTRACT FROM AUTHOR]

Purpose: High body mass index (BMI) is a strong predictor of posttraumatic osteoarthritis (OA) after anterior cruciate ligament reconstruction (ACLR). Altered gait mechanics are independently affected by BMI and ACLR, and influence OA risk. Yet, evidence directly assessing the impact of high BMI on gait or cartilage characteristics after ACLR are limited. Here, we evaluated if high BMI moderates associations between gait and trochlear cartilage structure in individuals with ACLR. Methods: Treadmill walking biomechanics were evaluated in 40 normal BMI and 24 high BMI participants with ACLR at self-selected speeds. Normalized and absolute peak and cumulative loads (i.e., impulse) were extracted for peak knee flexion and adduction moments (KFM, KAM) and vertical ground reaction force (GRF).Medial and lateral femoral cartilage thickness and medial/lateral thickness ratios were assessed via ultrasound. Results: Those with ACLR and high BMI walked with reduced normalized peak vertical GRFs, and greater absolute peak and cumulative loads compared with normal BMI individuals with ACLR. Those with ACLR and high BMI also exhibited thinner cartilage and greater medial/lateral ratios in ACLR limbs compared with contralateral limbs whereas norma lBMI individuals with ACLR exhibited thicker ACLR limb cartilage. Lastly, greater peak KAM and KAM cumulative load were associated with thicker lateral cartilage and lesser medial/lateral thickness ratios, but only in the high BMI group. Conclusions: We observed those with high BMI after ACLR exhibited trochlear cartilage structural alterations not observed in normal BMI patients, whereas differential associations between loading outcomes and cartilage thickness in ACLR knees were observed between groups. Those with high BMI after ACLR may require different therapeutic strategies to optimize joint health in this subset of patients. [ABSTRACT FROM AUTHOR]

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Background: The reported incidence of posttraumatic knee osteoarthritis (PTOA) after primary anterior cruciate ligament reconstruction (ACLR) varies considerably. Further, there are gaps in identifying which patients are at risk for PTOA after ACLR and whether there are modifiable factors. Purpose: To (1) determine the incidence of PTOA in a primary ACLR cohort and (2) identify patient and perioperative factors associated with the development of PTOA after primary ACLR. Study Design: Cohort study; Level of evidence, 3. Methods: Data from the Kaiser Permanente ACLR Registry were used to conduct a cohort study. Patients who had undergone primary ACLR without a previous diagnosis of osteoarthritis were identified (2009-2020). The crude incidence of PTOA was calculated using the Aalen-Johansen estimator with a multistate model. The association of patient and operative factors with the development of PTOA after primary ACLR was modeled as a time to event using multistate Cox proportional hazards regression. Models stratified by age (<22 and ≥22 years) were also conducted because of the effect modification of age. Results: The study sample included 41,976 cases of primary ACLR. The incidence of PTOA was 1.7%, 5.1%, and 13.6% at 2, 5, and 10 year follow-ups, respectively. Risk factors for PTOA that were consistently identified in the overall cohort and age-stratified groups included a body mass index ≥30 versus <30 and an allograft or quadriceps tendon autograft versus a hamstring tendon autograft. Patients presenting with knee pain after ACLR were further identified when considering postoperative factors. Other risk factors for PTOA in the overall cohort included age ≥22 versus <22 years, bone–patellar tendon–bone autograft versus hamstring tendon autograft, hypertension, cartilage injury, meniscal injury, revision after primary ACLR with concomitant meniscal/cartilage surgery, multiligament injury, other activity at the time of injury compared with sport, and tibial tunnel drilling technique rather than the anteromedial portal. Conclusion: Knee pain after ACLR may be an early sign of PTOA. Surgeons should consider the adverse associations of a higher body mass index and an allograft or quadriceps tendon autograft with the development of PTOA, as these were factors identified with a higher risk, regardless of a patient's age at the time of primary ACLR. [ABSTRACT FROM AUTHOR]

Background: Animal models that use open surgical transection of the anterior cruciate ligament (ACL) do not accurately simulate the clinical condition regarding the pivot-shift mechanism and the associated inflammatory response that occurs before reconstruction. Purpose/Hypothesis: The purpose was to characterize a reproducible manual, nonsurgical method to mimic an isolated ACL tear in a clinically relevant model and to evaluate the development of progressive posttraumatic osteoarthritis due to ACL injury. It was hypothesized that the ACL could be reproducibly torn with minimal damage to other ligaments and that there would be progressive development of degenerative joint disease after ACL injury. Study Design: Controlled laboratory study. Methods: A total of 37 mice (strain C57BL/6) were used to compare the manual procedure with sham surgery (sham group; n = 10) and with the established surgical ACL transection (ACLT) procedure (surgical group; n = 27). In the sham group, a closed manual procedure was performed on the right knee and sham surgery on the left knee. In the surgical group, the closed manual procedure was performed on the right knee and surgical ACLT on the left knee. Dissection using India ink, histological assessment with safranin O and hematoxylin-eosin staining, radiological evaluation through radiographs and microfocus computed tomography scans, and gait analyses were performed to assess cartilage/ligament status. Osteoarthritis Research Society International (OARSI) and synovitis scores, anterior tibial translation, range of motion, bone microstructure, osteophyte volume, and pain were assessed at 2, 4, and 8 weeks postoperatively. Results: The manual procedure successfully resulted in an ACL rupture and associated meniscal injury. The posterior cruciate, lateral collateral, and medial collateral ligaments were intact in all dissected knees. Two weeks after ACL tear, the surgical group showed a significantly higher synovitis score, whereas 8 weeks after ACL tear, the manual group showed a significantly higher volume of osteophytes. No significant differences were found between the groups in terms of OARSI score, anterior tibial translation, range of motion, bone microstructure computed tomography values, and stride distance/irregularity. Conclusion: This procedure can be used to create an ACL tear model without causing grossly evident injuries to other ligaments and avoiding the risk of cartilage damage from surgical instruments. Clinical Relevance: This procedure offers a more clinically relevant ACL tear model and facilitates simple, inexpensive, and reproducible development of posttraumatic osteoarthritis. [ABSTRACT FROM AUTHOR]

Traumatized knee greatly contributes to osteoarthritis (OA) of the knee in young adults. To intervene effectively before the onset of severe structural disruption, detection of the disease at the early onset is crucial. In this study, we put together the findings for the detection of OA from the femoral knee joint cartilage of the rabbit at 6 weeks posttrauma. Articular cartilage samples are taken from the impacted and nonimpacted joints at 0 week (serving as the control group) and at 6 weeks posttrauma by minimal force. The samples were imaged using microscopic magnetic resonance imaging (µMRI) at 11.7 µm/pixel and polarized light microscopy (PLM) at 1 µm/pixel. In addition, an inductively coupled plasma ‐ optical emission spectrometry analysis was performed using the adjacent cartilage samples. The outcomes of this study demonstrate an increase in T2 values in 6 weeks samples compared to the 0 week samples by µMRI technique, indicating a general increase of tissue hydration within cartilage. PLM detects a decrease in the average thickness of the superficial zones in the posttraumatic osteoarthritis samples, significant in the impacted femurs. There was an average increasing trend of maximum retardation in the tide mark in comparison to the reported calcium concentration (mg/L) in impacted samples suggesting a possible rise in mineralization in the 6 weeks samples. Qualitatively, physical observation of the joint after 6 weeks showed signs of reddening in the anterior femur suggesting the disease process is a localized phenomenon. Through microscopic imaging, we are able to detect these changes at 6 weeks posttrauma qualitatively and quantitatively. [ABSTRACT FROM AUTHOR]

Objectives: Ankle fractures have an incidence of around 90,000 per year in the United Kingdom. They affect younger patients following high energy trauma and, in the elderly, following low energy falls. Younger patients with pre-existing comorbidities including raised BMI or poor bone quality are also at risk of these injuries which impact the bony architecture of the joint and the soft tissues leading to a highly unstable fracture pattern, resulting in dislocation. At present, there is no literature exploring what effect ankle fracture-dislocations have on patients' quality of life and activities of daily living, with only ankle fractures being explored. Methods: Relevant question formatting was utilised to generate a focused search. This was limited to studies specifically mentioning ankle injuries with a focus on ankle fracture-dislocations. The number of patients, fracture-dislocation type, length of follow up, prognostic factors, complications and outcome measures were recorded. Results: Nine hundred and thirty-nine fractures were included within the studies. Eight studies looked at previously validated foot and ankle scores, two primarily focused on the American Orthopaedic Foot and Ankle Society score (AOFAS), three on the foot and ankle outcome score (FAOS), and one study on the Olerud-Molander score (OMAS). Patient, injury, and management factors were identified as being associated with poorer clinical outcomes. Conclusions: Not only are age and BMI a risk factor for posttraumatic osteoarthritis but they were also identified as prognostic indicators for functional outcome in this review. Patients sustaining a concurrent fracture-dislocation were found to have poorer clinical outcomes, and the timing and success of reduction further influenced outcomes. This review found that the quality of reduction was directly related to the patients' functional outcomes post-follow up, and the risk of developing posttraumatic osteoarthritis, which was more frequent in patients sustaining Bosworth fractures, posterior malleolar fractures, and in patients with increasing age. Level of evidence: IV. [ABSTRACT FROM AUTHOR]

Copyright of Die Radiologie is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background: Concerns have arisen that anterior cruciate ligament reconstruction (ACLR) with lateral extra-articular tenodesis (LET) may accelerate the development of posttraumatic osteoarthritis in the lateral compartment of the knee. Purpose/Hypothesis: The purpose of this study was to evaluate whether the augmentation of ACLR with LET affects the quality of lateral compartment articular cartilage on magnetic resonance imaging (MRI) at 2 years postoperatively. We hypothesized that there would be no difference in T1rho and T2 relaxation times when comparing ACLR alone with ACLR + LET. Study Design: Randomized controlled trial; Level of evidence, 1. Methods: A consecutive subgroup of patients at the Fowler Kennedy Sport Medicine Clinic participating in the STABILITY 1 Study underwent bilateral 3-T MRI at 2 years after surgery. The primary outcome was T1rho and T2 relaxation times. Articular cartilage in the lateral compartment was manually segmented into 3 regions of the tibia (lateral tibia [LT]–1 to LT-3) and 5 regions of the femur (lateral femoral condyle [LFC]–1 to LFC-5). Analysis of covariance was used to compare relaxation times between groups, adjusted for lateral meniscal tears and treatment, cartilage and bone marrow lesions, contralateral relaxation times, and time since surgery. Semiquantitative MRI scores according to the Anterior Cruciate Ligament OsteoArthritis Score were compared between groups. Correlations were used to determine the association between secondary outcomes (including results of the International Knee Documentation Committee score, Knee injury and Osteoarthritis Outcome Score, Lower Extremity Functional Scale, 4-Item Pain Intensity Measure, hop tests, and isokinetic quadriceps and hamstring strength tests) and cartilage relaxation. Results: A total of 95 participants (44 ACLR alone, 51 ACLR + LET) with a mean age of 18.8 years (61.1% female [58/95]) underwent 2-year MRI (range, 20-36 months). T1rho relaxation times were significantly elevated for the ACLR + LET group in LT-1 (37.3 ± 0.7 ms vs 34.1 ± 0.8 ms, respectively; P =.005) and LFC-2 (43.9 ± 0.9 ms vs 40.2 ± 1.0 ms, respectively; P =.008) compared with the ACLR alone group. T2 relaxation times were significantly elevated for the ACLR + LET group in LFC-1 (51.2 ± 0.7 ms vs 49.1 ± 0.7 ms, respectively; P =.03) and LFC-4 (45.9 ± 0.5 ms vs 44.2 ± 0.6 ms, respectively; P =.04) compared with the ACLR alone group. All effect sizes were small to medium. There was no difference in Anterior Cruciate Ligament OsteoArthritis Scores between groups (P =.99). Weak negative associations (rs = –0.27 to –0.22; P <.05) were found between relaxation times and quadriceps and hamstring strength in the anterolateral knee, while all other correlations were nonsignificant (P >.05). Conclusion: Increased relaxation times demonstrating small to medium effect sizes suggested early biochemical changes in articular cartilage of the anterolateral compartment in the ACLR + LET group compared with the ACLR alone group. Further evidence and long-term follow-up are needed to better understand the association between these results and the potential risk of the development of osteoarthritis in our patient cohort. [ABSTRACT FROM AUTHOR]

Aberrant gait biomechanics in individuals with anterior cruciate ligament reconstruction (ACLR) are linked to posttraumatic osteoarthritis (PTOA) development, indicating a need to normalize gait biomechanics to prevent PTOA. Anterior cruciate ligament reconstruction individuals walk slower than uninjured controls and slower speeds are associated with aberrant gait biomechanics. Yet, it is unclear if increasing walking speed normalizes gait biomechanics post-ACLR. Purpose: To determine the effect of acutely increasing walking speed on gait biomechanics in ACLR individuals compared with their habitual speed and uninjured matched-controls. Methods: Gait biomechanics were collected on 30 ACLR individuals (20 females; age, 22.0 ± 4.2 yr; body mass index, 24.0 ± 3.0 kg·m−2) at their habitual speed and at 1.3 m·s−1, a speed similar to controls, and 30 uninjured matched-controls (age: 21.9 ± 3.8, body mass index: 23.6 ± 2.5) at their habitual speed. Functional waveform analyses compared biomechanics between: i) walking at habitual speed vs 1.3 m·s−1 in ACLR individuals; and ii) ACLR individuals at 1.3 m·s−1 vs controls. Results: In the ACLR group, there were no statistically significant biomechanical differences between walking at habitual speed (1.18 ± 0.12 m·s−1) and 1.3 m·s−1 (1.29 ± 0.05 m·s−1). Compared with controls (habitual speed: 1.34 ± 0.12 m·s−1), the ACLR group while walking at 1.3 m·s−1 exhibited smaller vertical ground reaction force (vGRF) during early and late stance (13–28, 78–90% stance phase), greater midstance vGRF (47–61%), smaller early-to-midstance knee flexion angle (KFA; 1–44%), greater mid-to-late stance KFA (68–73, 96–101%), greater internal knee abduction moment (69–101%), and smaller internal knee extension moment (4–51, 88–96%). Conclusions: Increasing walking speed to a speed similar to uninjured controls did not elicit significant changes to gait biomechanics, and ACLR individuals continued to demonstrate biomechanical profiles that are associated with PTOA development and differ from controls. [ABSTRACT FROM AUTHOR]

Excessive tissue deformation near cartilage lesions and acute inflammation within the knee joint after anterior cruciate ligament (ACL) rupture and reconstruction surgery accelerate the loss of fixed charge density (FCD) and subsequent cartilage tissue degeneration. Here, we show how biomechanical and biochemical degradation pathways can predict FCD loss using a patient-specific finite element model of an ACL reconstructed knee joint exhibiting a chondral lesion. Biomechanical degradation was based on the excessive maximum shear strains that may result in cell apoptosis, while biochemical degradation was driven by the diffusion of pro-inflammatory cytokines. We found that the biomechanical model was able to predict substantial localized FCD loss near the lesion and on the medial areas of the lateral tibial cartilage. In turn, the biochemical model predicted FCD loss all around the lesion and at intact areas; the highest FCD loss was at the cartilage-synovial fluid-interface and decreased toward the deeper zones. Interestingly, simulating a downturn of an acute inflammatory response by reducing the cytokine concentration exponentially over time in synovial fluid led to a partial recovery of FCD content in the cartilage. Our novel numerical approach suggests that in vivo FCD loss can be estimated in injured cartilage following ACL injury and reconstruction. Our novel modeling platform can benefit the prediction of PTOA progression and the development of treatment interventions such as disease-modifying drug testing and rehabilitation strategies.

Diabetes mellitus (DM) and osteoarthritis (OA) are commonly known metabolic diseases that affect a large segment of the world population. These two conditions share several risk factors such as obesity and aging; however, there is still no consensus regarding the direct role of DM on OA development and progression. Interestingly, both animal and human studies have yielded conflicting results, with some showing a significant role for DM in promoting OA, while others found no significant interactions between these conditions. In this review, we will discuss preclinical and clinical data that assessed the interaction between DM and OA. We will also discuss possible mechanisms associated with the effect of high glucose on the articular cartilage and chondrocytes. An emerging theme dominates the breath of published work in this area: most of the studies discussed in this review do not take into consideration the role of other factors such as the type of diabetes, age, biological sex, type of animal model, body mass index, and the use of pain medications when analyzing and interpreting data. Therefore, future studies should be more rigorous when designing experiments looking at DM and its effects on OA and should carefully account for these confounding factors, so that better approaches can be developed for monitoring and treating patients at risk of OA and DM. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Type 1 diabetes mellitus (T1DM) affects 9.5% of the population. T1DM is characterized by severe insulin deficiency that causes hyperglycemia and leads to several systemic effects. T1DM has been suggested as a risk factor for articular cartilage damage and loss, which could expedite the development of osteoarthritis (OA). OA represents a major public health challenge by affecting 300 million people globally, yet very little is known about the correlation between T1DM and OA. In addition, current studies that have looked at the interaction between diabetes mellitus and OA have reported conflicting results with some suggesting a positive correlation whereas others did not. In this study, we aimed to evaluate whether T1DM exacerbates the development of spontaneous OA or accelerates the progression of posttraumatic osteoarthritis (PTOA) after joint injury. Histological evaluation of T1DM and control joints determined that T1DM mice displayed cartilage degeneration measurements consistent with mild OA phenotypes. RNA sequencing analyses identified significantly upregulated genes in T1DM corresponding to matrix-degrading enzymes known to promote cartilage matrix degradation, suggesting a role of these enzymes in OA development. Next, we assessed whether preexisting T1DM influences PTOA development subsequent to trauma. At 6 weeks post-injury, T1DM injured joints displayed significantly less cartilage damage and joint degeneration than injured non-diabetic joints, suggesting a significant delay in PTOA disease progression. At the single-cell resolution, we identified increased number of cells expressing the chondrocyte markers Col2a1, Acan, and Cytl1 in the T1DM injured group. Our findings demonstrate that T1DM can be a risk factor for OA but not for PTOA. This study provides the first account of single-cell resolution related to T1DM and the risk for OA and PTOA. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

BackgroundAfter anterior cruciate ligament (ACL) reconstruction, patient-reported outcomes are improved 10 years post-surgery; however, cytokine concentrations remain elevated years after surgery with over 80% of those with combined ACL and meniscus injuries having posttraumatic osteoarthritis (PTOA) within 10-15 years. The purpose of this multicenter, randomized, placebo-controlled trial is to assess whether a 6-month course of oral montelukast after ACL reconstruction reduces systemic markers of inflammation and biochemical and imaging biomarkers of cartilage degradation.MethodsWe will enroll 30 individuals undergoing primary ACL reconstruction to participate in this IRB-approved multicenter clinical trial. This trial will target those at greatest risk of a more rapid PTOA onset (age range 25-50 with concomitant meniscus injury). Patients will be randomly assigned to a group instructed to take 10 mg of montelukast daily for 6 months following ACL reconstruction or placebo. Patients will be assessed prior to surgery and 1, 6, and 12 months following surgery. To determine if montelukast alters systemic inflammation following surgery, we will compare systemic concentrations of prostaglandin E2, monocyte chemoattractant protein-1, and pro-inflammatory cytokines between groups. We will also compare degradative changes on magnetic resonance imaging (MRI) collected 1 and 12 months following surgery between groups with reductions in early biomarkers of cartilage degradation assessed with urinary biomarkers of type II collagen breakdown and bony remodeling.DiscussionThere is a complex interplay between the pro-inflammatory intra-articular environment, underlying bone remodeling, and progressive cartilage degradation. PTOA affects multiple tissues and appears to be more similar to rheumatoid arthritis than osteoarthritis with respect to inflammation. There is currently no treatment to delay or prevent PTOA after ACL injury. Since there is a larger and more persistent inflammatory response after ACL reconstruction than the initial insult of injury, treatment may need to be initiated after surgery, sustained over a period of time, and target multiple mechanisms in order to successfully alter the disease process. This study will assess whether a 6-month postoperative course of oral montelukast affects multiple PTOA mechanisms. Because montelukast administration can be safely sustained for long durations and offers a low-cost treatment option, should it be proven effective in the current trial, these results can be immediately incorporated into clinical practice.Trial registrationClinicalTrials.gov NCT04572256 . Registered on October 1, 2020.

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. 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. 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%). 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. [ABSTRACT FROM AUTHOR]

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. Summary: Harnessing the pro-resolving potential of SPMs may hold promise for preventing PTOA and restoring tissue homeostasis and function after joint injuries. [ABSTRACT FROM AUTHOR]

The purpose of this proof-of-concept study was to develop three-dimensional patient-specific mechanobiological knee joint models to simulate alterations in the fixed charged density (FCD) around cartilage lesions during the stance phase of the walking gait. Two patients with anterior cruciate ligament (ACL) reconstructed knees were imaged at 1 and 3 years after surgery. The magnetic resonance imaging (MRI) data were used for segmenting the knee geometries, including the cartilage lesions. Based on these geometries, finite element (FE) models were developed. The gait of the patients was obtained using a motion capture system. Musculoskeletal modeling was utilized to calculate knee joint contact and lower extremity muscle forces for the FE models. Finally, a cartilage adaptation algorithm was implemented in both FE models. In the algorithm, it was assumed that excessive maximum shear and deviatoric strains (calculated as the combination of principal strains), and fluid velocity, are responsible for the FCD loss. Changes in the longitudinal T1ρ and T2 relaxation times were postulated to be related to changes in the cartilage composition and were compared with the numerical predictions. In patient 1 model, both the excessive fluid velocity and strain caused the FCD loss primarily near the cartilage lesion. T1ρ and T2 relaxation times increased during the follow-up in the same location. In contrast, in patient 2 model, only the excessive fluid velocity led to a slight FCD loss near the lesion, where MRI parameters did not show evidence of alterations. Significance: This novel proof-of-concept study suggests mechanisms through which a local FCD loss might occur near cartilage lesions. In order to obtain statistical evidence for these findings, the method should be investigated with a larger cohort of subjects.

Introduction: Patients with anterior cruciate ligament injury are at high risk of posttraumatic osteoarthritis and their response to reconstructive surgery and rehabilitation vary. Proteins identified in the orchestration of the acute inflammatory response may be predictive of patient outcomes. Objective: An unbiased, bottom-up proteomics approach was used to discover novel targets for therapeutics in relation to dysregulation in the orchestration of inflammatory pathways implicated in persistent joint inflammation subsequent to joint trauma. Methods: Synovial fluid was aspirated from patients at 1 week and 4 weeks after anterior cruciate ligament reconstruction (ACLR) and interleukin 6 (IL-6) concentrations were quantified by enzyme-linked immunosorbent assay. Patients were segregated into IL-6low and IL-6high groups based on IL-6 concentrations in synovial fluid at 4-weeks postoperation and proteins in synovial fluid were analyzed using qualitative, bottom-up proteomics. Abundance ratios were calculated for IL-6high and IL-6low groups as 4 weeks postoperation:1 week postoperation. Results: A total of 291 proteins were detected in synovial fluid, 34 of which were significantly (P < .05) differentially regulated between groups. Proteins associated with the classical and alternative complement cascade pathways were increased in the IL-6high compared to IL-6low group. Insulin-like growth factor-binding protein 6 (IGFBP-6) was increased by nearly 60-fold in the IL-6low group. Conclusions: Patients segregated by IL-6 concentration in synovial fluid at 4 weeks post-ACLR demonstrated differential regulation of multiple pathways, providing opportunities to investigate novel targets, such as IGFBP-6, and to take advantage of therapeutics already approved for clinical use in other diseases that target inflammatory pathways, including the complement system.

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. [ABSTRACT FROM AUTHOR]

Posttraumatic osteoarthritis (PTOA) arises secondary to joint injuries and is characteristically driven by inflammatory mediators. PTOA is often studied in the setting of ACL tears. However, a wide range of other injuries also lead to PTOA pathogenesis. The purpose of this study was to characterize the morphological changes in the uninjured ACL in a PTOA inflammatory environment. We retrospectively reviewed 14 ACLs from 13 Yucatan minipigs, 7 of which had undergone our modified intra-articular drilling (mIAD) procedure, which induced PTOA through inflammatory mediators. Seven ACLs were harvested from mIAD minipigs (PTOA) and seven ACLs from control minipigs with no cartilage degeneration (non-PTOA). ACL degeneration was evaluated using histological scoring systems. IL-1β, NF-κB, and TNF-α mRNA expression in the synovium was measured using qRT-PCR. PTOA minipigs demonstrated significant ACL degeneration, marked by a disorganized extracellular matrix, increased vascularity, and changes in cellular shape, density, and alignment. Furthermore, IL-1β, NF-κB, and TNF-α expression was elevated in the synovium of PTOA minipigs. These findings demonstrate the potential for ACL degeneration in a PTOA environment and emphasize the need for anti-inflammatory disease-modifying therapies following joint injury. [ABSTRACT FROM AUTHOR]

To evaluate mitochondrial DNA (mtDNA) release from injured chondrocytes and investigate the utility of synovial fluid mtDNA concentration in early detection of posttraumatic osteoarthritis. We measured mtDNA release using four models of osteoarthritis: in vitro interleukin-1β 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. 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. 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. [ABSTRACT FROM AUTHOR]

BACKGROUND: There is a high incidence of posttraumatic osteoarthritis (PTOA) after anterior cruciate ligament (ACL) injury, and these injuries represent an enormous health care economic burden. In an effort to address this unmet clinical need, there has been increasing interest in cell-based therapies. PURPOSE: To establish a translational large animal model of PTOA and demonstrate the feasibility of intra-articular human cell-based interventions. STUDY DESIGN: Descriptive laboratory study. METHODS: Nine Yucatan mini-pigs underwent unilateral ACL transection and were monitored for up to 12 weeks after injury. Interleukin 1 beta (IL-1β) levels and collagen breakdown were evaluated longitudinally using enzyme-linked immunosorbent assays of synovial fluid, serum, and urine. Animals were euthanized at 4 weeks (n = 3) or 12 weeks (n = 3) after injury, and injured and uninjured limbs underwent magnetic resonance imaging (MRI) and histologic analysis. At 2 days after ACL injury, an additional 3 animals received an intra-articular injection of 107 human bone marrow-derived mesenchymal stem cells (hBM-MSCs) combined with a fibrin carrier. These cells were labeled with the luciferase reporter gene (hBM-MSCs-Luc) as well as fluorescent markers and intracellular iron nanoparticles. These animals were euthanized on day 0 (n = 1) or day 14 (n = 2) after injection. hBM-MSC-Luc viability and localization were assessed using ex vivo bioluminescence imaging, fluorescence imaging, and MRI. RESULTS: PTOA was detected as early as 4 weeks after injury. At 12 weeks after injury, osteoarthritis could be detected grossly as well as on histologic analysis. Synovial fluid analysis showed elevation of IL-1β shortly after ACL injury, with subsequent resolution by 2 weeks after injury. Collagen type II protein fragments were elevated in the synovial fluid and serum after injury. hBM-MSCs-Luc were detected immediately after injection and at 2 weeks after injection using fluorescence imaging, MRI, and bioluminescence imaging. CONCLUSION: This study demonstrates the feasibility of reproducing the chondral changes, intra-articular cytokine alterations, and body fluid biomarker findings consistent with PTOA after ACL injury in a large animal model. Furthermore, we have demonstrated the ability of hBM-MSCs to survive and express transgene within the knee joint of porcine hosts without immunosuppression for at least 2 weeks. CLINICAL RELEVANCE: This model holds great potential to significantly contribute to investigations focused on the development of cell-based therapies for human ACL injury-associated PTOA in the future (see Appendix Figure A1, available online).

Posttraumatic osteoarthritis (PTOA) is a common complication secondary to tibial plateau fractures (TPFs) after internal fixation. Early continuous passive motion (CPM) and needle-knife therapy are both alternative medicine treatments that have been beneficial to PTOA. CPM and needle-knife therapy are commonly applied separately in the treatment of orthopedic diseases and soft tissue injuries, but they both have limitations. In this study, we combined CPM and needleknife therapy to observe its efficacy on PTOA caused by postoperative TPFs and its possible mechanisms. A rabbit model of TPFs after internal fixation was established by surgical method. Rabbits were randomly divided into five groups: Normal control (NC) group, Sedentary (SED) group, CPM group, Needle-knife group, CPM + Needle-knife group. Range of motion (ROM), knee diameter and medial cartilaginous surface of the tibial plateau were observed after 4 weeks of treatment. Levels of inflammatory cytokines in the supernatants from knee joint fluid, including interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α, were determined by enzyme-linked immunosorbent assay (ELISA). The gross view of ligament tissues was detected by immunosorbent assay (ELISA). The gross view of ligament tissues was detected by histomorphology, including Hematoxylin and Eosin (H&E) staining and Masson's trichrome staining. Other than that, the protein expression of matrix metalloproteinase (MMP)-13 and tissue inhibitors of metalloproteinase (TIMP)-1 were evaluated by immunohistochemical staining, respectively. Finally, the apoptosis of ligament cells was assessed through DAPI and TUNEL assay. Our data showed that ROM was reduced while knee diameter was increased in the SED group, but they were relieved by CPM and needle-knife—either singly or in combination treatment. CPM and needle-knife therapy also improved the effect of TPFs on other parameters, including the medial cartilaginous surface of the tibial plateau improvement, MMP-13 and TIMP-1 expression in the medial collateral ligament (MCL), and lateral collateral ligament (LCL), knee joint fluid IL-1β, IL-6, and TNF-α levels, and condition of ligament cells apoptosis. Our findings suggested that early CPM plus needle-knife therapy might be a useful and promising therapeutic method for PTOA. [ABSTRACT FROM AUTHOR]

Background: Mechanical loading and alendronate (ALN) can be used as noninvasive physical therapy methods for osteoarthritis (OA). However, the timing and efficacy for treatments are unknown. Purpose: To determine whether the timing of mechanical loading and ALN influences the pathobiological changes of OA. Study Design: Controlled laboratory study. Methods: Mice with OA induced by anterior cruciate ligament transection were subjected to early (1-3 weeks) or late (5-7 weeks) axial compressive dynamic load or intraperitoneal injection of ALN. Changes in gait were analyzed using gait analysis system, pathobiological changes in subchondral bone, cartilage, osteophyte, and synovitis were assessed using micro–computed tomography, tartrate-resistant acid phosphatase staining, pathologic section staining, and immunohistochemistry at 1, 2, 4, and 8 weeks. Results: At 1, 2, and 4 weeks, the OA limb had lower mean footprint pressure intensity, lower bone volume per tissue volume (BV/TV) in the subchondral bone, and more osteoclasts. At 4 weeks, the early loading, ALN, and load + ALN treatments induced less cartilage destruction, with a corresponding reduction in Osteoarthritis Research Society International score and increased hyaline cartilage thickness. The treatments also resulted in fewer osteoclasts and higher BV/TV and bone mineral density of subchondral bone and suppressed inflammation and interleukin 1β– and tumor necrosis factor α-positive cells in synovium. At 8 weeks, early loading or load + ALN improved the mean footprint pressure intensity and knee flexion. At 8 weeks, early load + ALN had a synergistic effect on protecting hyaline cartilage and proteoglycans. Footprint pressure intensity and cartilage destruction were worse in late loading limbs, and no differences in BV/TV, bone mineral density, osteophyte formation, and synovium inflammation were found between the late load, ALN, and load + ALN groups and the anterior cruciate ligament transection group. Conclusion: Dynamic axial mechanical loading or ALN in the early stages of knee trauma protected against OA by suppressing subchondral bone remodeling. However, late loading promoted cartilage degeneration in advanced OA, indicating that reduced loading should be performed in the late stages of OA to avoid the acceleration of OA. Clinical Relevance: Early low-level functional exercise or antiosteoporotic drugs could clearly slow or prevent the progression of early OA. For patients with mild to severe OA, loading reduction via brace protection or maintenance of joint stability via early ligament reconstruction surgery may ameliorate OA exacerbation. [ABSTRACT FROM AUTHOR]

Background: There is a significant long-term risk of posttraumatic osteoarthritis (PTOA) after anterior cruciate ligament reconstruction (ACLR). Elucidating the risk factors and successfully identifying at-risk patients is challenging. Purpose/Hypothesis: The purpose of this study was to produce machine learning survival models that can identify (1) patients at risk of symptomatic PTOA and (2) patients who are at risk of undergoing total knee arthroplasty (TKA) after ACLR. It was hypothesized that these models would outperform traditional Kaplan-Meier estimators. Study Design: Case-control study; Level of evidence, 3. Methods: A geographic database was used to identify patients undergoing ACLR between 1990 and 2016 with a minimum 7.5-year follow-up. Models were used to analyze various factors to predict the rate and time to (1) symptomatic osteoarthritis and (2) TKA using random survival forest (RSF) algorithms. Performance was measured using out-of-bag (OOB) c-statistic, calibration, and Brier score. The predictive performances of the RSF models were compared with Kaplan-Meier estimators. Model interpretability was enhanced utilizing global variable importance and partial dependence curves. Results: A total of 974 patients with ACLR and a minimum follow-up of 7.5 years were included; among these, 215 (22.1%) developed symptomatic osteoarthritis, and 25 (2.6%) progressed to TKA. The RSF algorithms achieved acceptable good to excellent predictive performance for symptomatic arthritis (OOB c-statistic, 0.75; Brier score, 0.128) and progression to TKA (OOB c-statistic, 0.89; Brier score, 0.026), respectively. Significant predictors of symptomatic PTOA included increased pain scores, older age, increased body mass index, increased time to ACLR, total number of arthroscopic surgeries before the diagnosis of arthritis, positive pivot-shift test after reconstruction, concomitant chondral injury, secondary meniscal tear, early (<250 days) or delayed (>500 days) return to sports or activity, and use of allograft. Significant predictors for TKA included older age, increased pain scores, total number of arthroscopic surgeries, high-demand activity/occupation, hypermobility, higher body mass index, systemic inflammatory disease, increased time to surgery, early (<250 days) or delayed (>500 days) return to sports or activity, and midsubstance tears. The Brier score over time revealed that RSF models outperformed traditional Kaplan-Meier estimators. Conclusion: Machine learning survival models were used to reliably identify patients at risk of developing symptomatic PTOA, and these models consistently outperformed traditional Kaplan-Meier estimators. Strong predictors for the development of PTOA after ACLR included increased pain scores at injury and postoperative visit, older age at injury, total number of arthroscopic procedures, positive postoperative pivot-shift test, and secondary meniscal tear. [ABSTRACT FROM AUTHOR]

Posttraumatic osteoarthritis may lead to surgical fusion of the ankle joint if non-surgical therapy fails. The indication for a fusion of the joint is based on the pain and disability of the patient, radiographic imaging, and surgeon experience, with no strict guidelines. We aimed to compare outcomes after tibiotalocalcaneal arthrodesis (TTCA) and tibiotalar arthrodesis (TTA) to highlight the functional importance of the subtalar joint. In total, 432 patients with ankle arthrodesis were retrospectively enrolled. Group A (n = 216) underwent TTCA; group B (n = 216) underwent TTA. Demographics, Olerud & Molander Ankle Score (OMAS), Foot Function Index (FFI-D), and Short Form-12 Questionnaire (SF-12) were recorded at a mean follow-up of 6.2 years. The mean OMAS was 50.7; the mean FFI-D was 68.9; the mean SF-12 physical component summary was 39.1. These scores differed significantly between the groups (p < 0.001). The overall revision rate was 18%, primarily for revision of non-union and infection (p < 0.001). Approximately 16% of group A and 26% of group B were able to return to previous work (p < 0.001). Based on significantly worse clinical scores of TTCA compared to TTA and the prolonged downtime and permanent incapacity, the indication for a generous subtalar joint arthrodesis with planned ankle arthrodesis should always be critically examined. [ABSTRACT FROM AUTHOR]

Post-traumatic osteoarthritis (PTOA) is one of the leading causes of disability in developed countries and accounts for 12% of all osteoarthritis cases in the United States. After trauma, inflammatory cells (macrophages amongst others) are quickly recruited within the inflamed synovium and infiltrate the joint space, initiating dysregulation of cartilage tissue homeostasis. Current therapeutic strategies are ineffective, and PTOA remains an open clinical challenge. Here, the targeting potential of liposome-based nanoparticles (NPs) is evaluated in a PTOA mouse model, during the acute phase of inflammation, in both sexes. NPs are composed of biomimetic phospholipids or functionalized with macrophage membrane proteins. Intravenous administration of NPs in the acute phase of PTOA and advanced in vivo imaging techniques reveal preferential accumulation of NPs within the injured joint for up to 7 days post injury, in comparison to controls. Finally, imaging mass cytometry uncovers an extraordinary immunomodulatory effect of NPs that are capable of decreasing the amount of immune cells infiltrating the joint and conditioning their phenotype. Thus, biomimetic NPs could be a powerful theranostic tool for PTOA as their accumulation in injury sites allows their identification and they have an intrinsic immunomodulatory effect.

Background: Infiltration of cluster of differentiation (CD) 3+ (CD3+) T cells into the synovium and synovial fluid occurs in most patients with posttraumatic osteoarthritis. During disease progression, proinflammatory T helper 17 cells and anti-inflammatory regulatory T cells infiltrate the joint in response to inflammation. This study aimed to characterize the dynamics of regulatory T and T helper 17 cell populations in synovial fluid from equine clinical patients with posttraumatic osteoarthritis to determine whether phenotype and function are associated with potential immunotherapeutic targets. Hypothesis: An imbalance of the ratio of regulatory T cells and T helper 17 cells would be associated with disease progression in posttraumatic osteoarthritis, suggesting opportunities for immunomodulatory therapy. Study Design: Descriptive laboratory study. Methods: Synovial fluid was aspirated from the joints of equine clinical patients undergoing arthroscopic surgery for posttraumatic osteoarthritis resulting from intra-articular fragmentation. Joints were classified as having mild or moderate posttraumatic osteoarthritis. Synovial fluid was also obtained from nonoperated horses with normal cartilage. Peripheral blood was obtained from horses with normal cartilage and those with mild and moderate posttraumatic osteoarthritis. Synovial fluid and peripheral blood cells were analyzed by flow cytometry, and native synovial fluid was analyzed by enzyme-linked immunosorbent assay. Results: CD3+ T cells represented 81% of lymphocytes in synovial fluid, which increased in animals with moderate posttraumatic osteoarthritis to 88.3% (P =.02). CD14+ macrophages were doubled in those with moderate posttraumatic osteoarthritis compared with mild posttraumatic osteoarthritis and controls (P <.001). Less than 5% of CD3+ T cells found within the joint were forkhead box P3 protein+ (Foxp3+) regulatory T cells, but a 4- to 8-times higher percentage of nonoperated and mild posttraumatic osteoarthritis joint regulatory T cells secreted interleukin (IL)–10 than peripheral blood Tregs (P <.005). T regulatory-1 cells that secreted IL-10 but did not express Foxp3 accounted for approximately 5% of CD3+ T cells in all joints. T helper 17 cells and Th17-like regulatory T cells were increased in those with moderate posttraumatic osteoarthritis (P <.0001) compared with mild and nonoperated patients. IL-10, IL-17A, IL-6, chemokine (C-C motif) ligand (CCL) 2 (CCL2), and CCL5 concentrations detected by enzyme-linked immunosorbent assay in synovial fluid were not different between groups. Conclusions: An imbalance of the ratio of regulatory T cells and T helper 17 cells and an increase in T helper 17 cell–like regulatory T cells in synovial fluid from joints with more severe disease provide novel insights into immunological mechanisms that are associated with posttraumatic osteoarthritis progression and pathogenesis. Clinical Relevance: Early and targeted use of immunotherapeutics in the mitigation of posttraumatic osteoarthritis may improve patient clinical outcomes. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Aims: This studied aimed to compare rates of reoperation for patients who received primary ankle arthrodesis (AA) versus total ankle replacement (TAR) for posttraumatic indications between 2010 and 2016 Q2 using a nationwide claims database. Methods: A retrospective cohort study analyzing patients who received primary AA or TAR for posttraumatic indications was performed using PearlDiver. Reoperations assessed included prosthetic joint infection (PJI), hardware removal, adjacent joint fusion, and local open reduction internal fixation (ORIF). Multivariable logistic regression was used to compare rates of reoperations at 1 and 2 years postdischarge. Results: A total of 862 (74%) patients received AA and 318 (26%) patients underwent TAR for a posttraumatic indication. At 1 year, 305 (35.4%) AA patients had at least 1 reoperation compared with 55 (17.3%) TAR patients (OR 2.32; 95% CI, 1.68-3.26). At 2 years, 364 (42.2%) AA patients and 66 (20.8%) TAR patients had at least 1 reoperation (OR 2.51; 95% CI, 1.84-3.45). ORIF, hardware removal, and adjacent joint fusions were more likely for AA patients at both time intervals (all P s <.05). Conclusion: Patients who received primary AA for posttraumatic indications exhibited higher rates of major reoperations in the short to medium term compared with patients who underwent TAR. Levels of Evidence: Level III: Retrospective cohort study [ABSTRACT FROM AUTHOR]

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Anterior cruciate ligament (ACL) injury often leads to posttraumatic osteoarthritis (PTOA), despite ACL reconstruction (ACLR). Medial meniscal extrusion (MME) is implicated in PTOA progression but remains understudied after ACL injury and ACLR.It was hypothesized that MME would increase longitudinally after ACL injury and ACLR, with greater changes in the ipsilateral knee compared with the contralateral knee, leading to cartilage degeneration. The study aimed to assess MME 3 years after ACLR and its relationship with magnetic resonance imaging (MRI) T1ρ and T2 as cartilage degeneration markers.Cohort study; Level of evidence, 2.MME and relative percentage of extrusion (RPE) were measured on 3 coronal slices of 3-dimensional fast spin-echo images and the mean values were used. T1ρ and T2 sequences were obtained and cartilage compositional measurements were performed using in-house developed software with MATLAB. Mixed models were used to assess the longitudinal changes and linear regression was used to assess the relationships between RPE and T1ρ and T2 values.A total of 54 participants with unilateral ACL injuries underwent preoperative bilateral knee MRI. A total of 36 participants completed MR scans at 6 months and 3 years after ACLR. MME and RPE measurements demonstrated high reliability (ICC > 0.88 and > 0.91, respectively). The predicted values of MME and RPE from the mixed models showed that the ipsilateral side had significantly greater MME and RPE than the contralateral side at all 3 time points (P = .023 for MME; P = .013 for RPE at baseline; and P < .001 at 6 months and P < .001 at 3 years for both MME and RPE). The rate of change of MME and RPE on the ipsilateral side was significantly greater than that on the contralateral side (P < .001). Postoperative RPE was associated with T1ρ and T2 values in the posterior medial femoral condyle.MME and RPE obtained pre- and postoperatively after ACLR on the ipsilateral side were significantly greater than those on the contralateral side, and the longitudinal increases on the ipsilateral side were greater than those on the contralateral side. Postoperative RPE was significantly associated with cartilage degeneration in the posterior medial femoral condyle. [ABSTRACT FROM AUTHOR]

BackgroundAnterior cruciate ligament tears can lead to posttraumatic osteoarthritis. In addition to biomechanical factors, changes in biochemical profiles within the knee joint after injury and anterior cruciate ligament reconstruction (ACLR) may play a role in accelerating joint degeneration. Hypothesis/Purpose: It was hypothesized that cartilage matrix composition after ACLR is associated with the degree of inflammatory response after initial injury. This study evaluated the association between the inflammatory response after injury-as indicated by cytokine, metalloproteinase, and cartilage degradation marker concentrations in synovial fluid-and articular cartilage degeneration, measured by T1ρ and T2 quantitative magnetic resonance imaging up to 3 years after ACLR.Study designCohort study; Level of evidence, 2.MethodsTwenty-six subjects from a longitudinal cohort study who underwent ACLR at a mean 8.5 weeks after injury (range, 4-19 weeks) had synovial fluid aspirated at the time of surgery. Immunoassays quantified biomarkers in synovial fluid. T1ρ and T2 values of articular cartilage were calculated with magnetic resonance scans acquired prior to surgery and at 6 months and 1, 2, and 3 years after surgery. Pearson correlation coefficients were calculated among the various biomarkers. K-means clustering was used to group subjects with similar biomarker profiles. Generalized estimating equations were used to find the overall differences in T1ρ and T2 values throughout these first 3 years after surgery between the clusters while controlling for other factors.ResultsSignificant and strong correlations were observed between several cytokines (interleukin 6 [IL-6], IL-8, IL-10, and tumor necrosis factor α) and 2 matrix metalloproteinases (MMP-1 and MMP-3) ( P < .05). Moderate correlations were found among combinations of C-terminal crosslinked telopeptide type II collagen, N-terminal telopeptide, cartilage oligomeric matrix protein, and sulfated glycosaminoglycan ( P < .05). Two clusters were generated, 1 of which was characterized by lower concentrations of cytokines (IL-6, IL-8, IL-10, tumor necrosis factor α) and MMP-1 and MMP-3 and higher sulfated glycosaminoglycan. This cluster was associated with significantly higher T1ρ and T2 values in the medial tibial and patellar cartilage over the first 3 years after ACLR.ConclusionAt the time of ACLR surgery, profiles of synovial fluid inflammatory cytokines, degradative enzymes, and cartilage breakdown products show promise as predictors of abnormal cartilage tissue integrity (increased T1ρ and T2 values) throughout the first 3 years after surgery.Clinical relevanceThe results suggest an intricate relationship between inflammation and cartilage turnover, which can in turn be influenced by timing after injury and patient factors.

Osteoarthritis occurs frequently after joint injury. Currently, osteoarthritis is diagnosed by radiographic changes that are typically found after the disease has progressed to multiple tissues. The primary objective was to compare potential metabolomic biomarkers of joint injury between synovial fluid and serum in a mouse model of posttraumatic osteoarthritis. The secondary objective was to gain insight into the pathophysiology of osteoarthritis by examining metabolomic profiles after joint injury. Twelve‐week‐old adult female C57BL/6 mice (n = 12) were randomly assigned to control, Day 1, or Day 8 postinjury groups. Randomly selected stifle joints were subjected to a single rapid compression. At Days 1 and 8 postinjury, serum was extracted before mice were euthanized for synovial fluid collection. Metabolomic profiling detected ~2500 metabolites across serum and synovial fluid. Of these, 179 were positively correlated and 51 were negatively correlated between synovial fluid and serum, indicating the potential for the development of metabolomic biomarkers. Synovial fluid captured injury‐induced differences in metabolomic profiles at both Days 1 and 8 after injury whereas serum did not. However, synovial fluid and serum were distinct at both time points after injury. In synovial fluid, pathways of interest mapped to amino acid synthesis and degradation, bupropion degradation, and transfer RNA (tRNA) charging. In serum, pathways were amino acid synthesis and degradation, the phospholipase pathway, and nicotine degradation. These results provide a rich picture of the injury response at early time points after joint injury. Furthermore, the correlations between synovial fluid and serum metabolites suggest the potential to gain insight into intra‐articular pathophysiology through analysis of serum metabolites. [ABSTRACT FROM AUTHOR]

Background: Several factors are thought to contribute to posttraumatic osteoarthritis (PTOA) development, including the posttraumatic inflammatory response. The purpose of this study was to compare 2 injuries at the same joint with a different severity and prognosis. This study compared the intra-articular inflammatory response after rotational ankle fracture (lower energy and less PTOA) with tibial plafond fracture (higher energy and more PTOA). Methods: This prospective comparative study was conducted at a level 1 trauma center between 2014-2019. Patients between 18 and 60 years of age with acute ankle or tibial plafond fractures were enrolled. Patients with preexisting ankle OA, autoimmune disease, additional injury, or open fractures were excluded. Synovial fluid aspirations were obtained within 24 hours of injury. The concentrations of interleukin (IL)-1β, IL-1 receptor antagonist (IL-1RA), IL-6, IL-8, and IL-10 and matrix metalloproteinase (MMP)-1, MMP-3, and MMP-13 were quantified. Results: Aspiration were obtained from 29 plafond fractures and 36 ankle fractures. Mean age was 43 years, and patients were predominately female (64%). Age, gender, and comorbidities did not vary between cohorts. Of the plafond fractures, 13 were 43-B and 16 were 43-C injuries. Ankle fractures were predominately 44-B injuries, and 15 ankle fracture had articular impaction. IL-10, IL-1β, IL-6, IL-8, MMP-1, MMP-3, and MMP-13 were all significantly higher in acute plafond fractures as compared to acute ankle fractures. Conclusion: This study compared articular inflammatory marker profiles after fractures of different severities. Several cytokines were elevated in plafond fractures as compared to ankle fractures, suggesting a greater inflammatory response with plafond fractures. Given the difference in prognosis for and higher rate of PTOA after plafond fractures, these data strengthen the case that postinjury inflammatory response plays a role in PTOA development. Given that the postinjury inflammatory response is one of the few modifiable variables of these injuries, future research in this area remains important. Level of Evidence: Level II, prospective. [ABSTRACT FROM AUTHOR]

Abstract Background After anterior cruciate ligament (ACL) reconstruction, patient-reported outcomes are improved 10 years post-surgery; however, cytokine concentrations remain elevated years after surgery with over 80% of those with combined ACL and meniscus injuries having posttraumatic osteoarthritis (PTOA) within 10–15 years. The purpose of this multicenter, randomized, placebo-controlled trial is to assess whether a 6-month course of oral montelukast after ACL reconstruction reduces systemic markers of inflammation and biochemical and imaging biomarkers of cartilage degradation. Methods We will enroll 30 individuals undergoing primary ACL reconstruction to participate in this IRB-approved multicenter clinical trial. This trial will target those at greatest risk of a more rapid PTOA onset (age range 25–50 with concomitant meniscus injury). Patients will be randomly assigned to a group instructed to take 10 mg of montelukast daily for 6 months following ACL reconstruction or placebo. Patients will be assessed prior to surgery and 1, 6, and 12 months following surgery. To determine if montelukast alters systemic inflammation following surgery, we will compare systemic concentrations of prostaglandin E2, monocyte chemoattractant protein-1, and pro-inflammatory cytokines between groups. We will also compare degradative changes on magnetic resonance imaging (MRI) collected 1 and 12 months following surgery between groups with reductions in early biomarkers of cartilage degradation assessed with urinary biomarkers of type II collagen breakdown and bony remodeling. Discussion There is a complex interplay between the pro-inflammatory intra-articular environment, underlying bone remodeling, and progressive cartilage degradation. PTOA affects multiple tissues and appears to be more similar to rheumatoid arthritis than osteoarthritis with respect to inflammation. There is currently no treatment to delay or prevent PTOA after ACL injury. Since there is a larger and more persistent inflammatory response after ACL reconstruction than the initial insult of injury, treatment may need to be initiated after surgery, sustained over a period of time, and target multiple mechanisms in order to successfully alter the disease process. This study will assess whether a 6-month postoperative course of oral montelukast affects multiple PTOA mechanisms. Because montelukast administration can be safely sustained for long durations and offers a low-cost treatment option, should it be proven effective in the current trial, these results can be immediately incorporated into clinical practice. Trial registration ClinicalTrials.gov NCT04572256 . Registered on October 1, 2020.

BackgroundPosttraumatic osteoarthritis (PTOA) can be a crippling sequela of acetabular fracture (AF), and total hip arthroplasty (THA) is often necessary to alleviate the clinical progression of symptoms. The purpose of this study was to summarize the existing clinical evidence concerning the surgical management of AF with THA through meta-analyses.MethodsDatabases were searched for articles published between 1995 and January 2022 that contained the keywords “acetabular,” “fracture,” “arthroplasty,” and “osteoarthritis.” Our study was registered in PROSPERO under number CRD42022314997.ResultsWe screened 3,125 studies and included data from 31 studies with 1,284 patients. The median patient age at the time of THA was 52 years and ranged from 19 to 94 years. The pooled overall survival rate was 88% [86%–90%, 95% confidence interval (CI)] and could reach 83% at ≥15-year follow-up. For the Harris Hip Score, we pooled 22 studies with an overall mean difference of 43.25 (40.40–46.10, 95% CI; P

Posttraumatic osteoarthritis (PTOA) arises secondary to joint injuries and is characteristically driven by inflammatory mediators. PTOA is often studied in the setting of ACL tears. However, a wide range of other injuries also lead to PTOA pathogenesis. The purpose of this study was to characterize the morphological changes in the uninjured ACL in a PTOA inflammatory environment. We retrospectively reviewed 14 ACLs from 13 Yucatan minipigs, 7 of which had undergone our modified intra-articular drilling (mIAD) procedure, which induced PTOA through inflammatory mediators. Seven ACLs were harvested from mIAD minipigs (PTOA) and seven ACLs from control minipigs with no cartilage degeneration (non-PTOA). ACL degeneration was evaluated using histological scoring systems. IL-1β, NF-κB, and TNF-α mRNA expression in the synovium was measured using qRT-PCR. PTOA minipigs demonstrated significant ACL degeneration, marked by a disorganized extracellular matrix, increased vascularity, and changes in cellular shape, density, and alignment. Furthermore, IL-1β, NF-κB, and TNF-α expression was elevated in the synovium of PTOA minipigs. These findings demonstrate the potential for ACL degeneration in a PTOA environment and emphasize the need for anti-inflammatory disease-modifying therapies following joint injury.